Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

TLR5 (Toll-Like Receptor 5)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_639

Synonyms

Historical Background

Toll-like receptors (TLRs) are innate immune receptors that play an important role during infections and diseases. Upon recognition of specific microbe-associated molecular patterns (MAMPs) or self molecules, TLRs initiate signaling cascade that result in the production of pro-inflammatory cytokines, upregulation of co-stimulatory molecules, and molecules necessary for cross-priming of T-cell-dependent immune responses. TLR5 was first reported in humans (Rock et al. 1998), and its location was mapped on chromosome 1. Later in the year 2000, mouse TLR5 was identified and characterized using gene cloning approach (Sebastiani et al. 2000). Hayashi et al., in 2001, showed that innate immune response to bacterial flagellin is mediated through TLR5 (Hayashi et al. 2001). TLR5 recognizes monomeric form of flagella as its ligand and initiates signaling program leading to the activation of several transcription factors and pro-inflammatory genes. Recently, it has been shown that TLR5 not only controls immune response to bacterial infection but also regulates immune response to cancer, metabolic syndromes, or aging process. Therefore, complete understanding of TLR5 will not only help in preventing diseases or infections but will also help in developing vaccines that will impart long-lasting memory immune responses irrespective of age.

Introduction

The presence of pattern recognition receptors on the cell surface and in the cytosol allows the host to sense variety of microbial ligands ranging from proteins, lipopolysaccharides, to nucleic acids. Once these ligands are recognized and bound to their cognate receptors, it results in the receptor dimerization and initiation of downstream signaling (Janeway and Medzhitov 2002; Kawai and Akira 2010). Among all the known TLRs, only TLR3 utilizes TRIF (TIR-domain-containing adapter-inducing interferon-β) as their downstream adaptor molecule, and TLR4 uses both TRIF and MyD88 (myeloid differentiation primary response) for initiating signaling cascade.

In the case of TLR5, conventional signaling utilizes MyD88 as an adaptor molecule, and in the absence of MyD88, TLR5 could regulate adaptive immune response by interacting with non-conventional adaptor molecules, viz., syk (spleen tyrosine kinase) and CARD9 (Letran et al. 2011b; Atif et al. 2014, 2015). However, the presence of alternative signaling or adaptor molecules that could play an important role in the absence of these known adapter/s is not very well dissected. During bacterial infection, MyD88 dependent TLR5 responses showed immense potential of controlling infection by sensing virulent fl agellin (Hayashi et al. 2001).

Flagellin binding to TLR5 allows stable interaction between amino acids present in the D1 domain of flagellin and (174–401) region of solenoidal structure encoded by multiple LRRs (leucine-rich repeats) within the extracellular domain of TLR5 (Andersen-Nissen et al. 2007). This receptor ligand engagement allows TLR5 dimerization and leading to the recruitment of downstream adaptor molecule MyD88 via their TIR domain. The interaction between cytosolic domains of TLR5 and death domain of MyD88 allows the recruitment of various, IRAK (IL-1 receptor associated kinases, 1–4), which then interacts with other downstream kinases (TBK1 and IKKε) to recruit and activate ubiquitin ligases (pellino1 and TRAF6). TRAF6 upon modification by K63-linked autoubiquitylation allows the engagement of Ikk with TRAF6 via NEMO (ubiquitin-binding domain of the IKKγ) subunit. Further, ubiquitylated TRAF6 also engages TAB1/TAB2, causing activation of TAK1 kinase, which then phosphorylates the IKKβ subunit. IKKβ, IKKγ, and IKKα together activate and induce ubiquitination of IkBα, leading to the release of NF-κB that allows it to translocate into the nucleus and to promote the transcription of various inflammatory molecules. On the other hand, TRAF6 can directly activate MEKK1 to initiate phosphorylation of MKK3/MKK6 or can induce via TBK1, where the signaling culminates in activating p38MAPK. TAK1 can also phosphorylate MKK4/MKK7 to activate JNK. Both p38MAPK and JNK kinase-dependent signaling activate transcription factors in the nucleus, resulting in the production of pro-inflammatory cytokines and activation of transcription factors as illustrated in Fig. 1.
TLR5 (Toll-Like Receptor 5), Fig. 1

MyD88 dependent and independent TLR5 signaling pathways involved in pro-inflammatory responses and antigen presentation

