Activation of Dendritic Cells through the Interleukin 1 Receptor 1 Is Critical for the Induction of Autoimmune Myocarditis (1)
In the context of autoimmunity, IL-1 promotes collagen-induced arthritis in mice and plays an important role in the pathogenesis of rheumatoid arthritis in humans. IL-1 is produced by a variety of cell types including macrophages, B cells, T cells, and dendritic cells (DCs). Two forms of biologically active IL-1 exist, IL-1α and IL-1β, which exert similar activities through the IL-1R type 1 (IL-1R1; CD121a).
Female mice in the age of 8–10 wk were immunized at days 0 and 7 with 50 μg of a murine specific α-myosin-heavy chain–derived peptide (myhc-α 614–629 [Ac-SLKLMATLFSTYASAD-OH]) in a 1:1 emulsion with CFA (1 mg/ml; H37Ra; Difco). IL-1R1+/+ mice developed severe cardiac inflammation, In contrast, inflammatory infiltrates were absent in immunized IL-1R1−/− mice.
Transfer of autoreactive CD4+ T cells from IL-1R1+/+ BALB/c mice resulted in myocarditis in SCID recipients. In contrast, IL-1R1−/−CD4+ T cells did not induce any disease after adoptive transfer into SCID mice.
Surface expression of MHC class II, CD40, ICAM-1, CD80, and CD86 differed only minimally on bone marrow–derived DCs (BM-DCs) from IL-1R1−/− and IL-1R1+/+ mice before and after (8 and 24 h) stimulation with either LPS, anti-CD40 mAb, or LPS/anti-CD40 mAb.
Production of inflammatory cytokines including IL-6, TNF-α, IL-1β, and IL-12p70 by wild-type BM-DCs were considerably induced only after stimulation of Toll-like receptor (TLR)4 with LPS but not by stimulation with either anti-CD40, IL-1β, or TNF-α. Interestingly, stimulation of both TLR4 and CD40 further augmented production of IL-12p70 but not IL-6 and TNF-αProduction of IL-6, TNF-α, IL-1β and, in particular, IL-12p70 was largely impaired in IL-1R1−/− DCs upon stimulation with LPS or LPS/anti-CD40.
Subsequently, mice were immunized with myhc-α/CFA. Intriguingly, disease susceptibility was completely restored in IL-1R1−/−mice receiving IL-1R1+/+ DCs but not in those receiving IL-1R1−/− DCs. Triggering of IL-1R1 on DCs is critical for induction of a pathogenic autoreactive CD4+ T cell response and development of autoimmune heart disease.
Transfer of immature BM-DCs from wild-type mice completely restored disease in IL-1R1−/− mice suggesting that DCs lacking the IL-1R1 are incapable to prime CD4+ T cells and induce autoimmunity. Injection of immature IL-1R1−/− DCs did not prevent disease in immunized IL-1R1+/+ mice.