Secondary Logo

Journal Logo

Toll-like receptor signaling in hematopoietic stem and progenitor cells

Capitano, Maegan L.

Current Opinion in Hematology: July 2019 - Volume 26 - Issue 4 - p 207–213
doi: 10.1097/MOH.0000000000000511
HEMATOPOIESIS: Edited by Hal E. Broxmeyer and Maegan L. Capitano

Purpose of review The innate immune system is essential in the protection against microbial infection and facilitating tissue repair mechanisms. During these stresses, the maintenance of innate immune cell numbers through stress-induced or emergency hematopoiesis is key for our survival. One major mechanism to recognize danger signals is through the activation of Toll-like receptors (TLRs) on the surface of hematopoietic cells, including hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC), and nonhematopoietic cells, which recognize pathogen-derived or damaged-induced compounds and can influence the emergency hematopoietic response. This review explores how direct pathogen-sensing by HSC/HPC regulates hematopoiesis, and the positive and negative consequences of these signals.

Recent findings Recent studies have highlighted new roles for TLRs in regulating HSC and HPC differentiation to innate immune cells of both myeloid and lymphoid origin and augmenting HSC and HPC migration capabilities. Most interestingly, new insights as to how acute versus chronic stimulation of TLR signaling regulates HSC and HPC function has been explored.

Summary Recent evidence suggests that TLRs may play an important role in many inflammation-associated diseases. This suggests a possible use for TLR agonists or antagonists as potential therapeutics. Understanding the direct effects of TLR signaling by HSC and HPC may help regulate inflammatory/danger signal-driven emergency hematopoiesis.

Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA

Correspondence to Maegan L. Capitano, PhD, Department of Microbiology and Immunology, Indiana University School of Medicine, R2 Room 312, 950 West Walnut Street, Indianapolis, IN 46202, USA. Tel: +1 317 274 7555; fax: +1 317 274 7592; e-mail:

Back to Top | Article Outline


Hematopoietic stem cells (HSCs) are in low frequency within the bone marrow and have multilineage differentiation potential as well as the ability for life-long self-renewal potential [1,2]. Long-term-HSCs are retained in a bone marrow microenvironment that promotes their survival and maintains them in a noncycling state [3,4]. Thus, when there is a demand for more mature immune cells following infection, blood loss, or tissue repair, the bone marrow has the required pool of HSCs and hematopoietic progenitor cells (HPC) needed to ramp up production of replacement mature hematopoietic cells. This stress-induced increase in production of mature immune cells has been dubbed emergency hematopoiesis. How the hematopoietic system recognizes when to switch gears from normal, steady-state production to emergency hematopoiesis is driven by many factors such as pathogen-sensing (either directly by the HSC/HPC or indirectly by mature hematopoietic or other nonhematopoietic cells), cytokine/growth factor production, or other ‘danger’ signals [e.g., reactive oxygen species (ROS) production] and can vary greatly depending on the type of infection, site of injury, and duration of inflammatory response. How mature hematopoietic and nonhematopoietic cells regulate emergency hematopoiesis by external cues such as cytokine/growth factor production has been extensively reviewed [5▪▪,6]. Therefore, in this review the focus is on how immune cell numbers are regulated under emergency conditions via direct pathogen-sensing by HSCs and HPCs, and positive and negative consequences of these signals.

Box 1

Box 1

Back to Top | Article Outline


To induce emergency hematopoiesis the hematopoietic system must first recognize that a stress event has taken place. Toll-like receptors (TLRs; a type of pattern recognition receptor) recognize pathogen-associated molecular patterns (PAMPs) [7,8]. TLRs are expressed on cells of hematopoietic origin (e.g., dendritic cells, macrophages, lymphocytes, HSCs, and HPCs) as well as nonhematopoietic cells (e.g., endothelial and mesenchymal stem cells) [9–14]. Some TLRs are localized to the plasma membrane (e.g., TLR1, TLR2, TLR4, TLR5, TLR6, and TLR11) while others are found in endosomes (e.g., TLR3, TLR7, TLR8, and TLR9) with most acting as homodimers with the exception of TLR2 which heterodimerizes with TLR1 or TLR6 [11,15,16]. The ligands for TLRs, PAMPs, are unique to groups of related microorganisms, for example lipopolysaccharide (LPS) found in bacteria cell walls or viral single-stranded RNA, that are not associated with normal host cells. In addition to recognizing pathogen-associated danger signals, TLRs can also recognize injury or tissue repair danger-associated molecular patterns (DAMPs) [17]. DAMPs (e.g., HMGB1 and ATP) are cell-derived molecules that are normally expressed by cells undergoing necrosis that can trigger an innate immune response.

