Neuroprotective effects of IL-22 during CNS inflammation

Abstract

Purpose : IL-22 has opposing effects in different tissues, from pro-inflammatory (skin, joints) to protective (liver, intestine) but little is known about its effects on neural tissue. We examined this using the induced models of experimental autoimmune uveitis (EAU) and experimental autoimmune encephalomyelitis (EAE).

Methods : EAU or EAE were induced in WT or IL-22^-/- mice by active immunization with a peptide from IRBP or from MOG, respectively, in Freund’s complete adjuvant. Intravitreal injections of the substances specified below were administered to anesthetized mice in a volume of 1 µl. Neuroprotection was assessed after intravitreal glutamate injection by counting surviving retinal ganglion cells (RGC) following retrograde fluorogold labeling.

Results : During EAU, IL-22 was produced by CD4+ eye-infiltrating cells, many of which co-produced IL-17. IL-22^-/- mice immunized for EAU or for EAE developed exacerbated disease, as did wild type mice immunized for EAU and treated systemically or intraocularly with anti-IL-22 during the expression phase of disease. Mechanistic studies revealed that retinal glial Müller cells in uveitic eyes had upregulated IL-22rα1 expression. IL-22 upregulated IL-22rα1 expression in cultured primary Müller cells and enhanced their ability to suppress T cell activation in vitro. Finally, IL-22 injected into the eye concurrently with IL-1β, inhibited IL-1-induced expression of multiple proinflammatory and proapoptotic genes in retinal tissue. ‘Ingenuity’ pathway analysis suggested activation of neuroprotective pathways. In keeping with this, co-injection of IL-22 had protective effects on RGC in vivo in a model of glutamate-induced neurotoxicity.

Conclusions : These results suggest that IL-22 activates multiple molecular and cellular pathways within the CNS tissue to limit inflammatory damage and provide neuroprotection.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.