Toll-like receptor 5, also known asTLR5, is aprotein which in humans is encoded by theTLR5gene.[5] It is a member of thetoll-like receptor (TLR) family. TLR5 is known to recognize bacterialflagellin from invading mobile bacteria.[6] It has been shown to be involved in the onset of many diseases, includingInflammatory bowel disease due to the high expression of TLR in intestinal lamina propria dendritic cells.[7][8] Recent studies have also shown that malfunctioning of TLR5 is likely related to rheumatoid arthritis,[9][10] osteoclastogenesis, and bone loss.[11] Abnormal TLR5 functioning is related to the onset ofgastric,cervical,endometrial andovarian cancers.[12][13]
The TLR family plays a fundamental role in pathogen recognition and activation ofinnate immunity. TLRs are highly conserved fromDrosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. TLR5 is expressed on both immune and non-immune cells.[14] TLR5 recognizes bacterialflagellin, a principal component of bacterial flagella and a virulence factor. The activation of this receptor mobilizes the nuclear factorNF-κB and stimulatestumor necrosis factor-alpha production.[15]
TLR5 recognizes bacterial flagellin,[16] the protein monomer of bacterial flagella and a virulence factor. Flagellin are found on nearly all motile bacteria and contains regions that are highly conserved among all bacteria, facilitating the recognition of flagellin by a germ-line encoded receptor such as TLR5. The activation of this receptor mobilizes the nuclear factorNF-κB and stimulatestumor necrosis factor-alpha production.[17] However, some Proteobacteria flagella have acquired mutations preventing their recognition by TLR5.[18]
The TLR5 signaling cascade is commonly triggered by the binding of bacterialflagellum to TLR5 on the cell surface. Binding of flagellum induces the dimerization of TLR5, which in turn recruitsMyD88 and Mal/TIRAP.[19][20][21] The recruitment of MyD88 leads to subsequent activation ofIRAK4,IRAK1,TRAF6, and eventually IκB kinases.[22][23] Activation of IκB kinases contributes to the nuclear localization ofNF-κB (a proinflammatory cytokine).NF-κB induces many downstream gene expressions, which initiates the canonical proinflammatory pathway. This TLR5/flagellum interaction results in different responses in difference cell types. In epithelial cells, binding of flagellum to TLR5 inducesIL8 production. In human monocytes and dendritic cells, this interaction results in the secretion of proinflammatory cytokines such asTNF.[6]
Recent study has identifiedCaveolin-1 as a potential regulator of TLR5 expression.[24] In contrast to the decreasedTLR4 level in senescent cells, TLR5 expression maintains relatively stable during the aging process, which is correlated with the high level of Caveolin-1 in aging cells. Data from Caveolin-1 knockout mice demonstrated that TLR5 expression significantly decreases in the absence of Caveolin-1 expression in aging cells.[24] It is hypothesized that the Caveolin-1 directly interacts with TLR5 to stabilize it and hence increases the level of TLR5.
TLR5 may play a role ininflammatory bowel disease (IBD), since TLR5 expression on intestinal epithelial cells (IEC's) are important for maintaining the composition of intestinal microbiota.[25] Additionally, TLR5-deficient mice develop spontaneous colitis[26] and metabolic syndrome which are associated with altered gut microbiota.[27]Statistically significant lower levels of TLR5 expression have been found in patients exhibiting moderate to severeulcerative colitis (UC). In these patients, lower TLR5 mRNA levels were found along with decreased immunoreactivity of TLR5 in the inflamed mucosa of UC patients.[7]
Bone loss and osteoclastogenesis are induced by inflammation in infectious and autoimmune diseases.[11] A recent study has identified TLR5 as a novel mediator in the process of inflammation-induced bone loss and osteoclastogenesis.Flagellin, which is a TLR5-activating ligand, is present insynovial fluid from patients withrheumatoid arthritis. Activation of TLR5 in these patients leads to subsequent activation ofreceptor activator of NF-κB ligand (RANKL). Activation of RANKL leads to increased expression of osteoclastic genes. Activation of these genes results in robustosteoclast formation and bone loss.[11] This process is absent in TLR5 knockout mice model.[11]
Chronic inflammation in GI tract has been known to increase the risk of gastric cancer, withH. pylori being one of the most common resources of infection.[12] TLR5 is an essential factor in inducing inflammatory response toH. pylori infection. During infection, expression and ligation of TLR5 andTLR2 are required for the activation of proinflammatory cytokines such asNF-κB.[28] However, TLR5 interaction withH. pylori only induces weak TLR5 activation. The inflammatory response induced by TLR5 duringH. pylori is also considered to be possiblyflagellin independent. This suggests that an unknownH. pylori factor is responsible for this response[12] In addition to inflammation induction, TLR5 is also shown to enhancegastric cancer cell proliferation through anERK-dependent pathway.[29] This is supported by the increased level of TLR5 expression from normal gastricmucosa to gastric cancer cells.[30]
TLR5 is suggested to be possibly involved inHPV induced inflammation and subsequent cervical neoplasia formation.[13] TLR5 is generally absent in normal cervical squamous epithelium. However, a gradually increased level of TLR5 expression has been detected in low-gradecervical intraepithelial neoplasia (CIN), high grade CIN, and invasivecervical cancer.[31] However, the exact mechanism of interaction between TLR5 and HPV is not known.
It has been reported that TLR5 expression is detected in both ovarian epithelium andovarian cancer cell lines but not in ovarian stroma, suggesting a possible role of TLR5 in inflammation induced ovarian cancer onset.[32]
^abMiao EA, Andersen-Nissen E, Warren SE, Aderem A (September 2007). "TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system".Seminars in Immunopathology.29 (3):275–88.doi:10.1007/s00281-007-0078-z.PMID17690885.S2CID21209470.
^abStanislawowski M, Wierzbicki PM, Golab A, Adrych K, Kartanowicz D, Wypych J, et al. (October 2009). "Decreased Toll-like receptor-5 (TLR-5) expression in the mucosa of ulcerative colitis patients".Journal of Physiology and Pharmacology.60 (Suppl 4):71–5.PMID20083854.
^Nagai Y, Takatsu K (10 March 2014). "Chapter 26 - Role of the Immune System in Obesity-Associated Inflammation and Insulin Resistance". In Watson RR (ed.).Nutrition in the Prevention and Treatment of Abdominal Obesity. pp. 281–293.doi:10.1016/B978-0-12-407869-7.00026-X.ISBN978-0-12-407869-7.
^abHusseinzadeh N, Davenport SM (November 2014). "Role of toll-like receptors in cervical, endometrial and ovarian cancers: a review".Gynecologic Oncology.135 (2):359–63.doi:10.1016/j.ygyno.2014.08.013.PMID25135000.
^Smith KD, Andersen-Nissen E, Hayashi F, Strobe K, Bergman MA, Barrett SL, et al. (December 2003). "Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility".Nature Immunology.4 (12):1247–53.doi:10.1038/ni1011.PMID14625549.S2CID6157006.
