TLR5

Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene.[5] It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria.[6] It has been shown to be involved in the onset of many diseases, which includes Inflammatory bowel disease.[7] Recent studies have also shown that malfunctioning of TLR5 is likely related to rheumatoid arthritis,[8][9] osteoclastogenesis, and bone loss.[10] Abnormal TLR5 functioning is related to the onset of gastric, cervical, endometrial and ovarian cancers.[11][12]

TLR5
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTLR5, MELIOS, SLE1, SLEB1, TIL3, toll like receptor 5
External IDsOMIM: 603031 MGI: 1858171 HomoloGene: 20698 GeneCards: TLR5
Gene location (Human)
Chr.Chromosome 1 (human)[1]
Band1q41Start223,109,404 bp[1]
End223,143,248 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

7100

53791

Ensembl

ENSG00000187554

ENSMUSG00000079164

UniProt

O60602

Q9JLF7

RefSeq (mRNA)

NM_003268

NM_016928

RefSeq (protein)

NP_003259

NP_058624

Location (UCSC)Chr 1: 223.11 – 223.14 MbChr 1: 182.95 – 182.98 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

The TLR family plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila 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.[13] TLR5 recognizes bacterial flagellin, a principal component of bacterial flagella and a virulence factor. The activation of this receptor mobilizes the nuclear factor NF-κB and stimulates tumor necrosis factor-alpha production.[14]

TLR5 recognizes flagellin,[15] which is the protein monomer that makes up the filament of bacterial flagella, found on nearly all motile bacteria. There are highly conserved regions in the flagellin protein among all bacteria, facilitating the recognition of flagellin by a germ-line encoded receptor such as TLR5.[16] However, some Proteobacteria flagella have acquired mutations preventing their recognition by TLR5.[17]

Signaling pathway and regulation

The TLR5 signaling cascade is commonly triggered by the binding of bacterial flagellum to TLR5 on the cell surface. Binding of flagellum induces the dimerization of TLR5, which in turn recruits MyD88.[18] The recruitment of MyD88 leads to subsequent activation of IRAK4, IRAK1, TRAF6, and eventually IκB kinases.[19][20] Activation of IκB kinases contributes to the nuclear localization of NF-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 induces IL8 production. In human monocytes and dendritic cells, this interaction results in the secretion of proinflammatory cytokines such as TNF.[6]

Recent study has identified Caveolin-1 as a potential regulator of TLR5 expression.[21] In contrast to the decreased TLR4 level in senescent cells, TLR5 expression maintains relative 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.[21] It is hypothesized that the Caveolin-1 directly interacts with TLR5 to stabilize it and hence increases the level of TLR5.

Clinical significance

Inflammatory bowel disease

TLR5 may play a role in inflammatory bowel disease (IBD). TLR5-deficient mice develop spontaneous colitis [22] and metabolic syndrome which are associated with altered gut microbiota.[23] Statistically significant lower levels of TLR5 expression have been found in patients exhibiting moderate to severe ulcerative 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]

Osteoclastogenesis and bone loss

Bone loss and osteoclastogenesis are induced by inflammation in infectious and autoimmune diseases.[10] 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 in synovial fluid from patients with rheumatoid arthritis. Activation of TLR5 in these patients leads to subsequent activation of receptor activator of NF-κB ligand (RANKL). Activation of RANKL leads to increased expression of osteoclastic genes. Activation of these genes results in robust osteoclast formation and bone loss.[10] This process is absent in TLR5 knockout mice model.[10]

Gastric

Chronic inflammation in GI tract has been known to increase the risk of gastric cancer, with H. pylori being one of the most common resources of infection.[11] TLR5 is an essential factor in inducing inflammatory response to H. pylori infection. During infection, expression and ligation of TLR5 and TLR2 are required for the activation of proinflammatory cytokines such as NF-κB.[24] However, TLR5 interaction with H. pylori only induces weak TLR5 activation. The inflammatory response induced by TLR5 during H. pylori is also considered to be possibly flagellin independent. This suggests that an unknown H. pylori factor is responsible for this response[11] In addition to inflammation induction, TLR5 is also shown to enhance gastric cancer cell proliferation through an ERK-dependent pathway.[25] This is supported by the increased level of TLR5 expression from normal gastric mucosa to gastric cancer cells.[26]

Cervical

TLR5 is suggested to be possibly involved in HPV induced inflammation and subsequent cervical neoplasia formation.[12] TLR5 is generally absent in normal cervical squamous epithelium. However, a gradually increased level of TLR5 expression has been detected in low-grade cervical intraepithelial neoplasia (CIN), high grade CIN, and invasive cervical cancer.[27] However, the exact mechanism of interaction between TLR5 and HPV is not known.

Ovarian

It has been reported that TLR5 expression is detected in both ovarian epithelium and ovarian cancer cell lines but not in ovarian stroma, suggesting a possible role of TLR5 in inflammation induced ovarian cancer onset.[28]

