title: Toll/Interleukin-1 Receptor Domain Derived from TcpC (TIR-TcpC) Ameliorates Experimental Autoimmune Arthritis by Down-modulating Th17 Cell Response.
abstract: Evasion through immunomodulation is one of the several strategies adopted by pathogens to prolong their survival within the host. One such pathogen, Escherichia coli CFT073, utilizes an immunomodulatory protein, TcpC, to combat the host's innate immune defense. TcpC abrogates the function of MyD88 in macrophages, thus perturbing all the signaling processes that involve this adaptor protein. Although central to various signaling pathways initiated by IL-1, IL-18, and toll-like receptors, the precise contribution of MyD88 to the development of autoimmunity, particularly rheumatoid arthritis, still needs extensive exploration. Herein, by using the toll/interleukin-1 receptor (TIR) domain homologous C-terminal motif of TcpC, i.e. TIR-TcpC, we found MyD88 to be critical for the induction and progression of rheumatoid arthritis through its pivotal role in the development of Th17 cells, the subset of CD4(+) T-cells widely implicated in various autoimmune disorders. The TIR-TcpC mediated inhibition of signaling through MyD88, and subsequent amelioration of experimental autoimmune arthritis was observed to be an outcome of perturbations in the NFκB-RORγt (RAR-related orphan receptor γt) axis.
authors.affiliation: From the Molecular Science Laboratory, National Institute of Immunology, New Delhi 110067, India and Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Shweta
authors.initials: S
authors.lastname: Pasi
authors.affiliation: From the Molecular Science Laboratory, National Institute of Immunology, New Delhi 110067, India and Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Ravi
authors.initials: R
authors.lastname: Kant
authors.affiliation: From the Molecular Science Laboratory, National Institute of Immunology, New Delhi 110067, India and Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India surolia@mbu.iisc.ernet.in.
authors.forename: Avadhesha
authors.initials: A
authors.lastname: Surolia
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005434:Flow Cytometry; D053583:Interleukin-1beta / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D029968:Escherichia coli Proteins; D053583:Interleukin-1beta; D053594:Myeloid Differentiation Factor 88; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D017472:Receptors, Interleukin-1; C549538:TcpC protein, E coli; D051193:Toll-Like Receptors; D037521:Virulence Factors
keywords: NF-κB; arthritis; autoimmunity; collagen; myeloid differentiation primary response gene 88 (MYD88); toll/interleukin-1 receptor (TIR)