Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction

Area of Science:

• Immunology
• Molecular Biology
• Autoimmune Disease Research

Background:

• Cytokine dysregulation, particularly IL-17A and IL-6, is central to autoimmune diseases.
• IL-6 promotes T helper 17 (Th17) cell differentiation, crucial for immune self-recognition disorders.
• Fibroblasts play a role in immune responses and inflammatory processes.

Purpose of the Study:

• To elucidate the mechanism of an IL-17A-triggered positive-feedback loop involving IL-6 signaling in fibroblasts.
• To investigate the contribution of this feedback loop to autoimmune disease development, specifically arthritis.
• To assess the broader implications of this mechanism in Th17 cell-mediated autoimmune diseases.

Main Methods:

• Investigated IL-17A-induced activation of NF-kappaB and STAT3 transcription factors in fibroblasts.
• Examined the role of SOCS3-dependent negative regulation of gp130 in the IL-6 signaling pathway.
• Utilized mouse models to study the impact of enhanced feedback loop activity on arthritis and experimental autoimmune encephalomyelitis (EAE).

Main Results:

• Described a novel IL-17A-triggered positive-feedback loop of IL-6 signaling in fibroblasts involving NF-kappaB and STAT3 activation.
• Demonstrated that disruption of SOCS3-mediated negative regulation enhances this loop, contributing to arthritis development.
• Showed that this mechanism exacerbates experimental autoimmune encephalomyelitis (EAE) in wild-type mice.

Conclusions:

• The identified IL-17A-IL-6 positive-feedback loop in fibroblasts is a significant contributor to autoimmune disease pathogenesis.
• Impaired SOCS3 regulation of IL-6 signaling exacerbates autoimmune conditions like arthritis and EAE.
• This mechanism represents a potential general pathway underlying various Th17 cell-mediated autoimmune diseases.