References
  1. GRCh38: Ensembl release 89: ENSG00000187554 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000079164 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF (January 1998). "A family of human receptors structurally related to Drosophila Toll". Proceedings of the National Academy of Sciences of the United States of America. 95 (2): 588–93. doi:10.1073/pnas.95.2.588. PMC 18464. PMID 9435236.
  6. Miao 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. PMID 17690885.
  7. Stanislawowski 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. PMID 20083854.
  8. Kim S, Chen Z, Chamberlain ND, Essani AB, Volin MV, Amin MA, et al. Ligation of TLR5 promotes myeloid cell infiltration and differentiation into mature osteoclasts in RA and experimental arthritis. J Immunol. 2014 Oct 15;193(8):3902–13. pmid:25200955
  9. Badr MT, Häcker G (2019) Gene expression profiling meta-analysis reveals novel gene signatures and pathways shared between tuberculosis and rheumatoid arthritis. PLoS ONE 14(3): e0213470. https://doi.org/10.1371/journal.pone.0213470
  10. Kassem A, Henning P, Kindlund B, Lindholm C, Lerner UH (November 2015). "TLR5, a novel mediator of innate immunity-induced osteoclastogenesis and bone loss". FASEB Journal. 29 (11): 4449–60. doi:10.1096/fj.15-272559. PMID 26207027.
  11. Castaño-Rodríguez N, Kaakoush NO, Mitchell HM (2014-01-01). "Pattern-recognition receptors and gastric cancer". Frontiers in Immunology. 5: 336. doi:10.3389/fimmu.2014.00336. PMC 4105827. PMID 25101079.
  12. Husseinzadeh 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. PMID 25135000.
  13. Sharma N, Akhade AS, Qadri A (April 2013). "Sphingosine-1-phosphate suppresses TLR-induced CXCL8 secretion from human T cells". Journal of Leukocyte Biology. 93 (4): 521–8. doi:10.1189/jlb.0712328. PMID 23345392.
  14. "Entrez Gene: TLR5 toll-like receptor 5".
  15. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al. (April 2001). "The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5". Nature. 410 (6832): 1099–103. doi:10.1038/35074106. PMID 11323673.
  16. 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. PMID 14625549.
  17. Andersen-Nissen E, Smith KD, Strobe KL, Barrett SL, Cookson BT, Logan SM, Aderem A (June 2005). "Evasion of Toll-like receptor 5 by flagellated bacteria". Proceedings of the National Academy of Sciences of the United States of America. 102 (26): 9247–52. doi:10.1073/pnas.0502040102. PMC 1166605. PMID 15956202.
  18. Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL (August 2001). "Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression". Journal of Immunology. 167 (4): 1882–5. doi:10.4049/jimmunol.167.4.1882. PMID 11489966.
  19. Gohda J, Matsumura T, Inoue J (September 2004). "Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling". Journal of Immunology. 173 (5): 2913–7. doi:10.4049/jimmunol.173.5.2913. PMID 15322147.
  20. Moors MA, Li L, Mizel SB (July 2001). "Activation of interleukin-1 receptor-associated kinase by gram-negative flagellin". Infection and Immunity. 69 (7): 4424–9. doi:10.1128/IAI.69.7.4424-4429.2001. PMC 98515. PMID 11401982.
  21. Lim JS, Nguyen KC, Han JM, Jang IS, Fabian C, Cho KA (December 2015). "Direct Regulation of TLR5 Expression by Caveolin-1". Molecules and Cells. 38 (12): 1111–7. doi:10.14348/molcells.2015.0213. PMC 4697003. PMID 26615831.
  22. Singh V, Yeoh BS, Carvalho F, Gewirtz AT, Vijay-Kumar M (July 2015). "Proneness of TLR5 deficient mice to develop colitis is microbiota dependent". Gut Microbes. 6 (4): 279–83. doi:10.1080/19490976.2015.1060390. PMC 4615783. PMID 26067589.
  23. Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, et al. (April 2010). "Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5". Science. 328 (5975): 228–31. doi:10.1126/science.1179721. PMC 4714868. PMID 20203013.
  24. Smith MF, Mitchell A, Li G, Ding S, Fitzmaurice AM, Ryan K, et al. (August 2003). "Toll-like receptor (TLR) 2 and TLR5, but not TLR4, are required for Helicobacter pylori-induced NF-kappa B activation and chemokine expression by epithelial cells". The Journal of Biological Chemistry. 278 (35): 32552–60. doi:10.1074/jbc.M305536200. PMID 12807870.
  25. Song EJ, Kang MJ, Kim YS, Kim SM, Lee SE, Kim CH, et al. (July 2011). "Flagellin promotes the proliferation of gastric cancer cells via the Toll-like receptor 5". International Journal of Molecular Medicine. 28 (1): 115–9. doi:10.3892/ijmm.2011.656. PMID 21455558.
  26. Pimentel-Nunes P, Afonso L, Lopes P, Roncon-Albuquerque R, Gonçalves N, Henrique R, et al. (September 2011). "Increased expression of toll-like receptors (TLR) 2, 4 and 5 in gastric dysplasia". Pathology Oncology Research. 17 (3): 677–83. doi:10.1007/s12253-011-9368-9. PMID 21455638.
  27. Lee JW, Choi JJ, Seo ES, Kim MJ, Kim WY, Choi CH, et al. (November 2007). "Increased toll-like receptor 9 expression in cervical neoplasia". Molecular Carcinogenesis. 46 (11): 941–7. doi:10.1002/mc.20325. PMID 17440926.
  28. Zhou M, McFarland-Mancini MM, Funk HM, Husseinzadeh N, Mounajjed T, Drew AF (September 2009). "Toll-like receptor expression in normal ovary and ovarian tumors". Cancer Immunology, Immunotherapy. 58 (9): 1375–85. doi:10.1007/s00262-008-0650-y. PMID 19184006.

Further reading
  • Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al. (April 2001). "The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5". Nature. 410 (6832): 1099–103. doi:10.1038/35074106. PMID 11323673.
  • Lien E, Ingalls RR (January 2002). "Toll-like receptors". Critical Care Medicine. 30 (1 Suppl): S1-11. doi:10.1097/00003246-200201001-00001. PMID 11782555.
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