IL-23 inhibits autoimmunity by facilitating clearance of apoptotic bodies in the marginal zone (171.26)

Abstract

Abstract IL-23 helps expansion of Th17 cells which are important in the pathogenesis of spontaneous autoimmune disease in BXD2 mice. In this study, we surprisingly found that IL-23p19-deficient BXD2 mice (BXD2-Il23-/-) exhibit accelerated development of spontaneous germinal centers (GCs) and production of pathogenic autoantibodies, compared with wild-type BXD2 mice. Expression of IL-23 by adenovirus in BXD2-Il23-/- mice reversed these phenotypes. IL-23R was mainly expressed by marginal zone macrophages (MZMs) in the spleen of mice, as indicated by the GFP-IL-23R reporter. In BXD2-Il23-/-, however, there was an age-related loss of both MZMs and CD21hiIgMhi marginal zone (MZ) B cells. MZMs are a small subset of specialized splenic macrophages essential for clearance of apoptotic cells entering to the spleen from circulation to prevent generation of immunogenic autoantigens. MZM specific depletion by clondronate liposome severely accelerated BXD2 autoimmune disease progression. Absence of IL-23 correlates with downregulated expression of BAFF by MZMs which is essential for the differentiation of MZ B cells. Our results suggest a unique mechanism for IL-23 to limit autoimmunity in that IL-23 supports the cross-talk between MZM and MZ B cells. In this model, IL-23 acts on MZM to upregulate BAFF to promote the survival of MZ B cells, and MZ B cells help to maintain the survival of MZM. Loss of MZM is associated with defective clearance of apoptotic cells and acceleration of autoimmunity.