In the healthy gastrointestinal tract, homeostasis is an active process that requires a critical balance of host responses to the enteric luminal contents. Intestinal macrophages and dendritic cells (DCs) comprise a unique group of tissue immune cells that are ideally situated at the interface of the host and the enteric luminal environment to appropriately respond to microbes and other potential stimuli. Both commensal and pathogenic bacteria are recognized through conserved molecular microbial patterns by pattern-recognition receptors (PRRs). Mechanisms by which the host distinguishes commensal from pathogenic bacteria are not well defined and represent a fundamental gap in the understanding of homeostatic immune function and inflammatory bowel diseases (IBD).
How do Intestinal Macrophages and DCs Interact with the Microbial Environment?
Intestinal macrophages and DCs sense conserved molecular patterns on microbes (pathogen-associated molecular patterns [PAMPs]) through germ-line encoded PRRs.1,2 PRRs are divided into 4 families based on the shared functional domains: toll-like receptors (TLRs), nucleotide-binding oligomerization domain, leucine-rich repeat receptors, C-type lectin receptors, and retinoic acid (RA)–inducible gene 1–like receptors.3 Signaling downstream of each family of PRRs culminates in activation of central immune response pathways: nuclear factor kappa light-chain enhancer of activated B cells, mitogen-activated protein kinases, and interferon regulatory factors.4 Upon engagement of PRRs, immune and nonimmune cells produce inflammatory cytokines, type I interferons, chemokines, and antimicrobial peptides. As a result, neutrophils are recruited and macrophages are activated, leading to the direct killing and clearance of microbes. Additionally, these inflammatory products induce the maturation of DCs, promoting the induction of adaptive immune responses. A carefully orchestrated process, microbial sensing, and subsequent immune responses are highly regulated. Dysregulation of these pathways can lead to both enhanced susceptibility to infections and development of chronic inflammatory diseases.3
PRR recognition of its cognate PAMPs culminates in the initiation of pathogen-specific programs, designed to eradicate the prevailing insult. But how does the host recognize an intact microbe and decide which program to initiate? In reality, 1 microbe has many different PAMPs, and many PRRs may recognize 1 PAMP. Additionally, different cell types express unique sets of PRRs, and each PRR may play fundamentally different roles in the temporally distinct phases of an infection (i.e. initial infection versus memory response). The complex cross talk between PRR families also confers specificity to and regulates each immune response. Thus, the assembly of a successful immune response to microbes depends on the context of the infection, the cell types responding to it, and the array of PRRs that are engaged during the infection.3 Furthermore, the local microenvironment provides contextual cues to immune cells through cytokines and growth factors produced by host cells and metabolic products from microbes.5 It is likely through this complex context of recognition that innate immune cells distinguish between commensal and pathogenic microbes and initiate an appropriate response program. However, the precise mechanism of discernment of helpful from harmful microbes and regulation of subsequent immune responses and how this relates to intestinal homeostasis and IBDs remains incompletely understood.
PAMP recognition by PRRs on intestinal macrophages and DCs leads to the efficient removal of potential stimuli while remaining immunologically nonresponsive. This feature is unique to intestinal tissue-resident macrophages and DCs.6 The importance of the remaining “inflammation anergic” is emphasized by the development of chronic intestinal inflammation in the absence or dysregulation of macrophage and DC responses to microbial stimuli.7 Ultimately, inappropriate host responses to the luminal microbiota in genetically susceptible individuals disrupt homeostasis, leading to the development of IBDs.
IBD Pathogenesis: A Macrophage-centric and DC-centric View
The pathogenesis of IBDs, including Crohn's disease (CD) and ulcerative colitis (UC), is multifactorial and encompasses incompletely defined and complex interactions between host immune responses, genetic susceptibility, environmental factors, and enteric luminal contents.8 Recent genome-wide association studies have highlighted the importance of host innate immune responses to microbes in the pathogenesis of IBDs.9 Single-nucleotide polymorphisms (SNPs) associated with increased risk of developing IBDs were identified in genes involving microbial sensing (NOD2, IRF5, NFKB1, RELA, REL, RIPK2, CARD9, and PTPN22) and clearance (ATG16L1, IRGM, and NCF4), and integrating antimicrobial adaptive immune responses (IL23R, IL10, IL12, IL18RAP/IL1R1, IFNGR/IFNAR1, JAK2, STAT3, and TYK2).10 Intestinal macrophages and DCs reside in the lamina propria (LP), and thus are ideally positioned to continuously sample intestinal luminal contents. LP mononuclear cells (LPMCs), including macrophages and DCs, are the sentinels and first responders of the gut-associated lymphoid tissues. Additionally, resident LPMCs possess unique attributes that shape the gastrointestinal tract as a largely tolerant environment while maintaining effective clearance of microbes. Importantly, LPMCs direct subsequent adaptive immune responses, thereby regulating local inflammation.
This review will explore how macrophages and DCs help to initiate inflammation in the gastrointestinal tract by first describing how these cells maintain intestinal homeostasis under physiological conditions. Next, the breakdown of homeostasis encouraged by macrophages and DCs as it pertains to the development of IBDs will be described. Intestinal macrophage and DC dysfunction are now widely recognized as central components to the pathogenesis of IBDs, and understanding this phenomenon is vital to the development of effective therapies for these debilitating diseases.
MACROPHAGES AND DCS IN GASTROINTESTINAL HOMEOSTASIS
The gut-associated lymphoid tissue represents the largest aggregate of lymphoid tissue in the body. The gut-associated lymphoid tissues includes various organized collections of immune cells within the gastrointestinal tract, such as Peyer's patches in the small intestine and cryptopatches in the large intestine, and the diffuse arrangement of intestinal mononuclear cells within the LP. The close proximity of LPMCs to the enteric luminal compartment, separated by an epithelial cell monolayer, is important for several reasons: (1) LPMCs sample luminal antigens that gain access to the LP under physiological conditions to maintain local and systemic tolerance, and (2) they efficiently clear microbes and stimuli that cross the intestinal epithelial cell (IEC) barrier. Resident LP macrophages demonstrate distinct attributes from peripheral monocyte populations. Although LP macrophages maintain robust microbicidal effector functions, they do not produce inflammatory mediators on encountering microbial stimuli.6 Additionally, LP macrophages promote the transition from protective inflammatory responses to resolving anti-inflammatory responses on encountering a danger signal. Thus, LPMCs are integral to directing appropriate immune responses and maintaining intestinal homeostasis in the gut.
There remains active debate about the classification and ontogeny of LP macrophages and LP DCs (LPDCs). The surface integrins CD11b and CD11c are routinely used to distinguish between macrophages and DCs in peripheral lymphoid tissues (CD11b+CD11c− and CD11b+/−CD11chigh are characterized as macrophages and DCs, respectively). However, the distinction between LP macrophages and LPDCs is less clear, as LP macrophages express both CD11b and CD11c.6 It has been proposed that differential expression of CX3CR1 (the receptor for the chemokine fractalkine, CX3CL1) and CD103 (αEβ7 integrin) reliably distinguish between LP macrophages and LPDCs.6,11 CD103−CX3CR1hi LP macrophages express the classical macrophage marker F4/80, demonstrate ultrastructural characteristics of macrophages, and under physiological conditions do not traffic to draining mesenteric lymph nodes (MLNs) where priming of adaptive immune responses is initiated. However, there is evidence that CX3CR1hi LP macrophages travel to MLNs during enteric microbial dysbiosis.12 Conversely, CD103+CX3CR1low LPDCs are F4/80− and perform functions typically associated with DC, including constitutive trafficking to MLN, antigen presentation to T lymphocytes, and inducing gut-homing receptors on T cells. Both LP macrophages and LPDCs express high levels of MHC class II, demonstrating their ability to interact with and shape adaptive immune responses. Although controversy remains over the exact nature and origin of these LP subsets, for our purposes, we will classify LP macrophages as CD103−CX3CR1hi and LPDCs as CD103+CX3CR1low cells.
