IL-23 controls autoimmunity by maintaining the integrity of marginal zone barrier that clears apoptotic bodies (P4178)

Abstract

Abstract Th17 cells, which are maintained by IL-23, are important for the spontaneous germinal center (GC) response in autoimmune BXD2 mice. Here, we unexpectedly found that BXD2-Il23-/- mice exhibit accelerated development of spontaneous GCs and production of pathogenic autoantibodies compared with wild-type (WT) BXD2 mice. Administration of adenovirus expressing IL-23 to BXD2-Il23-/- mice at early age delayed the disease onset. Despite a decline of Th17 cells in the spleen of BXD2-Il23-/- mice, there was a severe impairment in clearance of apoptotic bodies and an accelerated age-related loss of marginal zone macrophages (MZMs). In the spleens of both B6 and BXD2 mice, IL-23R was expressed primarily by MZMs which is the major cell that clears apoptotic debris in the spleens. Absence of IL-23 and loss of MZMs in BXD2-Il23-/- mice are associated with elevated production of type I interferons (IFNs) from plasmacytoid dendritic cells (pDCs). Selective depletion of MZMs by repeated injection of clondronate liposome to BXD2-WT, but not BXD2-Ifnar-/- mice, mimicked the phenotypes of BXD2-Il23-/-. Our results suggest a novel mechanism that IL-23 can act as a double edge sword to control autoimmunity in that over-expression of IL-23 can provoke autoimmunity through the maintenance of Th17 yet a complete deficiency of IL-23 induced autoimmunity through the gradual loss of marginal zone barrier, defective clearance of apopototic debris and elevated induction of type I IFNs.