TLR5 Expression in Mouse and Human Tissues

Toll-like receptor 5 is a type-I transmembrane glycoprotein consisting of three domains, extracellular hydrophobic domain for ligand binding, transmembrane domain for homo- or heterotypic interaction that allows dimerization with same or different TLRs, and an intracellular cytosolic domain that consists of TIR domain for initiating downstream signaling cascade by recruiting various adapter molecules (Fig. 2). Based on Immgen (immunological genome consortium, NIH) data, RNA seq, and RT PCR analysis, RNA transcript for TLR5 is present in many immune cell types including dendritic cells, monocytes, and macrophages. However, little is known about the expression of TLR5 on other myeloid cell population and their role in controlling immune responses. After careful examining the expression of TLR5 in specific population of myeloid cells, we have reported the differential expression of TLR5 in CD11b+ or CD8a+ DCs in the spleen or CD11b or CD103 DCs in non-lymphoid tissue (Atif et al. 2014). However, initial work of Uematsu et al. has limited the TLR5 expression to the gut DCs (Uematsu et al. 2007).
TLR5 (Toll-Like Receptor 5), Fig. 2

Schematic diagram of various domains of TLR5 and illustrating their function

In humans, TLR5 is expressed in almost each and every tissue with variable expression. The heart, colon, and brain showed very low expression, whereas the ovary, lung, peripheral blood leukocytes, prostate gland, and pancreas showed very high expression of TLR5. On the other hand, the spleen, placenta, and testis have moderate expression of TLR5 (Zarember and Godowski 2002) as shown in Table 1. In mouse tissue, TLR5 is highly expressed in the lung and liver, while moderate to low expression is observed in the gut, spleen, and kidney.
TLR5 (Toll-Like Receptor 5), Table 1

Comparative expression of TLR5 in various tissues of human and mice. High expression (+++++), medium (++) and low expression (+) of TLR5. NA information not available

Tissues/cells

Human

Mouse

Lung

+++++

+++++

Liver

+++++

+++++

Pancreas

+++++

NA

PBL (Peripheral blood leukocytes)

+++++

++

Ovary

+++++

NA

Testis

++

NA

Spleen

++

++/+

Placenta

++

NA

Heart

+

NA

Brain

+

++/+

Colon

+

++

Gut

NA

++

Kidney

NA

++/+

Adjuvant Effects of TLR5

TLR5 act as a strong adjuvant for flagellin-specific B- and T-cell responses (Mcsorley et al. 2002). After sensing flagellin molecules, TLR5 has been shown to enhance both CD4+ and CD8+T-cell responses (Mcsorley et al. 2002; Letran et al. 2011b; Atif et al. 2014; O’Donnell et al. 2014). At low concentration of flagellin, flagellin-specific CD4+T cell makes IFNγ and other Th1 cytokines in vitro (Atif et al. 2015). However, in contrast to in vitro findings, mice immunized with soluble flagellin (sFliC) showed the development of Th2 immune responses and is not limited to flagellin, as immune responses to antigens administered along with flagellin also induced Th2 immune response (Flores-Langarica et al. 2015). In a recent study by Oh et al., it was shown that TLR5-deficient animals have reduced antibody responses to trivalent inactivated influenza vaccine (TIV) and is more pronounced during early time points after immunization from their littermate wild-type control mice. This difference in antibody response is also shown to be dependent on the gut microbiota as mice treated with antibiotics showed similar trend of reduced antibody responses. However, when antibiotic treated or germ-free mice were reconstituted with flagellin-expressing E. coli strain, the antibody responses were restored to normal (Oh et al. 2014). Further, in the same study, DCs lacking MyD88 has only marginal effect on antibody production.

Thus, TLR5-enhanced adaptive immune response can occur in both MyD88-dependent and MyD88-independent fashion. In general, MyD88-dependent pathway is involved in rapid immune responses by activating several transcription factors, providing co-stimulatory signals, and induced secretion of cytokines or chemokines (Atif et al. 2015) within hours of recognition of flagellin molecules.

However, in the absence of MyD88, TLR5 utilizes an alternative pathway to promote flagellin-specific CD4+ T-cell responses, which is partially dependent on spleen tyrosine kinase. Syk and CARD9 are adaptor molecules that are known to regulate C-type lectin receptor (CLR)-mediated immune responses to fungal molecules (Kaden et al. 2009). In comparison to the deficiency of syk in dendritic cells, in vitro experiments performed with CARD9-deficient DCs showed further dampening of immune response to flagellin, which is present downstream of syk, indicating several possible ways of involvement of unknown adaptor molecules in the process of uptake or processing of antigen (Fig. 3ac), and a more central role for CARD9 in regulating TLR-mediated immune responses (Atif et al. 2015). However, the possible effect of syk or CARD9 signaling in MyD88-independent B-cell immune responses is not examined. Further, MyD88-independent immune responses to flagellin have led us to speculate that any antigen, if conjugated to a TLR ligand, may be able to preferentially enhance subsequent antigen-specific T-cell responses in a process that is fundamentally distinct from the well-described adjuvant effects of TLR ligands.
TLR5 (Toll-Like Receptor 5), Fig. 3

