Absence of interleukin-17 receptor a signaling prevents autoimmune inflammation of the joint and leads to a Th2-like phenotype in collagen-induced arthritis.

Abstract

OBJECTIVE:

Interleukin-17A (IL-17A) signals through the IL-17 receptor (IL-17R) A/C heterodimer. IL-17RA serves as a common receptor subunit for several IL-17 cytokine family members. Lack of IL-17RA signaling may therefore have additional effects beyond those of lack of IL-17A alone. The present study was undertaken to determine the role of IL-17RA signaling in autoimmune arthritis.

METHODS:

Disease incidence and severity were scored in type II collagen-treated wild-type, IL-17RA-deficient, and IL-23p19-deficient mice. T helper cell profiles and humoral immune responses were analyzed at several time points. Pathogenicity of T cells and total splenocytes was determined by in vitro functional assay. IL-17RA signaling was blocked in vivo in mice with antigen-induced arthritis (AIA).

RESULTS:

Comparable to the findings in IL-23p19-deficient mice, IL-17RA-deficient mice were completely protected against the development of collagen-induced arthritis (CIA). However, IL-17RA-deficient mice exhibited an increased number of IL-4-producing CD4+ T cells, distinct from IL-17A+CD4+ T cells. This was associated with fewer plasma cells, lower production of pathogenic IgG2c antibody, and increased production of IgG1 antibody. Both isolated CD4+ T cells and total splenocytes from IL-17RA-deficient mice had a reduced ability to induce IL-6 production by synovial fibroblasts in the setting of CIA, in a functional in vitro assay. Furthermore, blocking of IL-17RA signaling in AIA reduced synovial inflammation.

CONCLUSION:

These results demonstrate that absence of IL-17RA leads to a Th2-like phenotype characterized by IL-4 production and suggest that IL-17RA signaling plays a critical role in the regulation of IL-4 in CIA and the development of autoimmune inflammation of the joint.

• Authors: Odilia B J Corneth, Adriana M C Mus, Patrick S Asmawidjaja, Roel G J Klein Wolterink, Menno van Nimwegen, Maarten D Brem, Yara Hofman, Rudi W Hendriks, Erik Lubberts
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 66 Issue 2 Pg. 340-9 (Feb 2014) ISSN: 2326-5205 [Electronic] United States
• PMID: 24504806 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 by the American College of Rheumatology.

Chemical References

• Il17ra protein, mouse
• Interleukin-17
• Interleukin-23 Subunit p19
• Receptors, Interleukin-17
• Interleukin-4

Topics

• Animals
• Arthritis, Experimental (pathology, physiopathology)
• Autoimmune Diseases (physiopathology, prevention & control)
• CD4-Positive T-Lymphocytes (metabolism, pathology)
• Disease Models, Animal
• Inflammation (physiopathology, prevention & control)
• Interleukin-17 (metabolism)
• Interleukin-23 Subunit p19 (deficiency, genetics, physiology)
• Interleukin-4 (metabolism)
• Joints (pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phenotype
• Plasma Cells (pathology)
• Receptors, Interleukin-17 (deficiency, genetics, physiology)
• Severity of Illness Index
• Signal Transduction (physiology)
• Th2 Cells (pathology)