In recent years, the incidence of systematic severe infection in intensive care units (ICUs) has increased significantly. Sepsis is a complex, multifactorial syndrome that can develop into conditions of different severity, described as severe sepsis or septic shock.1 The immunology of severe sepsis and septic shock is poorly defined, despite many studies investigating the pathogenesis of this syndrome. With mortality rates of up to 50%,2,3 greater understanding of the interactions between host and microbe is necessary to improve patient outcome. Given the rapid progression of sepsis and immediate recruitment of the inflammatory cytokine cascade, the early innate response of the immune system to the pathogen is likely to play a critical role.4
The innate immune system possesses many, germ line encoded, receptors that recognize structural components conserved among classes of microorganisms, also known as pathogen associated molecular patterns (PAMPs).5 PAMP recognition involves a well characterized family of pattern recognition receptors designated as Toll like receptors (TLRs).6 Mammalian TLRs are a family of proteins that share sequence similarity with the Drosophila Toll receptor proteins.7 A family of 11 mammalian Toll like receptors (TLRs 1–11) has been identified to date, each recognizing specific, highly conserved structures present on infectious microorganisms. TLRs control the activation of innate immunity through the induction of antimicrobial activity and the production of inflammatory cytokines. TLRs control the generation of adaptive immunity through the induction of antigen presenting (major histocompatibility complex, MHC, class II) and costimulatory molecules (CD80/86) and specific cytokines (IL-6) on antigen presenting cells (APCs).8
Microbes, microbial products and pharmaceuticals that are ligands for TLR2, 3, 4, 5, 6, 7 and 9 have been identified.9–11 Ligands for TLR1, 2 and 6 are Gram positive bacteria and yeast cell wall components, while the predominant Gram negative bacterial product, lipopolysaccharide (LPS), is a ligand for TLR4, which is expressed on monocytes/macrophages, airway epithelia and endothelial and smooth muscle cells. TL4 appears to be unique among the TLR proteins in that it uses two additional proteins, CD14 and MD-2 (a molecule that confers LPS responsiveness on TLR4), as coreceptors. Cells that express TLR4, but lack these coreceptors fail to be activated by most TLR4 agonists.12–14 Recently, TLR4 was reported to interact with other endogenous ligands such as high mobility group box 1(HMGB-1),15 neutrophil elastase16,17 and fibrinogen.18 Recent reports have also documented that dsRNA (poly I:C), bacterial flagellin, single stranded RNA and CpG oligodeoxynucleotides are ligands for TLR3, 5, 7 and 9 respectively (Fig. 1). The interaction between a TLR and its ligand results in the secretion of antibacterial peptides, defensins and proinflammatory cytokines such as TNF-α and IL-6, which initiate an inflammatory response to clear the invading organism.
Recent studies indicate the emerging role for TLRs in the pathogenesis of diseases. First, there is now substantial evidence that the mediators and effectors of innate immune response including proinflammatory cytokines, NO and chemokines are expressed in the adult mammalian heart by cardiac myocytes in response to challenge by PAMPs, such as LPS and viral particles.19 The heart expresses at least four pattern recognition receptors for PAMPs, namely, CD 14, TLR2, TLR4 and TLR6. It is suggested that TLR4 activates downstream signalling pathways that are responsible for mediating LPS induced, left ventricular dysfunction. Thus, a dysregulated, innate immune response within the heart may significantly contribute to the pathophysiology of sepsis induced, myocardial dysfunction.20 Second, danger recognition via TLR signalling in response to infectious and noninfectious cellular damage may also be involved in renal disease. Some data strongly implicates a systemic response to sepsis, involving TLR4 and TNF-α in the development of acute renal failure during sepsis.21 Initial studies suggest that TLR2 and TLR4 can induce chemokine expression by tubular epithelial cells and that TLR9 is expressed on infiltrating antigen presenting cell (APC) during immune injury.22 Third, pattern recognition receptors of the innate immune system are not only important in the development of mucosal inflammation in inflammatory bowel diseases (TLR4), but also seem to drive colonic inflammation. A deficient innate immune response to bacteria caused by variants of TLR1, TLR2 and TLR6 results in more extensive disease localization in ulcerative colitis and in colonic disease in Crohn's disease.23 Besides, recognition of other pathogens requires TLR mediated signals. For instance, sensing of cryptococcus by the innate immune system requires TLR2, TLR4, MyD88 and CD14,24 while TLR2 and TLR4 are instrumental in the host's response against mycobacteria.25 Chlamydia elicits an unusual set of inflammatory responses via TLR2 and TLR4 in vivo and TLR2 is essential for development of oviduct pathology in chlamydial genital tract infection,26 while Neisseria gonorrhoea stimulates cytokine release and NF-κB activation in epithelial cells in a TLR2 dependent manner.27 Some researches also demonstrated that TLR2 and TLR4 were expressed in liver cirrhosis28 and TLR3 in primary biliary cirrhosis.29 TLRs were discovered relatively recently and their involvement in health and diseases remains a new and exciting field of study.