Once TLRs recognize PAMPs or DAMPS, a signaling cascade involving myeloid differentiation primary response gene 88 (MyD88) recruitment is followed by complex formation with the serine-threonine kinase interleukin-1 receptor-associated kinase family members, leading to nuclear factor k-light chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathway activation resulting in proinflammatory cytokine (e.g., IL-1, IL-6, IL-8, and TNFα) production [11,18–20]. However, there are exceptions such as TLR3 signaling which is MyD88-independent, instead depending on the toll/interleukin-1 receptor-domain-containing adaptor inducing IFN-B (TRIF) pathway which activates interferon regulatory factor-3 (IRF3) leading to production of type 1 interferons [21–23]. TRIF signaling can also lead to MyD88-independent activation of NF-κB and MAPK. TLR4, one of the most thoroughly investigated TLRs, utilizes both MyD88-dependent and TRIF-dependent signaling pathways [24].

Back to Top | Article Outline


Evidence that danger signals can trigger emergency hematopoiesis in vivo is strong as demonstrated by the fact that direct injection of PAMPs and DAMPs (e.g., LPS) and/or infecting mice with pathogens (e.g., Candida albicans or Staphylococcus aureus) can increase HSC proliferation and skew differentiation toward increased myeloid cell (e.g., neutrophil and macrophage) production in a TLR-dependent manner often at the expense of lymphopoiesis and erythropoiesis [25–30]. However, administration of systemic TLR agonists or the use of infection models such as those stated above do not address the direct role of TLRs within HSC and HPC populations. To test if TLR agonists can directly stimulate HSCs/HPCs, lineage marker negative, stem-cell antigen positive-1, c-kit positive bone marrow cells from wild type mice were transplanted into lethally irradiated TLR2, TLR4 or MyD88 knockout mice and then immediately exposed in vivo to soluble TLR ligands Pam3CSK4 (a TLR2 agonist), LPS (a TLR4 agonist) or CpG oligodeoxynucleotide (a TLR9 agonists that is dependent on MyD88 signaling), respectively. Transplanted HSCs and HPCs in response to these TLR ligands differentiated preferentially to macrophages demonstrating that TLR signaling directly from the HSC/HPC compartment can regulate specific blood cell production [29].

TLRs are expressed on HSCs and HPCs both in mice and humans and have been shown both in vitro and in vivo to affect HSC/HPC functions [12,31–34]. Both highly phenotypically-defined long-term-HSC populations and more broadly defined HSC/HPC populations express both TLR2 and TLR4. When purified mouse long-term-HSCs (sorted using signaling lymphocytic activation molecule or markers) were stimulated directly with LPS, the TLR4/NF-κB axis was activated [35]. In vitro stimulation of less strictly defined HSC/HPC populations with Pam3CSK4 or LPS has also been shown to drive myeloid differentiation in a MyD88-dependent manner [13,25–29,33,35–38]. Further studies utilizing HSCs/HPCs demonstrated that TLR4 signaling can also occur through a TRIF-dependent pathway, ultimately leading to activation of NF-κB and/or IRF transcription factors [8]. Stimulation of human CD34+ bone marrow cells with small interfering RNAs and R848 (specific ligands for TLR7 and TLR8) resulted in increased IL-1β, IL-6, IL-8, TNF-α, and granulocyte-macrophage colony-stimulating factor production as well as inducing these cells to differentiate into macrophages and monocytic dendritic precursors that expressed CD13, CD14, and/or CD11c markers [34] suggesting that TLR7 and TLR8 may also directly influence HSCs and/or HPCs. Supporting these findings, TLR7-mediated stimulation of common myeloid progenitors (CMPs), synergistically with type 1 interferons, promoted monocyte/macrophage differentiation. Significantly, this was through an mammalian target of rapamycin/phosphoinositide-3 kinase-dependent pathway [39]. These findings suggest that HSCs and HPCs can directly signal through TLRs driving myeloid differentiation, indicting that HSCs/HPCs themselves can act as pathogen sensors.

