Background/Purpose:  Previous studies implicate dendritic cells (DCs) in the initiation and persistence of systemic lupus erythematosus (SLE).  While DCs from SLE patients exhibit elevated activation, the factors responsible remain unknown.  Gain-of-function polymorphisms in the transcription factor IRF5 have been linked to SLE susceptibility.  Moreover, mice with an underlying defect in Fas (MRL/lpr) on an IRF5-deficient background were protected from disease.  We have shown that DC-specific loss of caspase 8, an enzyme in the Fas pathway classically linked to apoptosis initiation and necroptosis suppression, induces a SLE-like disease that originates from heightened DC activation.  Immune complexes containing self nucleic acids activate endosomal TLRs, which require the adaptor MyD88 for subsequent up-regulation of proinflammatory gene expression, in part through the action of IRF5.  The increased activation of caspase 8-deficient DCs is controlled by a MyD88-dependent mechanism, as DC-specific loss of MyD88 reduces disease, and caspase 8-deficient DCs display a hyperresponsiveness to endosomal TLR ligation with increased DNA binding activity of IRF.  To this end, we have examined the interaction between DC-specific caspase 8 and IRF5 in disease development.

Methods:  Mice lacking caspase 8 specifically in DCs were generated (Cre^CD11cCasp8^flox/flox) and crossed with IRF5^flox/flox mice (IRF5^flox/floxCre^CD11cCasp8^flox/flox).  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.  Further, caspase 8-deficient DCs are highly activated, leading to lymphocyte hyperactivation in a paracrine manner.  Moreover, 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.  Strikingly, DC-specific deletion of IRF5 in Cre^CD11cCasp8^flox/flox mice prevents development of nearly all of the above inflammatory phenotypes.

Conclusion:  Our previous studies showed that DC-specific loss of MyD88 reduced SLE-like disease pathogenesis associated with DC-specific deletion of caspase 8.  We now reveal that deletion of IRF5 in caspase 8-deficient DCs inhibits onset of almost all SLE-like disease phenotypes observed in Cre^CD11cCasp8^flox/flox mice.  These data substantiate a novel DC-specific mechanism whereby caspase 8 interacts withand regulates the action of MyD88 and IRF5 to control DC activation and subsequent autoimmune disease development, thereby highlighting potentially useful targets for therapy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/irf5-deletion-prevents-the-sle-like-disease-initiated-by-dendritic-cell-specific-loss-of-caspase-8/