Proposed model for Syk and CARD9 involvement in TLR5-mediated flagellin antigen presentation. DCs expressing TLR5 can engage a noncanonical pathway via Syk and CARD9 to enhance flagellin-specific T-cell activation. This may be the result of (a) direct signals via TLR5 to the Syk and CARD9 pathway to enhance flagellin processing and MHC class II loading during maturation of the phagosome/lysosome. This enhanced processing results in enhanced TCR ligation, upregulation of IL-2 production, and subsequent T-cell clonal expansion. (b, c) Alternatively, either (b) a Syk/CARD9 pathway may enhance flagellin processing downstream of a TLR5 coreceptor, or (c) Syk and CARD9 activation occurs during flagellin processing in the phago/lysosome, following Syk-independent, TLR5-mediated uptake of flagellin

TLR5 in Cancer

Cancer is a debilitating disease that results in large number of mortality worldwide. Here we discuss the possible involvement of PRR signaling in the progression of cancer. How does PRR signaling affects the cancer is an active area of research? Recent advancement in the field of tumor immunology is focused on targeting PRRs for improved immune responses against tumor. Adjuvanticity through PRRs resulted in enhanced T- and B-cell responses, which could eliminate potential tumors from spreading by improving their clearance or by inducing a potent cytotoxic T-cell response against them. So far among known TLR agonists, TLR7 ligand (Imiquimod) is approved clinically for only treating basal cell carcinoma because of its topical application (Stanley 2002). Since TLR7 expression is more ubiquitous compared to TLR5, which rendered it to be not very safe as uncontrolled TLR stimulation could lead to harmful effects. Therefore use of TLR5, as an adjuvant, is safer because of its restricted expression in the lung, liver, gut, bladder, spleen, and brain, and targeting it for boosting systemic anticancer immunity is of great use as it is unique among known TLRs. TLR5-mediated therapy using entolimod as agonist showed great improvement in the mouse models of liver metastases by reducing the tumor size and enhanced survival time and imparting long-term memory immune responses against secondary tumors (Burdelya et al. 2013).

However, a recent work by Rutkowski et al. showed that nonfunctional TLR5 protects against the progression of cancer in human patients (Rutkowski et al. 2015). This protective role of TLR5 lies in the sequence containing dominant mutation at 392 residues, which results in truncating the transmembrane signaling domain of TLR5, thus abrogating downstream signaling greatly, even for individuals who are heterozygous for this allele. This polymorphism has immunological consequences because heterozygous carriers have an enhanced susceptibility to Legionnaires disease (Hawn et al. 2003), urinary tract infections (Hawn et al. 2009), and bronchopulmonary dysplasia (Sampath et al. 2012). Further, study on mouse models showed that gut microbiota can promote tumor progression in mice, which results from systemic inflammation, and it is related to increased levels of IL-6 in the serum of tumor-bearing WT mice compared to TLR5-deficient mice. Increased IL-6 was responsible for the recruitment of myeloid-derived suppressor T cells (MDSCs), which are responsible for blocking the development of effector CD8+T-cell responses in WT mice (Rutkowski et al. 2015).

TLR5 in Autoimmunity

Rheumatoid arthritis (RA), a chronic autoimmune disease, results from recognition of endogenous ligand by pattern recognition receptors (Chamberlain et al. 2012). TLR2 and TLR4 are upregulated during RA on peripheral blood monocytes and synovial tissue macrophages. Similar to other TLRs, TLR5 has recently been shown to play an important role during RA and osteoarthritis (OA). Like TLR4, TLR5 expression is also elevated on synovial fluid macrophages, synovial tissue lining macrophages, and epithelial cells. Increased expression of TLR5 is correlated with increased TNFα production in the patients suffering from RA, as blocking of TLR5 on RA monocytes results in decreased levels of TNFα. TNFα, once increased in the synovial fluid, enhances TLR5 expression on the monocytes unless they get differentiated to macrophages (Chamberlain et al. 2012), which shows that there is an existence of feedback mechanism between TNFα production and TLR5 expression.

However, TLR5-mediated signaling is critical for the development of collagen-induced arthritis or osteoarthritis where the ligation of TLR5 to its ligand results in the production of pro-inflammatory cytokines by recruited monocytes and synovial joint macrophages (Kassem et al. 2015). Further, it was shown that TLR5 agonist, flagellin, can dose-dependently promote monocyte migration and osteoclast maturation through its direct effect on myeloid cell function and indirectly via TNFα production from RA and mouse myeloid cells or collagen-induced arthritis (CIA) ankle joints (Kim et al. 2014).