However, these findings do not necessarily indicate whether the triggering of emergency hematopoiesis (especially skewing toward increased production of mature myeloid cells) is through the direct regulation of transcription factors that lead to the differentiation of these mature cell populations (an autocrine effect), by the production of cytokines and/or growth factors that promote these pathways (a paracrine effect), or both. Further work to differentiate the importance of the autocrine and paracrine TLR signaling effects on HSCs and HPCs needs to be performed. It is becoming clearer, however, that HSC/HPC populations may be very important contributors to the proinflammatory cytokine and growth factor milieu following TLR stimulation. The stimulation of HSCs/HPCs, specifically short-term-HSCs and multipotent progenitors (MPPs), with various bacterial products resulted in production of a diverse cytokine milieu through NF-κB signaling [35]. In particular HSCs/HPCs produced large quantities of IL-6 which is known to drive myeloid differentiation and HSC/HPC proliferation. Significantly, cytokine production by short-term-HSC and MPP following TLR-stimulation often trumped mature immune cell production of cytokines following stimulation with the same doses of TLR agonist [35].

Stimulation of TLRs using PAMPs has also been demonstrated to change chemokine receptor expression on the surface of HSC/HPC and the ability of these cells to be retained within the bone marrow [12,40,41]. Following a stress event, the appearance of immature myeloid precursor cells and other earlier progenitor cells often occurs in the peripheral blood. This is referred to as a peripheral blood left shift [5▪▪]. Upon stimulation of TLRs, common dendritic cell progenitors (CDPs) downregulate expression of CXCR4 (a required chemokine receptor for CDP retention within the bone marrow) and upregulate the expression of CCR7 (a chemokine receptor required for CDPs to enter preferentially into inflamed lymph nodes) [12]. These findings suggest that TLR signaling in dendritic cell progenitors allows for dendritic cell homeostasis at sites of inflammation. Recently it was found that injecting a low dose of zymosan (a TLR2 agonist) into the peritoneal cavity of mice resulted in increased numbers of innate lymphoid cells, a phenomena dependent on the in-situ differentiation of bone marrow-derived HPCs and innate lymphoid cell precursors [42▪▪]. This suggests that TLR signaling may play a role in the migration and differentiation of innate lymphoid cells and their progenitors/precursors. It is important to note, however, that induction of HSC/HPC migration by TLR signaling is not straight forward. Significantly, MyD88 knockout mice injected with LPS and zymosan demonstrated normal HSC/HPC migration into the peripheral blood, similar to that of wild type controls, suggesting that another factor may influence the migration of these populations into the blood [40].

Back to Top | Article Outline


Granulocyte colony-stimulating factor (G-CSF) is thought to be one of the principle cytokines involved in regulating granulopoiesis under steady-state conditions and following many different stress events including infection [43–45]. One way G-CSF regulates granulopoiesis is by inducing commitment of MPPs down the myeloid lineage [46]. G-CSF and G-CSF receptor-deficient animals exhibit severe neutropenia (a condition when there is reduced neutrophil numbers in the blood) [47,48] which correlates with the fact that mice that are deficient in G-CSF receptor have increased numbers of common lymphoid progenitors and decreased CMPs thus influencing granulopoiesis [46]. Following a stress event, changes in proinflammatory cytokines such as TNF-α, IL-1, and IL-17 (amongst others) can increase G-CSF expression [49,50]. The enhanced induction of G-CSF expression following proinflammatory cytokine exposure, often induced by TLR stimulation, also contributes to the peripheral blood left shift phenomenon, as G-CSF induces release of bone marrow HSCs/HPCs and myeloid precursors into the blood by regulating surface expression of the chemokine receptor CXCR4 and production of its ligand CXCL12 (also known as stromal cell-derived factor-1) [51–54]. The fact that G-CSF turns off the HSC/HPC retention signal is used in the clinic to mobilize HSCs/HPCs to the peripheral blood for the use in transplantations [51–54].