Lamina Propria Macrophages
Macrophages are a highly heterogeneous population of cells that demonstrate a continuum of activation states. The wide spectrum of macrophage phenotypes is often somewhat oversimplified into 2 functional groups: “inflammatory” M1 (high IL-12, low IL-10) and “wound-healing” M2 (low IL-12, high IL-10) macrophages.13 Additionally, a recently appreciated subset of macrophages that produces high levels of IL-10 is referred to as “regulatory macrophages.”
Specific combinations of cytokines within the microenvironment polarize macrophages, and evidence suggests that macrophages maintain considerable plasticity between activation states. M1 macrophages are polarized by IFN-γ produced by natural killer and T helper (Th) 1 cells, tumor necrosis factor α (TNF-α) produced by granulocytes or other antigen-presenting cells, and engagement of PRRs by PAMPs, which activates SOCS3 to induce the M1 phenotype.14–16 M1 macrophages produce proinflammatory cytokines (TNF-α, IL-12, IL-6) and reactive oxygen and nitrogen species. Production of these mediators promotes the differentiation and activation of Th1 and Th17 cells.13,17–19 The Th1 response in turn helps macrophages by enhancing their ability to clear intracellular pathogens. Although M1 macrophages are essential for the eradication of intracellular infections, they also produce proinflammatory cytokines implicated in IBD pathogenesis. Furthermore, unregulated M1 macrophage activity can induce tissue damage, predispose the host to developing neoplastic lesions, and induce insulin resistance.20,21
M2 macrophages are polarized by IL-4 produced by granulocytes or Th2 cells in response to tissue injury and activation by some fungi and parasites and initiation of SOCS2 signaling.13 M2 macrophages produce matrix metalloproteases, growth factors, and demonstrate efficient phagocytosis of debris without producing proinflammatory cytokines. Th2 responses are aimed at inducing wound-healing and clearing parasites, although the exact mechanisms underlying parasite eradication are unknown. Indeed, downregulation of microbicidal functions in M2 macrophages can render the host more susceptible to certain infections.22–27 M2 macrophages are also efficient at recruiting Foxp3+ regulatory T cells (Treg) that would further downregulate local immune responses.16 Furthermore, unregulated M2 macrophage activity can promote the development of fibrotic lesions through elaboration of TGF-β and enhanced allergic responses.28,29
Regulatory macrophages are polarized by a wide array of signals, including IgG immune complexes, IL-10, prostaglandins, and apoptotic cells, potentially by activation of the mitogen-activated protein kinase extracellular signal-regulated kinase.13 However, typically 2 signals are necessary to induce regulatory macrophages, such as engagement of PRRs by PAMPs. Regulatory macrophages differ from M2 macrophages in that they do not produce extracellular matrix components but express high levels of costimulatory molecules (CD80, CD86) necessary for the activation of T cells. Like M2 macrophages, regulatory macrophages produce high amounts of the anti-inflammatory cytokine IL-10 and can render the host more susceptible to certain infections.30–36 Furthermore, unregulated regulatory macrophage activity may also play a role in the induction of neoplastic lesions by dampening antitumor macrophage defenses and promoting angiogenesis.37,38
LP macrophages are unique tissue-resident macrophages, characterized by the inability to produce inflammatory cytokines in response to microbial stimuli. However, these cells maintain robust phagocytic and microbicidal effector capabilities. The tolerant phenotype of LP macrophages is likely conditioned by the locally produced IL-10 and TGF-β.39,40 However, the ontogeny of these cells is unknown. LP macrophage maintenance may depend on local proliferation rather than repopulation from migrating blood monocytes, but this is experimentally difficult to determine due to the extremely low turnover rate of these cells. Additionally, the context during which blood monocytes are recruited to the intestines may determine the final phenotype of the LP macrophages. During noninflammatory homeostatic conditions, Ly6Chi monocytes almost exclusively repopulate the LP with CD11c+ (F4/80hiCX3CR1hiCD11b+CD103−) LP macrophages.41 In contrast, under inflammatory conditions, Ly6Chi monocytes recruited to the LP differentiate into CD103+CX3CR1intCD11b+ DCs that produce high levels of the inflammatory cytokines IL-12, IL-23, iNOS, and TNF-α.41
CX3CR1hi LP macrophages extend dendrites between IECs to sample luminal antigens and promote local tolerance through constitutive production of the anti-inflammatory cytokine IL-10,42 the absence of an inflammatory response to activating stimuli, very low expression of costimulatory molecules CD80 and CD86, and of the macrophage-activating receptor CD40.40 Although these cells that sample the luminal environment were originally defined as DCs,43 recent work supports that they may represent a macrophage population.44 IL-10 produced by LP macrophages promotes the persistence of Foxp3 expression in Treg cells in the intestine.45 Additionally, CX3CR1hi LP macrophages participate in the induction of systemic oral tolerance.42 It has been suggested that CX3CR1hi LP macrophages sample luminal antigens and deliver them to CD103+ LPDCs, which are then able to traffic to MLN to prime adaptive immune responses.46 However, there is recent compelling evidence that CX3CR1hi LP macrophages do traffic to MLNs in a CCR7-dependent manner during dysbiosis of the enteric microbiota.12
Unique intracellular signaling pathways contribute to the inflammation-anergic characteristic of LP macrophages; however, it remains unclear exactly what makes the LP macrophages distinct from circulating monocytes and other tissue-resident macrophages. Additionally, inflammation-anergic LP macrophages are distinct from the more widely studied endotoxin-resistant macrophages. For one, LP macrophages do express PRRs, whereas endotoxin-resistant macrophages downregulate expression of PRRs. Recent studies suggest that the enteric microbiota are not necessary to program LP macrophages to express high amounts of the anti-inflammatory cytokines IL-10 and TGF-β.47,48 One enticing candidate for inducing LP macrophage nonresponsiveness to PAMPs is IL-10. Importantly, IL-10–deficient mice49 and mice with myeloid-specific ablation of the IL-10–signaling molecule STAT350 develop spontaneous colitis reminiscent of human IBD. Additionally, blocking IL-10 restores PAMP responsiveness in LP macrophages. Our laboratory described a mechanism for IL-10–mediated suppression of IL-12p40 by altering histone acetylation and RNA polymerase II accessibility to the Il12b promoter,48 suggesting that IL-10 directly inhibits the production of proinflammatory cytokines in response to PAMP stimulation. IL-10 additionally exerts its anti-inflammatory effects on the innate immune system by regulating transcriptional elongation,51 microRNA induction,52 mRNA stability,53 and transcriptional repressors and corepressors.54
Additionally, the phosphoinositide 3-kinase (PI3K) pathway negatively regulates signaling through TLRs in macrophages. In particular, the p110δ isoform of PI3K is enriched in leukocytes and regulates IL-12p40 production in LP macrophages in response to microbial stimulation. PI3K p110δ is indispensable for intestinal homeostasis, as mice harboring an inactivating point mutation in p110δ (p110δ kinase-dead, or p110δKD, mice) develop spontaneous colonic inflammation. LP macrophages from p110δKD mice produce significantly more IL-12p40 and less IL-10 on stimulation with heat-killed Escherichia coli.55 Thus, a loss in the critical negative regulation of TLR signaling results in the disruption of intestinal homeostasis.