ROLE OF TOLL LIKE RECEPTORS AND CYTOKINES IN SEPSIS
The immune system has traditionally been divided into innate and adaptive components, each of which has a different role and function in defending the host against infectious agents. The innate immune response is a preprogrammed, nonspecific first line of defense that is primarily responsible for eliminating and/or containing pathogens at the site of entrance into the host.
It is found that infection due to Gram negative organisms is an important cause of sepsis and septic shock. CD14 and TLR4 are part of the LPS recognition/response pathway. The CD14 receptor of monocytes is an important mediator for the activation of monocytes and macrophages by Gram negative bacterial endotoxin. Enzymatic cleavage of membrane associated with CD14 releases a soluble CD14 (sCD14) fragment, which can bind circulating endotoxin, thereby reducing biological activity. Membrane bound CD14 enhances endotoxin initiated, signal transduction, which is mediated through TLR4.30 The TLR4 mediated signalling pathway is known to be critical for the induction of IL-1, IL-8, and IL-18 that results in the activation of NF-κB and mitogen activated protein (MAP) kinase.31,32 On the other hand, TLR2, a signalling receptor, also responds to endotoxin and activates NF-κB. TLR2 binds to CD14 to serve as an endotoxin receptor complex. IL-1 receptor associated kinase is recruited to the TLR2 complex.33 The identification of CD14 — TLR4 complex has provided significant insight into the mammalian innate immune response. However, the body's answer to a serious infection is likely to involve coordinated mechanisms from both the innate and adaptive immune systems. The role of CD14—TLR4 signalling in the complete in vivo picture of bacterial sepsis, therefore, remains to be determined.
During Gram negative bacterial infection, activation of blood monocytes and tissue macrophages occurs, likely through LPS mediated TLR4 receptor signalling. Andonegui et al34 reported that expression of TLR4, particularly on endothelial cells played an important role in the neutrophil recruitment into the lungs following endotoxin administration. Tsujimoto et al35 demonstrated that TLR4 expression on peripheral blood monocytes was significantly increased in patients with sepsis. The study suggested that endogenous neutrophil derived, neutrophil elastase (NE) as well as exogenous mediators might contribute to the changes in monocytic TLR4 expression and perhaps to the responsiveness of these cells to inflammatory signals. Inhibition of NE might prevent organ injury in sepsis not only by directly inhibiting NE activity but also by suppressing the further induction of chemokines induced by LPS through TLR4 receptor signalling.