Significantly, even though TLR signaling produces a proinflammatory microenvironment that regulates G-CSF production, utilizing G-CSF as a mobilizer in MyD88 knockout mice resulted in enhanced HSC/HPC migration into the peripheral blood [40]. Transplantation studies revealed that this enhancement in HSC/HPC migration was due to cells of hematopoietic origin. As TLR activation crosstalks with activation of the complement cascade associated with innate immune responses and augments production of proinflammatory regulators [40,55–57], it was proposed that one of these factors may be mechanistically involved in the altered mobilization of HSCs and HPCs following G-CSF administration. MyD88 knockout bone marrow cells, in particular, stem-cell antigen-1 positive cells, demonstrated greatly reduced expression of heme oxygenase-1 (a negative regulator of the complement cascade activation and a negative regulator of HSC/HPC mobilization) suggesting that TLR signaling enhances expression of heme oxygenase-1 in hematopoietic cells, especially within HSC/HPC populations, resulting in the reduced migration of HSCs and HPCs from the bone marrow to the blood [40,55,58]. This observation suggests that utilizing TLR antagonists may aid in enhancing G-CSF-mediated HSC/HPC mobilization.

G-CSF plays a role in regulating hematopoiesis. G-CSF treatment over a prolonged period of time in vivo can result in an initial increase in phenotyped HSC numbers. However, this is followed by an increase in HSC quiescence associated with a marked decrease in HSC repopulating capacity [59]. Reduction of HSC function after prolonged exposure to G-CSF is associated with increased TLR expression and signaling as the G-CSF-mediated alteration of HSC function is greatly reduced in mice lacking TLR2, TLR4, or the TLR signaling adaptor MyD88. These findings are further supported by the fact that prolonged exposure to G-CSF also can regulate TLR expression (e.g., TLR-1) and induce TLR signaling without the added presence of additional TLR ligands [59]. Significantly, mice maintained under germ-free conditions and mice given antibiotics to suppress intestinal flora manifest reduced HSC dysregulation following prolonged exposure to G-CSF, suggesting that TLR stimulation is most likely a result of TLR ligands produced by the animal's own microbiome [59]. Taken together, G-CSF treatment appears to act as a stress itself, altering TLR signaling that results not only in changes to G-CSF treatment-induced mobilization of HSCs and HPCs, but also to HSC function. The role of this pharmacologically induced stress in reduction of HSC/HPC mobilization by mature hematopoietic components of the bone marrow (associated with the increased expression of DAMPs, ROS, and proteolytic and lipolytic enzymes) has recently been reviewed [60▪▪] and will not be discussed here. However, this complicated interaction between G-CSF therapy and activation of TLR signaling poses a new and promising potential therapeutic target that deserves to be carefully explored.

Back to Top | Article Outline


Prolonged exposure to TLR stimulation is associated with impaired hematopoiesis [5▪▪,6,11,38,59]. Repeated, prolonged exposure of mice to LPS leads to increased HSC proliferation and an increase skewing toward myeloid cell differentiation, but is associated with decreased HSC repopulating capability following transplantation [36,38]. Similarly, chronic exposure of mice to PAM3CSK4 led to increased HSC numbers, both in bone marrow and spleen, but resulted in decreased HSC function [61]. Effects of prolonged exposure to either LPS or PAM3CSK4 on HSC function, however, do not appear to be linked to direct effects on HSCs or HPCs, but rather to increased production of proinflammatory stimuli such as TNF-α and G-CSF [38,61]. Negative effects to HSC function by prolonged exposure to TLR stimuli is further supported by the finding that prolonged exposure to cytokines/growth factors, such as the pharmacological administration of G-CSF, creating an environment constantly exposed to low doses of TLR ligands, had similar effects on HSC function [59]. However, short-term or single exposure to TLR agonists, as mentioned previously, resulted in increased HSC activity even though increased proinflammatory cytokine production was present [30]. These findings suggest that the specific effects of TLR agonists on HSC and HPC function are dependent on dose or duration of exposure (Fig. 1). Why short-term and long-term exposure to TLR agonists both resulted in increased cytokine production but have opposite effects on HSC function remains unclear but may represent a possible direct HSC autocrine TLR signaling mechanism or differential cytokine/chemokine protein or receptor production/expression. Understanding how this phenomenon occurs requires further investigation.