Lamina Propria Dendritic Cells
Broadly speaking, DCs are professional antigen-presenting cells with the ability to initiate adaptive immune responses against pathogens. Like macrophages, DCs comprise a heterogeneous population of cells with functional diversity. DCs originate from blood monocytes or a common DC progenitor in the bone marrow at steady state. DCs repopulating tissues from monocyte precursors rely on granulocyte macrophage-colony stimulating factor for local proliferation.56 Conventional DCs arising from the common DC progenitor express high levels of CD11c, varying levels of CD8α and CD11b, and reside in secondary lymphoid tissues. Plasmacytoid DCs (pDCs) also originate from the common DC progenitor and are specialized in the production of type I interferons. In addition to the functional subsets of DCs, the maturation state of DCs has important implications in immunity. Mature DCs that have previously encountered microbial products and inflammatory stimuli are highly specialized for antigen presentation. Thus, mature DCs express high levels of costimulatory molecules and tend to reside in secondary lymphoid organs where they are ideally positioned to prime antigen-specific T cells.57 However, immature DCs demonstrate low surface expression of costimulatory molecules and constitutively migrate in low numbers to lymph nodes, perhaps to maintain tolerizing signals there.57,58
LPDCs also comprise a heterogeneous group of cells in the intestines. Only recently has it also been appreciated that LPDCs play an active and direct role in maintaining peripheral tolerance to self and intestinal luminal antigens. Like LP macrophages, LPDCs represent a spectrum of functionally distinct phenotypes. CD8α+ pDCs in the LP are capable of inducing Treg cells and supporting their function.59 However, most LPDCs are CD11b+CD8α−, but CD11b−CD8α+ and CD11b−CD8α− subsets are also present. These DCs weakly stimulate antigen-specific T-cell proliferation and constitutively express IL-10 and type I interferons.60 Furthermore, LPDCs are divided into CD103+ and CD103− (E-cadherin receptor) populations, each demonstrating distinct functions. CD103+ LPDCs are able to induce Foxp3-expressing Treg cells,61–63 whereas CD103− LPDCs are efficient at inducing Th17 cells when stimulated with flagellin or microbial ATP.64–66 Although the Th17 response is important for antimicrobial immunity, dysregulation of Th17 lymphocytes and cytokines is implicated in a number of autoimmune disorders.67
CD103+ LPDCs represent a population of tolerizing innate immune cells that express the enzyme retinaldehyde dehydrogenase, which produces RA from retinaldehyde and the important regulatory cytokine TGF-β. Both CD103+ LPDC-produced RA and TGF-β are necessary for the induction of Treg lymphocytes in the intestine.61–63 Additionally, CD103+ LPDCs produce indoleamine 2,3-dioxygenase, which participates in the induction of Treg cells and the suppression of Th cell proliferation.68
The induction of CD103 expression in LPDCs is dependent on the vitamin A metabolite RA and the local production of factors from IECs and stromal cells. IECs induce CD103 expression in LPDCs in an RA-dependent, TGF-β-dependent, and contact-dependent manner.69 In addition to TGF-β, stromal cells in the LP constitutively produce prostaglandin E2, which inhibits the production of proinflammatory cytokines in DCs.70 Importantly, thymic stromal lymphopoietin produced by IECs conditions LPDCs to induce Th2 cell differentiation, although its necessity in inducing and maintaining Treg cells is controversial.69 Nonetheless, thymic stromal lymphopoietin produced by IECs confers a homeostatic phenotype on LPDCs to protect mice from colitis.69,71–73 CD103+ LPDC differentiation is dependent on Notch2 signaling, as Notch2 −/− mice demonstrate a selective loss of CD11b+CD103+ LPDCs.74 Furthermore, the preferential expansion of CD103+ LPDCs depends on the DC differentiating molecule Fms-related tyrosine kinase-3 ligand (Flt3L).75 The function of CD103+ LPDCs depends on several factors. Dietary vitamin A induces retinaldehyde dehydrogenase expression in CD103+ LPDCs76 and is necessary for these cells to imprint T cells with gut-homing receptors.77,78
Aside from inducing Th17 differentiation, CD103− LPDCs are involved in the induction of immunoglobulin A (IgA) class switching of B lymphocytes, both in the Peyer's patches and intestinal LP. IgA is abundantly produced in the intestine and prevents the harmful effects of bacterial overgrowth and bacterial adhesion to IECs in the intestinal lumen.79 In the isolated lymphoid follicles of the LP, CD70+ LPDCs expressing TLR5 and any of various ATP receptors induce IgA class switching in RA-dependent and T lymphocyte–independent manners.64 LPDCs that produce iNOS and TNF also support IgA class switching.80 Cytokines produced by IECs, stromal cells, and LPDCs, including B-cell activating factor, a proliferation-inducing ligand, IL-4, TGF-β, and IL-10, support the induction, maintenance, and expansion of IgA+ plasma cells.81
LPDCs have a higher turnover rate than LP macrophages due to frequent trafficking to MLN to present antigen to naive T lymphocytes.57 Evidence suggests that CD103+CD11b− LPDCs are replenished by DC-committed precursors (pre-cDC) in a Flt3L-dependent manner,82 whereas CD103−CD11b+ LPDCs are derived from circulating Ly6Chi monocytes in a granulocyte macrophage-colony stimulating factor–dependent manner.83 Additionally, the preferential expansion of regulatory CD103+ LPDCs is also Flt3L dependent.75 The conditions under which precursors are recruited to and the existing microenvironment of the LP likely determine the final phenotype of LPDCs. For instance, under steady-state conditions, F4/80lowCD103+CD11c+ LPDCs are repopulated from circulating Ly6Chi monocytes; however, during colitis, Ly6Chi monocytes repopulate inflammatory CD103−CX3CR1intCD11b+ LPDCs and exacerbate inflammation.41,83
Populations of macrophages and DCs within the intestinal LP are diverse. LP macrophages and LPDCs interact with the intestinal environment and luminal contents to maintain homeostasis through the production of protective mediators, dampening of proinflammatory responses, and the active induction of adaptive immune tolerance. Distinct functional populations of LP macrophages and LPDCs actively promote tolerance, whereas others have the propensity to enhance protective inflammatory responses to foreign antigens. However, an imbalance in any of these physiological processes may tip the balance toward chronic intestinal inflammation and IBD, as we will explore in the next section.
