Background/Purpose: Previous studies implicate dendritic cells (DCs) in the pathogenesis of systemic lupus erythematosus (SLE), yet the mechanisms underlying this involvement are not yet clear. Genome-wide association studies and experimental mouse models provide evidence of toll-like receptor (TLR) involvement in SLE. Immune complexes containing self nucleic acids activate endosomal TLRs 7/9, which require signaling adaptor MyD88 for subsequent up-regulation of proinflammatory gene expression, in part through the action of transcription factor IRF5. Functional polymorphisms in TLRs 7/9, MyD88 and IRF5 are linked to SLE susceptibility, and mice with an underlying defect in Fas (MRL/lpr) on a TLR7-, MyD88- or IRF5-deficient background are protected from disease. We have shown that DC-specific loss of caspase 8, an enzyme in the Fas pathway classically linked to programmed cell death, induces a SLE-like disease that originates from heightened DC activation. The increased activation of caspase 8-deficient DCs is in part controlled by a MyD88-dependent mechanism, as DC-specific loss of MyD88 reduces disease. We therefore examined the interaction between DC-specific caspase 8, endosomal TLR signaling and IRF5 in disease development.

Methods: Mice lacking caspase 8 specifically in DCs were generated (Cre^CD11cCasp8^flox/flox) and crossed with TLR7^-/-TLR9^-/- (TLR7^-/-TLR9^-/-Cre^CD11cCasp8^flox/flox), TRIF^mut/mutMyD88^flox/flox (TRIF^mut/mutMyD88^flox/floxCre^CD11cCasp8^flox/flox) and IRF5^flox/flox (IRF5^flox/floxCre^CD11cCasp8^flox/flox) mice. Flow cytometric analysis was used to characterize cell populations. ELISA and Luminex bead-based assays detected serum antibody and cytokine levels. Immunohistochemical and immunofluorescent analyses were used to evaluate spleen and kidney pathology.

Results: Cre^CD11cCasp8^flox/flox develop a SLE-like disease characterized by splenomegaly, lymphadenopathy, autoantibodies, elevated serum cytokines, glomerulonephritis, immune complex deposition in the kidney and proteinuria. Caspase 8-deficient DCs are highly activated, leading to lymphocyte hyperactivation in a paracrine manner. Further, we observe a disruption of the splenic architecture in Cre^CD11cCasp8^flox/flox mice, with a severe reduction in the marginal zone and metallophilic macrophage populations. Moreover, kidney pathology correlates with increased influx of myeloid populations. Strikingly, TLR7^-/-TLR9^-/-Cre^CD11cCasp8^flox/flox, TRIF^mut/mutMyD88^flox/floxCre^CD11cCasp8^flox/flox and IRF5^flox/floxCre^CD11cCasp8^flox/flox mice are virtually protected from all inflammatory phenotypes.

Conclusion: Our previous studies showed that DC-specific loss of MyD88 reduced, but not ablated, SLE-like disease pathogenesis associated with DC-specific deletion of caspase 8. We now show that deletion of TLR7/9, TRIF/MyD88 or IRF5 in caspase 8-deficient DCs prevents SLE-like disease in Cre^CD11cCasp8^flox/flox mice. These data substantiate a novel DC-specific mechanism whereby caspase 8 interacts with and regulates the action of endosomal TLR signaling and IRF5 to control DC activation and subsequent autoimmune disease development.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/caspase-8-in-dendritic-cells-suppresses-irf5-activation-through-endosomal-tlr-signaling-to-prevent-sle-like-disease/