Accumulating evidence also suggests a role for TLRs in development of hematopoietic malignancies and bone marrow failure, possibly shedding light as to how chronic stimulation of TLRs or aberrant TLR signaling may have detrimental effects on hematopoiesis. TLRs have been associated with myelodysplastic syndromes, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, mantle cell lymphoma, and activated B-cell diffuse large B-cell lymphoma amongst other hematological disease [11]. Aberrant TLR signaling (e.g., overexpression of the TLR effector TRAF6 and the chronic activation of epigenetic regulators such as KDM6B) has been linked to several lymphoproliferative disorders and myelodysplastic syndromes that possess a high risk of transformation to leukemia [11,62▪,63▪]. Whether this is due to autocrine effects on HSCs and/or HPCs or the release of proinflammatory cytokines that could create a microenvironment conducive to promoting tumorigenesis has been recently reviewed extensively [11].

Back to Top | Article Outline


There is still a lot unknown about how TLR signaling influences HSC and HPC cycling, differentiation and mobilization via both autocrine and paracrine mechanisms. However, as more and more studies find a role for TLRs in disease progression (e.g., cancer, autoimmune disease, graft-versus-host disease, etc.) where targeting TLR signaling pathways through the use of TLR agonist or antagonist is a possible therapeutic approach, utilizing cytokines/growth factors as therapeutics (e.g., G-CSF) that can activate TLR signaling, or utilizing TLR agonist and antagonist to mitigate emergency hematopoiesis itself, it has become increasingly essential that we understand how these treatments might regulate HSC/HPC function [11,40,59,60▪▪,64▪–68▪]. It is possible that with a better understanding as to how TLR stimulation effects HSC and HPC function directly, we may be able to create better therapeutics to regulate hematopoiesis or alter disease progression by manipulating the hematopoietic emergency response to danger signals.

Back to Top | Article Outline


The work was supported by Indiana University Simon Cancer Center American Cancer Society Institutional Research Pilot Grant IRG-16-192-31.

Back to Top | Article Outline

Financial support and sponsorship


Back to Top | Article Outline

Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
Back to Top | Article Outline


1. Kondo M, Wagers AJ, Manz MG, et al. Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu Rev Immunol 2003; 21:759–806.
2. Ogawa M. Differentiation and proliferation of hematopoietic stem cells. Blood 1993; 81:2844–2853.
3. Greenbaum A, Hsu YM, Day RB, et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 2013; 495:227–230.
4. Mendez-Ferrer S, Michurina TV, Ferraro F, et al. Mesenchymal and haematopoietic stem cells form a unique BM niche. Nature 2010; 466:829–834.
5▪▪. Boettcher S, Manz MG. Regulation of inflammation- and infection-driven hematopoiesis. Trends Immunol 2017; 38:345–357.

The review goes over in detail the importance of proinflammatory molecules in regulating emergency hematopoiesis and the influence of both mature hematopoietic and nonhematopoietic cells on this process.

