Deficiency of IL-27 Signaling Exacerbates Experimental Autoimmune Uveitis with Elevated Uveitogenic Th1 and Th17 Responses

Abstract

Human uveitis is an autoimmune disease of the central nervous system that is characterized by ocular inflammation with the involvement of uveitogenic Th1 and Th17 responses. In experimental autoimmune uveitis (EAU), the animal model for human uveitis, both responses are proven to be critical in disease development. Therefore, targeting both Th1 and Th17 cells has therapeutic implication for disease resolution. IL-27 is a multifunctional cytokine that can either promote or inhibit T cell responses and is implicated in both autoimmune and infectious diseases. The aim of this study is to characterize the role of IL-27/IL-27R signaling in regulating uveitogenic Th1/Th17 responses in EAU. By immunizing IL-27Rα−/− mice and their wild-type (WT) littermates for EAU, we demonstrated that IL-27 signaling deficiency exacerbated EAU with severe ocular inflammation and impairment of visual function. Furthermore, there was a significant increase in the eye-infiltrating Th1 and Th17 cells in IL-27Rα−/− EAU mice compared to WT. Their retinal antigen-specific Th1 and Th17 responses were also significantly increased, as represented by the elevation of their signature cytokines, IFN-γ and IL-17A, respectively. We also observed the upregulation of another pathogenic cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), from effector T cells in IL-27Rα−/− EAU mice. Mechanistic studies confirmed that IL-27 inhibited GM-CSF production from Th17 cells. In addition, the induction of IL-10 producing type 1 regulatory T (Tr1) cells was impaired in IL-27Rα−/− EAU mice. These results identified that IL-27 signaling plays a suppressive role in EAU by regulating multiple CD4+ cell subsets, including the effector Th1 and Th17 cells and the regulatory Tr1 cells. Our findings provide new insights for therapeutic potential in controlling uveitis by enhancing IL-27 signaling.

CD8+ T cells reduce neuroretina inflammation in mouse by regulating autoreactive Th1 and Th17 cells through IFN‐γ

“…EAU was induced as described previously [29]. Mice were immunized subcutaneously with 200 μL of 1:1 emulsion containing 200 μg of human IRBP 1‐20 (GPTHLFQP‐ SLVLDMAKVLLD, Hanhong, China) in PBS and an equal volume of complete Freund's adjuvant (CFA, Sigma‐Aldrich, MO) with 2.5 mg/mL Mycobacterium tuberculosis strain 37RA (Sigma‐Aldrich).…”

Multifunctional Interleukin-24 Resolves Neuroretina Autoimmunity via Diverse Mechanisms

“…As a negative control, 2 µL of PBS was injected into the right eye. Eyes were examined by funduscopy at regular intervals using the Micron-IV retinal imaging system for small animals (Phoenix Research Laboratories, Pleasanton, CA, USA) and scored on a scale of 0–4, as described in previous study [ 37 ]. Experiments were terminated on day 6–8 after disease onset for eye collection.…”

An updated advancement of bifunctional IL-27 in inflammatory autoimmune diseases

“…The findings were confirmed in IL-27rα −/− mice, where IL-27Rα −/− mice immunized with IRBP revealed higher EAU scores, severe vasculitis/retinitis and perivascular exudates, lower electroretinogram amplitudes, and greater CD4 + IFNγ + , CD4 + IL-17A + , CD4 + GM-CSF + , CD4 + IFNγ + GM-CSF + , and CD4 + IL-17A + GM-CSF + T-cell infiltration in the eyes. There was a higher expression of IFNγ and IL-17A in CD4 + T cells from spleen in IL-27rα −/− EAU mice ( 222 ). However, another study discussed IL-27rα −/− mice immunized with IRBP, showing lower EAU scores, and the margins of the optic discs were clear, with only minimal pathological changes and reduced expression of IFNγ, RANTES, IP-10, and MCP-1 in the eyes as compared to those in control mice on day 19 after induction.…”