MACROPHAGES AND DCS IN IBD PATHOGENESIS
Murine Experimental IBD
There are a number of phenotypic and functional alterations described in LP macrophages and LPDCs during IBD development. Recent research highlights a central role for macrophages and DCs in the pathogenesis of colitis since numerous IBD susceptibility SNPs affecting innate immune cell functions have been identified.9 Additionally, the selective depletion of macrophage and DC subsets in mouse models of colitis has been particularly informative about the protective and pathogenic roles innate immune cells play during discrete stages of disease pathogenesis. Lymphocyte-deficient mice (severe combined immunodeficiency) develop colitis on treatment with the intestinal irritant dextran sodium sulfate (DSS), suggesting that macrophages and DCs are pathogenic in this model in the absence of mature lymphocytes.84 Depletion of phagocytes in Il10 −/− mice,85 and blocking myeloid cell recruitment in both 2,4,6-trinitrobenzene sulfonic acid (TNBS)–induced86 and T-cell–adoptive transfer87 colitis ameliorate disease, as does selective depletion of LPDCs during DSS colitis.88,89 Contrary to these findings, depletion of LP macrophages and LPDCs before the induction of DSS colitis results in exacerbated disease.90,91 Furthermore, different subsets of macrophages and DCs have distinct effects on the severity of colitis in animal models. M2-polarized macrophages protect mice from DSS colitis, whereas M1-polarized macrophages contribute to disease pathogenesis.92–94 Selective expansion of CD103+ LPDCs by Flt3L protects TNFΔARE mice from ileitis,75 but E-cadherin-expressing DCs increase colonic pathology in DSS colitis.95 Thus, the protective/pathogenic role of distinct macrophage and DC populations in the LP remains an active area of investigation.
In general, there are 3 ways in which defects in innate immune cell functions can initiate IBD development: (1) by responding inappropriately to normally benign stimuli such as commensal microbes, (2) by inefficiently clearing microbes, leading to chronic immune stimulation, and (3) by failing to switch from an appropriate proinflammatory response to an inflammation-resolving anti-inflammatory response. Here, we will discuss each of these defects and how each leads to chronic inflammation and IBD.
The enteric microbiota is essential for the development of colonic inflammation in most murine models of colitis.96,97 Perturbations in the negative regulation of innate immune responses to stimuli enhance susceptibility to colitis development. The well-characterized Il10 −/− murine model of spontaneously developing colitis demonstrates the necessity of the potent anti-inflammatory cytokine IL-10 in the maintenance of intestinal homeostasis.49 Indeed, LP macrophages derived from germ-free Il10 −/− mice produce increased IL-12p40 compared with germ-free wild-type LP macrophages at baseline, suggesting that IL-10 is the critical driver of the LP macrophage phenotype.48 Furthermore, IL-10 produced by CD11b+ LP macrophages is necessary for the maintenance of Foxp3 expression in Treg cells and protection from colitis.45 The IL-10–inducible and microbiota-inducible nuclear transcription factor, interleukin-3–regulated (NFIL3) negatively regulates IL-12p40 production in LP macrophages and has been recently implicated in intestinal homeostasis.98 Thus, studying the regulation of IL-10 production and its downstream signaling effects is crucial to understanding intestinal homeostasis.
IL-10–independent regulation of innate immune responses also contributes to intestinal homeostasis. One negative regulator of intestinal macrophage activation is paired immunoglobulin-like receptor B (PIR-B). PIR-B is expressed on colonic LP macrophages, B cells, and neutrophils and contains several immunoreceptor tyrosine–based inhibitory motifs (ITIMs) that activate intracellular phosphatases, negatively regulating TLR signaling.99 PIR-B is highly upregulated on LP macrophages after DSS administration in mice. Furthermore, PIR-B–deficient (Pirb −/−) macrophages produce significantly more TNFα and IL-6 in response to E. coli, and wild-type mice reconstituted with Pirb −/− macrophages demonstrate increased susceptibility to DSS colitis. PIR-B expression is also important in human intestinal biology, as LP mononuclear cells from both healthy controls and patients with UC express immunoglobulin-like transcript-2/leukocyte Ig-like receptor 1, a human homolog of PIR-B. Our laboratory recently described spontaneous colitis development in mice harboring a kinase-dead PI3K catalytic subunit p110δ (p110δKD), a potent negative regulator of TLR responses in macrophages.55 CD11b+ LPMCs from p110δKD mice produced increased proinflammatory cytokines (IL-12p40, IL-23) and decreased anti-inflammatory IL-10 in response to enteric microbes compared with CD11b+ LPMCs from wild-type mice. Conversely, triggering receptor expressed on myeloid cells-1 (TREM-1) amplifies TLR-induced inflammatory responses in macrophages, and blocking its activity attenuates murine colitis.100,101 Indeed, resident LP macrophages do not express TREM-1, but abundant TREM-1–expressing LP macrophages can be found in patients with IBD.102,103 Thus, unrestrained proinflammatory responses of LP macrophages and LPDCs participate in the induction of chronic inflammation by continued recruitment of inflammatory cells, inducing altered barrier function of the IEC layer and promoting pathogenic adaptive immune responses.
The enteric microbiota interacts with the host immune cells to induce protective anti-inflammatory responses and maintain intestinal homeostasis. Dysregulation of these protective pathways, either by enteric microbial dysbiosis or intrinsic defects in macrophage and DC responses to stimuli, may underlie IBD pathogenesis. Short-chain fatty acids (SCFAs) are anti-inflammatory metabolites produced by specific phyla of enteric bacteria (Bacteroidetes and Firmicutes).104 When DSS colitis is induced in immune cell–specific Gpr43 −/− mice (a host receptor for SCFAs), colonic inflammation is exacerbated, pointing to the beneficial anti-inflammatory effect of SCFAs in the colon.105 Interestingly, bacteria also actively suppress intestinal inflammatory responses, although a bacterium can exploit this to promote its pathogenicity. Citrobacter rodentium and Helicobacter pylori express bacterial proteins with domains similar to host ITIMs.106 ITIMs negatively regulate immunoreceptor signaling pathways in immune cells, and bacterial ITIM-containing proteins dampen immune responses in murine colons. However, analysis of the enteric microbiota of patients with IBD demonstrates decreased biodiversity, decreased proportions of Firmicutes, and increased Gammaproteobacteria.107 Although it is unknown whether enteric dysbiosis in patients with IBD contributes to or is a consequence of colonic inflammation, researchers demonstrate reproducible increases in bacteria with unique abilities to adhere and invade mucosal cells in patients with IBD (i.e. adherent-invasive E. coli)108 and decreases in bacteria capable of producing protective SCFAs.109 Furthermore, it was recently shown that E. coli is especially adept at using nitrates as electron acceptors, supporting its selective growth during intestinal inflammation, when nitrates are produced in abundance.110 This suggests that the interplay between host and bacteria actively shapes intestinal homeostasis and participates in IBD pathogenesis.