6. Zhao JL, Baltimore D. Regulation of stress-induced hematopoiesis. Curr Opin Hematol 2015; 22:286–292.
7. Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol 2004; 5:987–995.
8. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010; 11:373–384.
9. Crack PJ, Bray PJ. Toll-like receptors in the brain and their potential roles in neuropathology. Immunol Cell Biol 2007; 85:476–480.
10. Fitzner N, Clauberg S, Essmann F, et al. Human skin endothelial cells can express all 10 TLR genes and respond to respective ligands. Clin Vaccine Immunol 2008; 15:138–146.
11. Monlish DA, Bhatt ST, Schuettpelz LG. The role of Toll-Like receptors in hematopoietic malignancies. Front Immunol 2016; 7:390.
12. Schmid MA, Takizawa H, Baumjohann DR, et al. BM dendritic cell progenitors sense pathogens via Toll-like receptors and subsequently migrate to inflamed lymph nodes. Blood 2011; 118:4829–4840.
13. Takizawa H, Boettcher S, Manz MG. Demand-adapted regulation of early hematopoiesis in infection and inflammation. Blood 2012; 119:2991–3002.
14. Zarember KA, Godowski PJ. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 2002; 168:554–561.
15. Oliveira-Nascimento L, Massari P, Wetzler LM. The role of TLR2 in infection and immunity. Front Immunol 2012; 3:79.
16. Takeuchi O, Kawai T, Muhlradt PF, et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol 2001; 13:933–940.
17. Piccinini AM, Midwood KS. DAMPening inflammation by modulating TLR signalling. Mediators Inflamm 2010; 2010:672395.
18. Burns K, Janssens S, Brissoni B, et al. Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J Exp Med 2003; 197:263–268.
19. Landstrom M. The TAK1-TRAF6 signalling pathway. Int J Biochem Cell Biol 2010; 42:585–589.
20. Lin SC, Lo YC, Wu H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 2010; 465:885–890.
21. Fitzgerald KA, McWhirter SM, Faia KL, et al. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 2003; 4:491–496.
22. Oshiumi H, Matsumoto M, Funami K, et al. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction. Nat Immunol 2003; 4:161–167.
23. Sato S, Sugiyama M, Yamamoto M, et al. Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol 2003; 171:4304–4310.
24. Hoebe K, Du X, Georgel P, et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 2003; 424:743–748.
25. Chen C, Liu Y, Liu Y, Zheng P. Mammalian target of rapamycin activation underlies HSC defects in autoimmune disease and inflammation in mice. J Clin Invest 2010; 120:4091–4101.
26. Granick JL, Falahee PC, Dahmubed D, et al. Staphylococcus aureus recognition by hematopoietic stem and progenitor cells via TLR2/MyD88/PGE2 stimulates granulopoiesis in wounds. Blood 2013; 122:1770–1778.
27. King KY, Goodell MA. Inflammatory modulation of HSCs: viewing the HSC as a foundation for the immune response. Nat Rev Immunol 2011; 11:685–692.
28. Megias J, Maneu V, Salvador P, et al. Candida albicans stimulates in vivo differentiation of haematopoietic stem and progenitor cells towards macrophages by a TLR2-dependent signalling. Cell Microbiol 2013; 15:1143–1153.
29. Megias J, Yanez A, Moriano S, et al. Direct Toll-like receptor-mediated stimulation of hematopoietic stem and progenitor cells occurs in vivo and promotes differentiation toward macrophages. Stem Cells 2012; 30:1486–1495.
30. Takizawa H, Regoes RR, Boddupalli CS, et al. Dynamic variation in cycling of hematopoietic stem cells in steady state and inflammation. J Exp Med 2011; 208:273–284.
31. Chicha L, Jarrossay D, Manz MG. Clonal type I interferon-producing and dendritic cell precursors are contained in both human lymphoid and myeloid progenitor populations. J Exp Med 2004; 200:1519–1524.
32. De Luca K, Frances-Duvert V, Asensio MJ, et al. The TLR1/2 agonist PAM (3)CSK(4) instructs commitment of human hematopoietic stem cells to a myeloid cell fate. Leukemia 2009; 23:2063–2074.
33. Nagai Y, Garrett KP, Ohta S, et al. Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity 2006; 24:801–812.
34. Sioud M, Floisand Y, Forfang L, Lund-Johansen F. Signaling through toll-like receptor 7/8 induces the differentiation of human BM CD34+ progenitor cells along the myeloid lineage. J Mol Biol 2006; 364:945–954.
35. Zhao JL, Ma C, O’Connell RM, et al. Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis. Cell Stem Cell 2014; 14:445–459.
36. Esplin BL, Shimazu T, Welner RS, et al. Chronic exposure to a TLR ligand injures hematopoietic stem cells. J Immunol 2011; 186:5367–5375.
37. Massberg S, Schaerli P, Knezevic-Maramica I, et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 2007; 131:994–1008.
38. Zhao Y, Ling F, Wang HC, Sun XH. Chronic TLR signaling impairs the long-term repopulating potential of hematopoietic stem cells of wild type but not Id1 deficient mice. PLoS One 2013; 8:e55552.
39. Buechler MB, Akilesh HM, Hamerman JA. Cutting edge: direct sensing of TLR7 ligands and type I IFN by the common myeloid progenitor promotes mTOR/PI3K-dependent emergency myelopoiesis. J Immunol 2016; 197:2577–2582.
40. Adamiak M, Abdelbaset-Ismail A, Kucia M, et al. Toll-like receptor signaling-deficient mice are easy mobilizers: evidence that TLR signaling prevents mobilization of hematopoietic stem/progenitor cells in HO-1-dependent manner. Leukemia 2016; 30:2416–2419.
41. Onai N, Obata-Onai A, Schmid MA, et al. Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse BM. Nat Immunol 2007; 8:1207–1216.
42▪▪. Korniotis S, Thornley TB, Kyriazis P, et al. Hematopoietic stem/progenitor cell dependent participation of innate lymphoid cells in low-intensity sterile inflammation. Front Immunol 2018; 9:2007.