Gram positive bacteria may induce a septic response by a number of cellular components including peptidoglycans, teichoic acids, exotoxins and superantigens. It had been previously thought that Gram positive PAMP molecules were recognized solely by TLR2 and TLR6.36,37 However, subsequent study has revealed that not only is TLR4 a necessary receptor for the innate immune response to LPS, but also critical in the response to staphylococcal enterotoxin B (SEB), an antigen previously thought to act primarily via the T-cell receptor β-chain and MHC class II receptor. Rather than serving as the sole receptor for SEB, TLR4 may function in a cooperative role with other cellular surface receptors to initiate a complete response to SEB.38
Upon bonding of PAMPs, TLR mediated intracellular signalling continues through a cytoplasmic Toll/IL-1R (TIR) domain containing adaptor, MyD88.39 MyD88 contains a death domain, so named because it was first identified in proteins involved in the regulation of programmed cell death, or apoptosis. The death domain of MyD88 includes family of IL-1 receptor associated kinases (IRAK). IRAK phosphorylation causes it to dissociate from the MyD88-TLR complex and instead bind to tumour necrosis receptor associated factor 6, which in turn activates various stress kinases, particularly members of the mitogen activated, protein kinase family as well as NF-κB. The result is transcription of genes leading to the development of an inflammatory response.40 Recent studies have indicated that both TLR4 deficient and MyD88 deficient mice are resistant to LPS induced septic shock. Thus, the TLR4 mediated MyD88 dependent pathways play an essential role in LPS induced septic shock. In addition to the MyD88 dependent pathways, accumulating evidence suggests that the TLR4 mediated MyD88 independent pathway leading to IFN-β expression may be implicated in LPS induced lethality. Moreover, the MyD88 independent IFN-β induction as well as proinflammatory cytokines may also be essential effectors.41 MyD88 is involved in most TLR mediated signalling pathways42 although the MyD88 independent pathways are shared by TLR3 and TLR4. Hence, these different roles of MyD88 and Toll/IL-1 receptor domain containing adaptor inducing IFN-beta (TRIF) and TIR domain containing adaptor molecule, in TLR4 mediated immune responses point to TRIF as a target for antisepsis drug development (Fig. 2).43
Acute lung injury and acute respiratory distress syndrome are complications of sepsis leading to significant morbidity and mortality. A large number of septic patients who develop pulmonary dysfunction have a proven bacterial infection.44 In the lungs, where gene expression for TLR2 and TLR4 increased, immunohistochemistry revealed a change in the spatial distribution of these receptors with increased detection of TLR2 on pulmonary endothelial cells and increased detection of TLR4 on airway epithelial cells. The increased expression of TLR2 and TLR4 could play an important role in the innate immune response to bacterial infection in the lungs and improve pathogen recognition and bacterial clearance. In contrast, in organs distal to the primary site of infection, there was a significant increase of TLR4/MD2 expression in the bone marrow and kidney, an obvious increase in the expression of TLR2 and TLR4 in the spleen and an increased expression of TLR2 in the liver. Because the CD14/TLR4/MD2 complex is important in the recognition of LPS, the increased gene expression of TLR4 and MD2 in distant organs may contribute to the deleterious systemic inflammatory response in Gram negative sepsis. Although TLR2 is a recognition pathway for Gram positive bacteria, it has been shown to recognize lipoproteins on Gram negative bacteria. The increased expression of TLR2 with or without an increased expression of TLR4 may also contribute to deleterious systemic inflammation in Gram negative sepsis.45
TLR5 specifically detects bacterial flagellin (Flg), the major protein component of the flagella from Gram negative and Gram positive motile bacteria.46 TLR5 is expressed on epithelial cells, immature dendritic cells, natural killer cells, T cells and monocytes.47 Our data relate TLR5 binding by Flg to protective or pathological functions of IL-18 in host defence or inflammation respectively. Upregulation of IL-18 has been associated with a broad array of acute and chronic inflammatory conditions, including sepsis.48,49 Sufficient concentrations of Flg greatly enhance release of mat-IL-18 and prototype Th1 like cytokines such as IFN-γ and interferon inducible protein-10 (IP-10) from human peripheral blood mononuclear cell (PBMC). These observations indicate that under certain conditions TLR5 may significantly contribute to immune defence against infections and to the pathogenesis of acute and chronic inflammation associated with infection by motile bacteria.50
DIFFERENTIAL EXPRESSION RELATED TO AGE
