Toll/Interleukin-1 Receptor Domain Derived from TcpC (TIR-TcpC) Ameliorates Experimental Autoimmune Arthritis by Down-modulating Th17 Cell Response

Shweta Pasi,Ravi Kant,Avadhesha Surolia

doi:10.1074/jbc.m116.722801

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.

Highlights

Immunopathology of RA and the active involvement of cells of both the innate and adaptive arms of the immune system, inhibition of multiple pathways is highly desirable
Identified as a gene up-regulated during myeloid differentiation in response to IL-6 [3], MyD88 has over the years emerged as a canonical adaptor protein for the toll-like receptors (TLRs) and IL-1 family of receptors including IL-18R [4]
The inhibitory potential of toll/IL-1 receptor (TIR)-TcpC was several times greater than that of p65IP.To analyze the therapeutic effect of TIR-TcpC, autoimmune arthritis with characteristics similar to RA was induced in C57BL6/J mice by immunization with heterologous chicken type II collagen (CII)

Summary

Introduction

Immunopathology of RA and the active involvement of cells of both the innate and adaptive arms of the immune system, inhibition of multiple pathways is highly desirable. The inhibitory potential of TIR-TcpC was several times greater than that of p65IP (commercially available positive control) (supplemental Fig. S2).To analyze the therapeutic effect of TIR-TcpC, autoimmune arthritis with characteristics similar to RA was induced in C57BL6/J mice by immunization with heterologous chicken type II collagen (CII). To study the impact of TIR-TcpC treatment on effector T-cell functions, C57BL6/J mice were immunized with CII and on clinical onset of the disease were treated with TIRTcpC.

Results

Conclusion