The article showed that the production of innate immune cells of lymphoid as well as myeloid lineage can occur following Toll-like receptor (TLR)-mediated hematopoietic stem cell/hematopoietic progenitor cell differentiation.

43. Metcalf D, Begley CG, Johnson GR, et al. Effects of purified bacterially synthesized murine multi-CSF (IL-3) on hematopoiesis in normal adult mice. Blood 1986; 68:46–57.
44. Metcalf D, Begley CG, Williamson DJ, et al. Hemopoietic responses in mice injected with purified recombinant murine GM-CSF. Exp Hematol 1987; 15:1–9.
45. Pojda Z, Tsuboi A. In vivo effects of human recombinant interleukin 6 on hemopoietic stem and progenitor cells and circulating blood cells in normal mice. Exp Hematol 1990; 18:1034–1037.
46. Richards MK, Liu F, Iwasaki H, et al. Pivotal role of granulocyte colony-stimulating factor in the development of progenitors in the common myeloid pathway. Blood 2003; 102:3562–3568.
47. Lieschke GJ, Grail D, Hodgson G, et al. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 1994; 84:1737–1746.
48. Liu F, Wu HY, Wesselschmidt R, et al. Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. Immunity 1996; 5:491–501.
49. Capitano ML, Nemeth MJ, Mace TA, et al. Elevating body temperature enhances hematopoiesis and neutrophil recovery after total body irradiation in an IL-1-, IL-17-, and G-CSF-dependent manner. Blood 2012; 120:2600–2609.
50. Panopoulos AD, Watowich SS. Granulocyte colony-stimulating factor: molecular mechanisms of action during steady state and ‘emergency’ hematopoiesis. Cytokine 2008; 42:277–288.
51. De La Luz Sierra M, Gasperini P, McCormick PJ, et al. Transcription factor Gfi-1 induced by G-CSF is a negative regulator of CXCR4 in myeloid cells. Blood 2007; 110:2276–2285.
52. Semerad CL, Christopher MJ, Liu F, et al. G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the BM. Blood 2005; 106:3020–3027.
53. Semerad CL, Liu F, Gregory AD, et al. G-CSF is an essential regulator of neutrophil trafficking from the BM to the blood. Immunity 2002; 17:413–423.
54. Suratt BT, Petty JM, Young SK, et al. Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis. Blood 2004; 104:565–571.
55. Adamiak M, Moore JBt, Zhao J, et al. Downregulation of heme oxygenase 1 (HO-1) activity in hematopoietic cells enhances their engraftment after transplantation. Cell Transplant 2016; 25:1265–1276.
56. Song WC. Crosstalk between complement and toll-like receptors. Toxicol Pathol 2012; 40:174–182.
57. Zhang X, Kimura Y, Fang C, et al. Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood 2007; 110:228–236.
58. Wysoczynski M, Ratajczak J, Pedziwiatr D, et al. Identification of heme oxygenase 1 (HO-1) as a novel negative regulator of mobilization of hematopoietic stem/progenitor cells. Stem Cell Rev 2015; 11:110–118.
59. Schuettpelz LG, Borgerding JN, Christopher MJ, et al. G-CSF regulates hematopoietic stem cell activity, in part, through activation of Toll-like receptor signaling. Leukemia 2014; 28:1851–1860.
60▪▪. Ratajczak MZ, Adamiak M, Plonka M, et al. Mobilization of hematopoietic stem cells as a result of innate immunity-mediated sterile inflammation in the BM microenvironment-the involvement of extracellular nucleotides and purinergic signaling. Leukemia 2018; 32:1116–1123.