Both macrophages and DCs actively promote the transition from inflammation to the return to homeostasis after immune system activation, and nonresolving inflammation is associated with many chronic diseases, including IBD.111 A study found that the proresolution mediator prostaglandin D2 was upregulated only in patients with UC who had achieved long-term remission, suggesting that intact proresolution pathways are necessary to halt damaging intestinal inflammation.112 Additionally, a SNP associated with low expression of the immune cell ectonucleotidase CD39, which generates the proresolving mediator adenosine, is associated with CD.113 Immune cells are the major contributors of extracellular adenosine at inflammatory sites. Adenosine interacts with its receptor A2B on macrophages and DCs to inhibit proinflammatory cytokine production, expression of costimulatory molecules, and induction of T-lymphocyte proliferation while increasing IL-10 production.114
Other proresolving soluble mediators with diverse effects on macrophages and DCs are resolvins, lipoxins, protectins, and maresins.115 These mediators are derived from polyunsaturated fatty acids (PUFAs), and patients with both CD and UC have demonstrated deficiencies in these resolving mediators.116,117 Interestingly, there was a very low incidence of IBD among a population in Northwest Greenland that consumes high amounts of PUFAs, suggesting that dietary precursors of proresolving factors help to prevent chronic gastrointestinal inflammation.118 PUFA-derived mediators enhance the capacity of macrophages and DCs to promote the resolution of inflammation by inducing efficient phagocytosis of apoptotic granulocytes and debris, preventing further recruitment of neutrophils, inducing anergy or deletion of effector T lymphocytes, and promoting repair of local damage.115 Treatment with resolvin E1 ameliorates pathology in 2 experimental murine models of colitis, illustrating the powerful effects of PUFA-derived mediators on resolving inflammation.119,120
Macrophages and DCs additionally respond to resolving mediators by switching to unique “resolution phase” phenotypes. DCs generated in the presence of resolvin E1 demonstrate decreased expression of costimulation molecules, TNF-α and IL-12, while inducing antigen-specific CD4+ T lymphocyte apoptosis through indoleamine 2,3-dioxygenase production and activation.121 A defining distinction of resolution phase DCs from tolerogenic DCs is the continued expression of CCR5, which enhances chemotaxis toward inflammatory sites, without upregulation of CCR7, which induces chemotaxis to lymph nodes, on resolution phase DCs.121 Similarly, resolution phase macrophages demonstrate a distinct phenotype from both M1 and M2 macrophages. Like M2 macrophages, resolution phase macrophages express high levels of molecules associated with the recognition and clearance of apoptotic cells, TGF-β, IL-10, and arginase 1.122,123 However, resolution phase macrophages also possess features of M1 macrophages, such as expression of iNOS, COX2, and CCR5.122,123 It is likely that local factors condition both macrophages and DCs to switch phenotypes and promote the resolution of inflammation and that the generation of these local factors or innate immune cell responses to these factors are defective in IBD.
In human IBD, inflammatory lesions demonstrate an increase in accumulation of macrophages that display enhanced expression of costimulatory molecules (CD80, CD86) and macrophage-activating receptors (CD40),124 TLRs,125 TREM-1,101,102 and CD14.103,126 Likewise, there are higher frequencies of LPDCs positive for markers of mature DCs (CD83, S-100, CD40)127–130 and for PRRs (CD209, TLR2/4) found in patients with IBD.128,129 Interestingly, IECs from patients with CD secreted less thymic stromal lymphopoietin, suggesting that the conditioning factors produced by IECs and stromal cells in the intestine that are necessary for inducing homeostatic LPDCs are deficient in IBDs.72 Indeed, LPDCs from patients with IBD also produce significantly more proinflammatory cytokines (IL-12, IL-6, IL-8, TNF-α) compared with those from healthy controls.129,130 Furthermore, there is an increase in frequency of LP pDCs from patients with IBD.131 However, stimulated peripheral blood pDCs from patients with IBD secrete significantly less IFN-α compared with those from healthy controls, suggesting that a decrease in functional tolerogenic pDCs in patients with IBD contributes to disease pathogenesis.131,132
There is accumulating evidence that inappropriate macrophage and DC responses to the enteric microbiota contribute to human IBD pathogenesis.8 These include both inadequate protective and enhanced pathogenic responses to such stimuli. Macrophages isolated from patients with both CD and UC demonstrate altered cytokine production in response to bacterial challenge: CD macrophages produce more proinflammatory IL-23 but less of the protective cytokine IL-10, whereas UC macrophages constitutively produce high levels of the proinflammatory cytokine IL-12.133 This may be in part due to impaired regulation of TLR-induced inflammatory responses in macrophages. For instance, patients with IBD demonstrate significantly decreased expression of intestinal NFIL3, an IL-10- and microbiota-induced transcriptional repressor of IL-12p40 expression compared with tissue from healthy noninflamed control patients.98 Additionally, increased numbers of TREM-1-expressing LP macrophages are found in intestinal tissue from patients with IBD compared with tissue from control patients.102 TREM-1 critically amplifies TLR-induced inflammatory responses of macrophages and is implicated in IBD pathogenesis. Conversely, LP macrophages from patients with IBD produce less of the cytokine granulocyte-colony stimulating factor, which is protective in experimental models of colitis, in response to the probiotic Lactobacillus rhamnosus GR-1 compared with those from healthy controls.134
There has long been evidence that patients with IBD demonstrate impaired ability to eradicate bacteria,135 and antibiotic therapy in certain clinical situations is efficacious for the induction and maintenance of remission in IBD.136,137 The human IBD susceptibility polymorphisms associated with NOD2 and ATG16L1 encode proteins involved in the autophagy pathway and lead to defective bacterial clearance.138 Macrophages isolated from patients with CD demonstrate decreased reactive oxygen species production and impaired eradication of bacteria.139,140 Additionally, peripheral blood monocytes isolated from patients with both CD and UC demonstrate decreased phagocytosis and killing of bacteria.141 Perhaps the most compelling evidence of the link between bacterial persistence and IBD is the long list of primary immunodeficiencies, such as chronic granulomatous disease, associated with IBD-like clinical manifestations.142–146 Approximately 50% of patients with chronic granulomatous disease, in which phagocyte reactive oxygen species production and bacterial clearance are greatly impaired, develop IBD-like manifestations that share clinical and pathological features of CD.142 Bacterial persistence and chronic stimulation of macrophages and DCs may contribute to IBD development by producing increased proinflammatory cytokines that shape pathogenic adaptive immune responses.
Innate immune cells are central to the pathogenesis of IBD, as susceptibility loci have been identified in genes encoding for innate immune cell functions.9 We are beginning to understand how macrophages and DCs maintain homeostasis in the gastrointestinal tract, a uniquely tolerant environment. Homeostasis requires an active process, and disruption of this balance contributes to chronic inflammation and IBD development. Defects in how macrophages and DCs respond to enteric antigens, eradicate bacteria, and induce resolution of inflammation underlie IBD pathogenesis (see Fig. 1 for summary of pathways and phenotypes). By understanding these pathways, we will be able to exploit them for the development of novel and more effective therapies.
1. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2:675–680.
2. Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197–216.
3. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34:637–650.
4. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.
5. Danese S. Nonimmune cells in inflammatory bowel disease: from victim to villain. Trends Immunol. 2008;29:555–564.
6. Mowat AM, Bain CC. Mucosal macrophages in intestinal homeostasis and inflammation. J Innate Immun. 2011;3:550–564.
7. Cario E. Toll-like receptors in inflammatory bowel diseases: a decade later. Inflamm Bowel Dis. 2010;16:1583–1597.
8. Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–434.
9. Cho JH, Brant SR. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology. 2011;140:1704–1712.
10. Jostins L, Ripke S, Weersma RK, et al.. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–124.
11. Schulz O, Jaensson E, Persson EK, et al.. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J Exp Med. 2009;206:3101–3114.
12. Diehl GE, Longman RS, Zhang JX, et al.. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX(3)CR1(hi) cells. Nature. 2013;494:116–120.
13. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–969.
14. Dale DC, Boxer L, Liles WC. The phagocytes: neutrophils and monocytes. Blood. 2008;112:935–945.
15. Mackaness GB. Cellular immunity and the parasite. Adv Exp Med Biol. 1977;93:65–73.
16. Spence S, Fitzsimons A, Boyd CR, et al.. Suppressors of cytokine signaling 2 and 3 diametrically control macrophage polarization. Immunity. 2013;38:66–78.
