New IL-22 function and its relevance in MS

Increasing evidences link Th17 cells and multiple sclerosis (MS), as this pro-inflammatory lymphocyte subset plays a central role in blood brain barrier (BBB) infiltration and central nervous system (CNS) inflammation. Interleukin (IL)-22, a Th17 cytokine acting exclusively on cells of nonhematopoietic origin, may participate to BBB breakdown and lymphocyte infiltration. Recently, IL-22 binding protein (IL-22BP) locus has been described as a genetic risk for MS. Thus, further studies on IL-22 and IL-22BP in MS are warranted. We performed ELISA for IL-22 detection in PBMC supernatants after 18 h of Staphylococcus enterotoxin B stimulation in healthy controls (HC), clinically active, respectively inactive, MS patients, and progressive MS patients. In parallel, IL-22BP expression in monocytes and monocyte-derived DCs was assessed by qPCR. The expression of IL-22 receptor subunit IL-10R2 and IL-22R1 was measured by qPCR in human tumoral CNS cell lines. Immunofluorescence on non-MS and MS human brain tissues was performed to detect IL-22 and IL-22 receptor in situ. Intra-cellular STAT3 phosphorylation upon IL-22 treatment of different CNS cell lines was assessed by western blot. Finally, apoptosis (Annexin V), cell death (7-AAD) and proliferation (CFSE) levels upon IL-22 and/or TNFα treatment on LN-319 astrocytic cell line were done by flow cytometry. We show that the expression of IL-22 and IL-22BP is increased in MS patients, in particular during relapses, as compared to HC. Next, we demonstrate that IL-22 receptor is specifically expressed on human astrocytes. Interestingly, astrocytic IL-22 receptor expression is maximal at lesion sites in MS patients. We also detect IL-22 itself, which colocalized with its receptor, mostly at perivacular location. Furthermore, IL-22 treatment of astrocytoma cell lines results in a cytokine-specific STAT3 phosphorylation. Ultimately, functional assays reveal that IL-22 treated astrocytic cells are less apoptotic and survive better than untreated ones. Altogether, these data suggest that IL-22 is involved in the pathogenesis of MS, where this cytokine might play a crucial role for astrocyte integrity.