TLR5 in Metabolic Syndrome and IBD

TLR5-dependent signaling is involved in maintaining both gut and mucosal homeostasis; however, in certain circumstances, this signaling is associated with harmful effects. The role of TLR5 in metabolic syndrome is a bit controversial in murine model, as not all the mice lacking TLR5 showed dysbiosis and development of metabolic syndrome (Vijay-Kumar et al. 2010; Letran et al. 2011a). Since metabolic syndrome associated with TLR5 is not found in the mouse colonies of several other labs clearly suggests that the phenomenon observed by Kumar et al. was an acquired phenotype specific to a particular housing facility. Recently the same group reported that the development of spontaneous colitis in TLR5-deficient mice is because of the presence of Proteobacteria, which was absent in non-colitogenic TLR5-deficient mice (Singh et al. 2015), thus raising concern about their mouse colony.

TLR5-associated innate and adaptive immune responses are involved in inflammatory bowel disease, which is characterized by deregulated intestinal inflammation. However, it is not clear of how TLR5 protects or exposes the host to inflammatory bowel disease, which needs further investigation. It is a general assumption that hyper-reactivity to flagellin results in IBD, but during DSS (dextran sulfate sodium)-induced colitis in WT- or TLR5-deficient mice, no difference was observed in the exacerbation of disease. In another study, role of TLR5 on CD4+T cells was examined in IBD disease model. CD4+T cells not only protect host during infections by acquiring effector functions but also are actively involved in maintaining homeostasis via developing into T regulatory cells (Tregs). In a study by Hardenberg et al., it was observed that effector CD4+T cells from WT- or TLR5-deficient mice can induce colitis and Treg from WT- or TLR5-deficient mice can reverse it. Overall the study concludes that TLR5 expression on T cells neither promotes nor protects from colitis (Hardenberg et al. 2012).

TLR5 in Aging

Aging affects wide variety of cellular processes and brings changes in cell numbers, including functional response to internal or external stimuli. The environmental factors play an important role in governing the function of an immune system with age. It has been noted that with age, there is an increase in pro-inflammatory mediators leading to the development of a condition called as inflamm-aging (Franceschi et al. 2000). Understanding the immune system in older people will help in targeting specific molecules for therapeutic use as age-associated decline in the function of immune system rendered the individuals more susceptible to infections. In old age, the improper function of neutrophil and macrophages is attributed more toward their inability to make functional molecules (reactive oxygen and nitrogen intermediates) that are involved in protecting the host against microbial invasion. The professional antigen-presenting cells also showed to be less responsive in their ability to prime adaptive immune cells. Similarly, aged NKT cells are also found to be less effective functionally (Plackett et al. 2004).

Among PRRs in aged cells, it has been found that TLR5 expression is maintained on immune cells with age and is directly controlled by the expression of caveolin-1. Caveolin-1 is a structural protein with specialized membrane micro-domains. It regulates various physiological processes, especially cellular senescence through direct binding with growth factors (Cho et al. 2003). Caveolin-1 inhibits TLR5-mediated signaling by preventing translocation of NF-κβ transcription factor and thereby abrogates pro-inflammatory signaling. Therefore caveolin-1/TLR5 axis can be targeted for future vaccines as they not only control their expression but also signaling pathways that lead to the secretion of pro-inflammatory molecules an important determinant of successful vaccines (Lim et al. 2015).

Conclusion

Toll-like receptor 5 is an endocytic receptor, which can maintain innate and adaptive immune responses to flagellin in the absence or presence of its known adaptor molecule, MyD88. Because of its location on the basolateral or apical surface in the intestine, it maintains homeostasis and protects from dysbiosis. TLR5 is stably expressed in cells and tissues irrespective of age than compared to other TLRs, so it could be used as a potential therapeutic target for developing vaccines in elderly candidates. Therefore, better understanding of TLR5 will help in exploring unknown signaling pathways and function of adaptor molecules involved in various immunological process (Fig. 4).
TLR5 (Toll-Like Receptor 5), Fig. 4

Schematic diagram shows the involvement of TLR5 in various immunological processes

Notes

Acknowledgment

I thank Prof. Stephen McSorley and Prof. Sangdun Choi for giving me this wonderful opportunity to contribute this book chapter in the second edition of encyclopedia of signaling molecules.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of PediatricsNational Jewish HealthDenverUSA