17. Bettelli E, Carrier Y, Gao W, et al.. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–238.
18. Edwards JP, Zhang X, Frauwirth KA, et al.. Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol. 2006;80:1298–1307.
19. Langrish CL, Chen Y, Blumenschein WM, et al.. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201:233–240.
20. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–795.
21. Swann JB, Vesely MD, Silva A, et al.. Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc Natl Acad Sci U S A. 2008;105:652–656.
22. Bishop JL, Sly LM, Krystal G, et al.. The inositol phosphatase SHIP controls Salmonella enterica serovar Typhimurium infection in vivo. Infect Immun. 2008;76:2913–2922.
23. Harris J, De Haro SA, Master SS, et al.. T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis. Immunity. 2007;27:505–517.
24. Kropf P, Fuentes JM, Fahnrich E, et al.. Arginase and polyamine synthesis are key factors in the regulation of experimental leishmaniasis in vivo. Faseb J. 2005;19:1000–1002.
25. Muller U, Stenzel W, Kohler G, et al.. IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans. J Immunol. 2007;179:5367–5377.
26. Shirey KA, Cole LE, Keegan AD, et al.. Francisella tularensis live vaccine strain induces macrophage alternative activation as a survival mechanism. J Immunol. 2008;181:4159–4167.
27. Tumitan AR, Monnazzi LG, Ghiraldi FR, et al.. Pattern of macrophage activation in yersinia-resistant and yersinia-susceptible strains of mice. Microbiol Immunol. 2007;51:1021–1028.
28. Fairweather D, Cihakova D. Alternatively activated macrophages in infection and autoimmunity. J Autoimmun. 2009;33:222–230.
29. Murray LA, Chen Q, Kramer MS, et al.. TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P. Int J Biochem Cell Biol. 2011;43:154–162.
30. Agrawal A, Pulendran B. Anthrax lethal toxin: a weapon of multisystem destruction. Cell Mol Life Sci. 2004;61:2859–2865.
31. Baetselier PD, Namangala B, Noel W, et al.. Alternative versus classical macrophage activation during experimental African trypanosomosis. Int J Parasitol. 2001;31:575–587.
32. Benoit M, Barbarat B, Bernard A, et al.. Coxiella burnetii, the agent of Q fever, stimulates an atypical M2 activation program in human macrophages. Eur J Immunol. 2008;38:1065–1070.
33. Kim C, Wilcox-Adelman S, Sano Y, et al.. Antiinflammatory cAMP signaling and cell migration genes co-opted by the anthrax bacillus. Proc Natl Acad Sci U S A. 2008;105:6150–6155.
34. Mahalingam S, Lidbury BA. Suppression of lipopolysaccharide-induced antiviral transcription factor (STAT-1 and NF-kappa B) complexes by antibody-dependent enhancement of macrophage infection by Ross River virus. Proc Natl Acad Sci U S A. 2002;99:13819–13824.
35. Miles SA, Conrad SM, Alves RG, et al.. A role for IgG immune complexes during infection with the intracellular pathogen Leishmania. J Exp Med. 2005;201:747–754.
36. Ruas LP, Bernardes ES, Fermino ML, et al.. Lack of galectin-3 drives response to Paracoccidioides brasiliensis toward a Th2-biased immunity. PLoS One. 2009;4:e4519.
37. Biswas SK, Gangi L, Paul S, et al.. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood. 2006;107:2112–2122.
38. Lin EY, Li JF, Gnatovskiy L, et al.. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 2006;66:11238–11246.
39. Denning TL, Wang YC, Patel SR, et al.. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol. 2007;8:1086–1094.
40. Smythies LE, Shen R, Bimczok D, et al.. Inflammation anergy in human intestinal macrophages is due to Smad-induced IkappaBalpha expression and NF-kappaB inactivation. J Biol Chem. 2010;285:19593–19604.
41. Rivollier A, He J, Kole A, et al.. Inflammation switches the differentiation program of Ly6Chi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon. J Exp Med. 2012;209:139–155.
42. Hadis U, Wahl B, Schulz O, et al.. Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity. 2011;34:237–246.
43. Niess JH, Brand S, Gu X, et al.. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science. 2005;307:254–258.
44. Medina-Contreras O, Geem D, Laur O, et al.. CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice. J Clin Invest. 2011;121:4787–4795.
45. Murai M, Turovskaya O, Kim G, et al.. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol. 2009;10:1178–1184.
46. Ruane DT, Lavelle EC. The role of CD103(+) dendritic cells in the intestinal mucosal immune system. Front Immunol. 2011;2:25.
47. Maheshwari A, Kelly DR, Nicola T, et al.. TGF-beta2 suppresses macrophage cytokine production and mucosal inflammatory responses in the developing intestine. Gastroenterology. 2011;140:242–253.
48. Kobayashi T, Matsuoka K, Sheikh SZ, et al.. IL-10 regulates Il12b expression via histone deacetylation: implications for intestinal macrophage homeostasis. J Immunol. 2012;189:1792–1799.
49. Kuhn R, Lohler J, Rennick D, et al.. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263–274.
50. Takeda K, Clausen BE, Kaisho T, et al.. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity. 1999;10:39–49.
51. Smallie T, Ricchetti G, Horwood NJ, et al.. IL-10 inhibits transcription elongation of the human TNF gene in primary macrophages. J Exp Med. 2010;207:2081–2088.
52. McCoy CE, Sheedy FJ, Qualls JE, et al.. IL-10 inhibits miR-155 induction by toll-like receptors. J Biol Chem. 2010;285:20492–20498.
53. Schaljo B, Kratochvill F, Gratz N, et al.. Tristetraprolin is required for full anti-inflammatory response of murine macrophages to IL-10. J Immunol. 2009;183:1197–1206.
54. El Kasmi KC, Smith AM, Williams L, et al.. Cutting edge: a transcriptional repressor and corepressor induced by the STAT3-regulated anti-inflammatory signaling pathway. J Immunol. 2007;179:7215–7219.
55. Uno JK, Rao KN, Matsuoka K, et al.. Altered macrophage function contributes to colitis in mice defective in the phosphoinositide-3 kinase subunit p110delta. Gastroenterology. 2010;139:1642–1653, 1653 e1641–1646.
56. Rutella S, Bonanno G, Pierelli L, et al.. Granulocyte colony-stimulating factor promotes the generation of regulatory DC through induction of IL-10 and IFN-alpha. Eur J Immunol. 2004;34:1291–1302.
57. Rescigno M, Di Sabatino A. Dendritic cells in intestinal homeostasis and disease. J Clin Invest. 2009;119:2441–2450.
58. Huang FP, Platt N, Wykes M, et al.. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J Exp Med. 2000;191:435–444.
59. Bilsborough J, George TC, Norment A, et al.. Mucosal CD8alpha+ DC, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties. Immunology. 2003;108:481–492.
60. Chirdo FG, Millington OR, Beacock-Sharp H, et al.. Immunomodulatory dendritic cells in intestinal lamina propria. Eur J Immunol. 2005;35:1831–1840.
61. Sun CM, Hall JA, Blank RB, et al.. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med. 2007;204:1775–1785.
62. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, et al.. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007;204:1757–1764.