Decline in immune function is a hallmark of aging, leading to increased susceptibility of elderly individuals to bacterial infections. As the thymus atrophies with age, there are fewer naive T cells available to respond to new pathogens and neoantigens. Similar to the decline in adaptive immune function, the functions of NK cells, macrophages and neutrophils; crucial cellular components of innate immunity, are decreased with aging.51,52 A recent study53 indicated that TLRs are differentially expressed on splenic and thioglycollate elicited macrophages and the expression declines with aging. The maximum decline was in TLR9 expression when compared with young mice. Translation efficiency differences, mRNA stability, signal transduction defects and other factors may also contribute to differences in surface expression and function.53 Alveolar or peritoneal resident or thioglycollate induced macrophages and monocytes from aged mice and rats secrete low levels of IL-6 consistent with the earlier observation.54 In addition, TNF-α enhances class I and class II MHC expressions and decreased levels in aging could affect antigen processing, thus affecting T cell responses.55 Reduced TNF-α level in aging may also contribute to reduced phagocytic activity, reduced NO, reduced tumour cell killing and delayed tissue repair process. Nevertheless, Boehmer et al56 presented evidence that macrophage TLR2 and TLR4 mediated signalling is defective with advanced age at the level of p38 expression and is not due to changes in receptor expression. Macrophage IL2R mediated signalling through NF-κB is not altered with age. The common inflammatory responses noted in aged cohorts are correlated with defective signalling through pathways that recognize foreign organisms.56
On the other hand, the differences in the course of neonatal and adult sepsis might be molecular mechanisms involved in the initiation process of systemic inflammatory response syndromes, i.e. the activation of innate immune cells through invading microbes. Viemann et al57 revealed that in healthy individuals, TLR2 is significantly but rather little lower expressed on neonatal granulocytes and monocytes compared with adult phagocytes, whereas the expression levels of TLR4 are comparable. Others showed the basal expressions of TLR2 and TLR4 were similar in neonatal and adult monocytes at the mRNA and/or protein level.58 The difference in data might be due to the blood samples collected from different locations. Moreover, TLR2 was differentially regulated in the course of neonatal sepsis, with a rapid and constant high expression on monocytes but only transient upregulation on granulocytes. However, adults showed no changes in the expression of TLR2 on granulocytes, supporting the hypothesis of a severer inflammatory state in neonatal sepsis.59
Interestingly, severe acute respiratory syndrome (SARS) which wreaked havoc in China, South East Asia and other parts of the world in 2003 appears to be a disease that predominantly affects adults. Less than 10% of those infected were children. Among the affected children, only 5% required admission to an intensive care unit and less than 1% required mechanical ventilation. No deaths were reported among the children affected by SARS.60 SARS is caused by a single stranded RNA, coronavirus (SARS-CoV). On the other hand, TLR7, a key receptor in the innate immune response, recognizes viral genomic nucleic acids, specifically single stranded RNA. Furthermore, activation of TLR7 has been implicated as a contributing factor to autoimmune diseases. Ng et al61 suggest that the coronavirus is unlikely to be transferred via the intrauterine route and none of the newborn infants shed the virus or developed SARS-CoV infection. There was marked elevation of circulating interleukin (IL)-1β levels suggesting selective caspase-1 dependent pathway activation in infected macrophages. Yet, IL-6 and TNF-α were only mildly raised in the acute phase of SARS.62 In addition, their data suggest that other chemokines, IFN-γ-inducible protein-10 (IP-10) and monokine induced by interferon-γ, were substantially elevated soon after the onset of fever. The activation of predominant type 1 T-helper lymphocyte mediated immune response facilitates viral clearance and may explain the rapid recovery of the paediatric cases.63 Some studies highlighted that although TLR3, which recognizes dsRNA, may not be required for viral clearance, it is necessary to maintain the proper immune environment in the lung to avoid developing pathological symptoms of disease.64 However, no studies have investigated possible connections between TLRs and cytokines in different cohorts. Therefore, the different mechanisms of TLRs mediated signal pathways in children and adults still remains undetermined.
Bacterial sepsis and its associated systemic inflammation remain a major cause of morbidity and mortality in the intensive care unit. The identification of TLRs has provided significant insight into the mammalian innate immune response. TLRs, along with some cytokines mediated by TLRs, not only play critical roles in pathogenic recognition and representation but contribute to deleterious systemic inflammation as well. Additionally, impaired Toll like receptor expression and function in aged individuals has been elucidated. However, the different mechanisms of TLRs mediated signal pathways in children and adults remains unanswered. Continuing work on the definition of TLR expression patterns might open a new field of therapeutic targets for sepsis.
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