This is a great review to understand the role of danger-associated molecular patterns in regulating hematopoiesis.

61. Herman AC, Monlish DA, Romine MP, et al. Systemic TLR2 agonist exposure regulates hematopoietic stem cells via cell-autonomous and cell-nonautonomous mechanisms. Blood Cancer J 2016; 6:e437.
62▪. Fang J, Bolanos LC, Choi K, et al. Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia. Nat Immunol 2017; 18:236–245.

First article to show that a component of the TLR signaling cascade, TRAF6, plays a role in malgninant transformation of hematopoietic cells.

63▪. Wei Y, Zheng H, Bao N, et al. KDM6B overexpression activates innate immune signaling and impairs hematopoiesis in mice. Blood Adv 2018; 2:2491–2504.

First article to show that aberrant TLR signaling can result in the chronic activation of the epigenetic regulator KDM6B leading to impaired hematopoiesis.

64▪. Kurkjian CJ, Guo H, Montgomery ND, et al. The Toll-like receptor 2/6 agonist, FSL-1 lipopeptide, therapeutically mitigates acute radiation syndrome. Sci Rep 2017; 7:17355.

Shows a potential new therapeutic approach that utilizes TLR agonist to mitigate radition-associated loss of hematopoietic function.

65▪. Lee YK, Kang M, Choi EY. TLR/MyD88-mediated innate immunity in intestinal graft-versus-host disease. Immune Netw 2017; 17:144–151.

TLRs are being shown to play a big role in graft-versus-host disease leading many people to propose the use of TLR agonists or antagonists to regulate disease progression and/or severity.

66▪. Ranganathan P, Ngankeu A, Zitzer NC, et al. Serum miR-29a is upregulated in acute graft-versus-host disease and activates dendritic cells through TLR binding. J Immunol 2017; 198:2500–2512.

TLRs are being shown to play a big role in graft-versus-host disease leading many people to propose the use of TLR agonists or antagonists to regulate disease progression and/or severity.

67▪. Zitzer NC, Garzon R, Ranganathan P. Toll-like receptor stimulation by microRNAs in acute graft-vs.-host disease. Front Immunol 2018; 9:2561.

TLRs are being shown to play a big role in graft-versus-host disease leading many people to propose the use of TLR agonists or antagonists to regulate disease progression and/or severity.

68▪. Zogas N, Karponi G, Iordanidis F, et al. The ex vivo toll-like receptor 7 tolerance induction in donor lymphocytes prevents murine acute graft-versus-host disease. Cytotherapy 2018; 20:149–164.

TLRs are being shown to play a big role in graft-versus-host disease leading many people to propose the use of TLR agonists or antagonists to regulate disease progression and/or severity.


hematopoiesis; infection; inflammation; Toll-like receptor

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.