63. Mucida D, Park Y, Kim G, et al.. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007;317:256–260.
64. Uematsu S, Fujimoto K, Jang MH, et al.. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat Immunol. 2008;9:769–776.
65. Kinnebrew MA, Buffie CG, Diehl GE, et al.. Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity. 2012;36:276–287.
66. Atarashi K, Nishimura J, Shima T, et al.. ATP drives lamina propria T(H)17 cell differentiation. Nature. 2008;455:808–812.
67. Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8:345–350.
68. Matteoli G, Mazzini E, Iliev ID, et al.. Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction. Gut. 2010;59:595–604.
69. Iliev ID, Mileti E, Matteoli G, et al.. Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning. Mucosal Immunol. 2009;2:340–350.
70. Newberry RD, McDonough JS, Stenson WF, et al.. Spontaneous and continuous cyclooxygenase-2-dependent prostaglandin E2 production by stromal cells in the murine small intestine lamina propria: directing the tone of the intestinal immune response. J Immunol. 2001;166:4465–4472.
71. Liu YJ, Soumelis V, Watanabe N, et al.. TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu Rev Immunol. 2007;25:193–219.
72. Rimoldi M, Chieppa M, Salucci V, et al.. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat Immunol. 2005;6:507–514.
73. Taylor BC, Zaph C, Troy AE, et al.. TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis. J Exp Med. 2009;206:655–667.
74. Lewis KL, Caton ML, Bogunovic M, et al.. Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity. 2011;35:780–791.
75. Collins CB, Aherne CM, McNamee EN, et al.. Flt3 ligand expands CD103(+) dendritic cells and FoxP3(+) T regulatory cells, and attenuates Crohn's-like murine ileitis. Gut. 2012;61:1154–1162.
76. Molenaar R, Knippenberg M, Goverse G, et al.. Expression of retinaldehyde dehydrogenase enzymes in mucosal dendritic cells and gut-draining lymph node stromal cells is controlled by dietary vitamin A. J Immunol. 2011;186:1934–1942.
77. Jaensson-Gyllenback E, Kotarsky K, Zapata F, et al.. Bile retinoids imprint intestinal CD103+ dendritic cells with the ability to generate gut-tropic T cells. Mucosal Immunol. 2011;4:438–447.
78. Wang S, Villablanca EJ, De Calisto J, et al.. MyD88-dependent TLR1/2 signals educate dendritic cells with gut-specific imprinting properties. J Immunol. 2011;187:141–150.
79. Mantis NJ, Rol N, Corthesy B. Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol. 2011;4:603–611.
80. Tezuka H, Abe Y, Iwata M, et al.. Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature. 2007;448:929–933.
81. Bemark M, Boysen P, Lycke NY. Induction of gut IgA production through T cell-dependent and T cell-independent pathways. Ann N Y Acad Sci. 2012;1247:97–116.
82. Liu K, Victora GD, Schwickert TA, et al.. In vivo analysis of dendritic cell development and homeostasis. Science. 2009;324:392–397.
83. Varol C, Vallon-Eberhard A, Elinav E, et al.. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity. 2009;31:502–512.
84. Dieleman LA, Ridwan BU, Tennyson GS, et al.. Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology. 1994;107:1643–1652.
85. Watanabe N, Ikuta K, Okazaki K, et al.. Elimination of local macrophages in intestine prevents chronic colitis in interleukin-10-deficient mice. Dig Dis Sci. 2003;48:408–414.
86. Palmen MJ, Dijkstra CD, van der Ende MB, et al.. Anti-CD11b/CD18 antibodies reduce inflammation in acute colitis in rats. Clin Exp Immunol. 1995;101:351–356.
87. Kanai T, Uraushihara K, Totsuka T, et al.. Ameliorating effect of saporin-conjugated anti-CD11b monoclonal antibody in a murine T-cell-mediated chronic colitis. J Gastroenterol Hepatol. 2006;21:1136–1142.
88. Abe K, Nguyen KP, Fine SD, et al.. Conventional dendritic cells regulate the outcome of colonic inflammation independently of T cells. Proc Natl Acad Sci U S A. 2007;104:17022–17027.
89. Berndt BE, Zhang M, Chen GH, et al.. The role of dendritic cells in the development of acute dextran sulfate sodium colitis. J Immunol. 2007;179:6255–6262.
90. Qualls JE, Kaplan AM, van Rooijen N, et al.. Suppression of experimental colitis by intestinal mononuclear phagocytes. J Leukoc Biol. 2006;80:802–815.
91. Qualls JE, Tuna H, Kaplan AM, et al.. Suppression of experimental colitis in mice by CD11c+ dendritic cells. Inflamm Bowel Dis. 2009;15:236–247.
92. Hunter MM, Wang A, Parhar KS, et al.. In vitro-derived alternatively activated macrophages reduce colonic inflammation in mice. Gastroenterology. 2010;138:1395–1405.
93. Weisser SB, Brugger HK, Voglmaier NS, et al.. SHIP-deficient, alternatively activated macrophages protect mice during DSS-induced colitis. J Leukoc Biol. 2011;90:483–492.
94. Arranz A, Doxaki C, Vergadi E, et al.. Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization. Proc Natl Acad Sci U S A. 2012;109:9517–9522.
95. Siddiqui KR, Laffont S, Powrie F. E-cadherin marks a subset of inflammatory dendritic cells that promote T cell-mediated colitis. Immunity. 2010;32:557–567.
96. Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008;134:577–594.
97. Guarner F. What is the role of the enteric commensal flora in IBD? Inflamm Bowel Dis. 2008;14(suppl 2):S83–S84.
98. Kobayashi T, Matsuoka K, Sheikh SZ, et al.. NFIL3 is a regulator of IL-12 p40 in macrophages and mucosal immunity. J Immunol. 2011;186:4649–4655.
99. Munitz A, Cole ET, Beichler A, et al.. Paired immunoglobulin-like receptor B (PIR-B) negatively regulates macrophage activation in experimental colitis. Gastroenterology. 2010;139:530–541.
100. Bouchon A, Dietrich J, Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol. 2000;164:4991–4995.
101. Schenk M, Bouchon A, Birrer S, et al.. Macrophages expressing triggering receptor expressed on myeloid cells-1 are underrepresented in the human intestine. J Immunol. 2005;174:517–524.
102. Schenk M, Bouchon A, Seibold F, et al.. TREM-1–expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases. J Clin Invest. 2007;117:3097–3106.
103. Smith PD, Smythies LE, Mosteller-Barnum M, et al.. Intestinal macrophages lack CD14 and CD89 and consequently are down-regulated for LPS- and IgA-mediated activities. J Immunol. 2001;167:2651–2656.
104. Cavaglieri CR, Nishiyama A, Fernandes LC, et al.. Differential effects of short-chain fatty acids on proliferation and production of pro- and anti-inflammatory cytokines by cultured lymphocytes. Life Sci. 2003;73:1683–1690.
105. Maslowski KM, Vieira AT, Ng A, et al.. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461:1282–1286.
106. Yan D, Wang X, Luo L, et al.. Inhibition of TLR signaling by a bacterial protein containing immunoreceptor tyrosine-based inhibitory motifs. Nat Immunol. 2012;13:1063–1071.
107. Sokol H, Seksik P. The intestinal microbiota in inflammatory bowel diseases: time to connect with the host. Curr Opin Gastroenterol. 2010;26:327–331.
108. Boudeau J, Glasser AL, Masseret E, et al.. Invasive ability of an Escherichia coli strain isolated from the ileal mucosa of a patient with Crohn's disease. Infect Immun. 1999;67:4499–4509.
109. Morgan XC, Tickle TL, Sokol H, et al.. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 2012;13:R79.
110. Winter SE, Winter MG, Xavier MN, et al.. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science. 2013;339:708–711.
111. Nathan C, Ding A. Nonresolving inflammation. Cell. 2010;140:871–882.
112. Vong L, Ferraz JG, Panaccione R, et al.. A pro-resolution mediator, prostaglandin D(2), is specifically up-regulated in individuals in long-term remission from ulcerative colitis. Proc Natl Acad Sci U S A. 2010;107:12023–12027.
113. Friedman DJ, Kunzli BM, A-Rahim YI, et al.. From the Cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease. Proc Natl Acad Sci U S A. 2009;106:16788–16793.
114. Hasko G, Csoka B, Nemeth ZH, et al.. A(2B) adenosine receptors in immunity and inflammation. Trends Immunol. 2009;30:263–270.
115. Uddin M, Levy BD. Resolvins: natural agonists for resolution of pulmonary inflammation. Prog Lipid Res. 2011;50:75–88.
116. Kuroki F, Iida M, Matsumoto T, et al.. Serum n3 polyunsaturated fatty acids are depleted in Crohn's disease. Dig Dis Sci. 1997;42:1137–1141.
117. Weylandt KH, Kang JX, Wiedenmann B, et al.. Lipoxins and resolvins in inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:797–799.
118. Kromann N, Green A. Epidemiological studies in the Upernavik district, Greenland. Incidence of some chronic diseases 1950-1974. Acta Med Scand. 1980;208:401–406.
119. Arita M, Yoshida M, Hong S, et al.. Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proc Natl Acad Sci U S A. 2005;102:7671–7676.
120. Ishida T, Yoshida M, Arita M, et al.. Resolvin E1, an endogenous lipid mediator derived from eicosapentaenoic acid, prevents dextran sulfate sodium-induced colitis. Inflamm Bowel Dis. 2010;16:87–95.
121. Vassiliou EK, Kesler OM, Tadros JH, et al.. Bone marrow-derived dendritic cells generated in the presence of resolvin E1 induce apoptosis of activated CD4+ T cells. J Immunol. 2008;181:4534–4544.
122. Bystrom J, Evans I, Newson J, et al.. Resolution-phase macrophages possess a unique inflammatory phenotype that is controlled by cAMP. Blood. 2008;112:4117–4127.
123. Stables MJ, Shah S, Camon EB, et al.. Transcriptomic analyses of murine resolution-phase macrophages. Blood. 2011;118:e192–e208.
124. Rugtveit J, Bakka A, Brandtzaeg P. Differential distribution of B7.1 (CD80) and B7.2 (CD86) costimulatory molecules on mucosal macrophage subsets in human inflammatory bowel disease (IBD). Clin Exp Immunol. 1997;110:104–113.
125. Hausmann M, Kiessling S, Mestermann S, et al.. Toll-like receptors 2 and 4 are up-regulated during intestinal inflammation. Gastroenterology. 2002;122:1987–2000.
126. Kamada N, Hisamatsu T, Okamoto S, et al.. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Invest. 2008;118:2269–2280.
127. te Velde AA, van Kooyk Y, Braat H, et al.. Increased expression of DC-SIGN+IL-12+IL-18+ and CD83+IL-12-IL-18- dendritic cell populations in the colonic mucosa of patients with Crohn's disease. Eur J Immunol. 2003;33:143–151.
128. Verstege MI, ten Kate FJ, Reinartz SM, et al.. Dendritic cell populations in colon and mesenteric lymph nodes of patients with Crohn's disease. J Histochem Cytochem. 2008;56:233–241.
129. Hart AL, Al-Hassi HO, Rigby RJ, et al.. Characteristics of intestinal dendritic cells in inflammatory bowel diseases. Gastroenterology. 2005;129:50–65.
130. Baumgart DC, Thomas S, Przesdzing I, et al.. Exaggerated inflammatory response of primary human myeloid dendritic cells to lipopolysaccharide in patients with inflammatory bowel disease. Clin Exp Immunol. 2009;157:423–436.
131. Baumgart DC, Metzke D, Guckelberger O, et al.. Aberrant plasmacytoid dendritic cell distribution and function in patients with Crohn's disease and ulcerative colitis. Clin Exp Immunol. 2011;166:46–54.
132. Baumgart DC, Metzke D, Schmitz J, et al.. Patients with active inflammatory bowel disease lack immature peripheral blood plasmacytoid and myeloid dendritic cells. Gut. 2005;54:228–236.
133. Campos N, Magro F, Castro AR, et al.. Macrophages from IBD patients exhibit defective tumour necrosis factor-alpha secretion but otherwise normal or augmented pro-inflammatory responses to infection. Immunobiology. 2011;216:961–970.
134. Martins AJ, Colquhoun P, Reid G, et al.. Reduced expression of basal and probiotic-inducible G-CSF in intestinal mononuclear cells is associated with inflammatory bowel disease. Inflamm Bowel Dis. 2009;15:515–525.
135. Rahman FZ, Marks DJ, Hayee BH, et al.. Phagocyte dysfunction and inflammatory bowel disease. Inflamm Bowel Dis. 2008;14:1443–1452.
136. Khan KJ, Ullman TA, Ford AC, et al.. Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol. 2011;106:661–673.
137. Pineton de Chambrun GP, Torres J, Darfeuille-Michaud A, et al.. The role of anti(myco)bacterial interventions in the management of IBD: is there evidence at all? Dig Dis. 2012;30:358–367.
138. Travassos LH, Carneiro LA, Ramjeet M, et al.. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol. 2010;11:55–62.
139. Smith AM, Rahman FZ, Hayee B, et al.. Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. J Exp Med. 2009;206:1883–1897.
140. Palmer CD, Rahman FZ, Sewell GW, et al.. Diminished macrophage apoptosis and reactive oxygen species generation after phorbol ester stimulation in Crohn's disease. PLoS One. 2009;4:e7787.
141. Caradonna L, Amati L, Lella P, et al.. Phagocytosis, killing, lymphocyte-mediated antibacterial activity, serum autoantibodies, and plasma endotoxins in inflammatory bowel disease. Am J Gastroenterol. 2000;95:1495–1502.
142. Marks DJ, Miyagi K, Rahman FZ, et al.. Inflammatory bowel disease in CGD reproduces the clinicopathological features of Crohn's disease. Am J Gastroenterol. 2009;104:117–124.
143. Diez R, Garcia MJ, Vivas S, et al.. Gastrointestinal manifestations in patients with primary immunodeficiencies causing antibody deficiency [in Spanish]. Gastroenterol Hepatol. 2010;33:347–351.
144. Ishii E, Matui T, Iida M, et al.. Chediak-Higashi syndrome with intestinal complication. Report of a case. J Clin Gastroenterol. 1987;9:556–558.
145. Marks DJ, Seymour CR, Sewell GW, et al.. Inflammatory bowel diseases in patients with adaptive and complement immunodeficiency disorders. Inflamm Bowel Dis. 2010;16:1984–1992.
146. Yamaguchi T, Ihara K, Matsumoto T, et al.. Inflammatory bowel disease-like colitis in glycogen storage disease type 1b. Inflamm Bowel Dis. 2001;7:128–132.