Abstract
Dysregulated sensing of self–nucleic acid is a leading cause of autoimmunity in multifactorial and monogenic diseases. Mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in immune cells, cause autoimmune manifestations and increased production of type I IFNs by innate cells. Here we show that immune complexes of self-DNA and autoantibodies (DNA-ICs) contribute to elevated IFN levels via activation of the cGAS/STING pathway of cytosolic sensing. Mechanistically, lack of endosomal F-actin nucleation by WASp caused a delay in endolysosomal maturation and prolonged the transit time of ingested DNA-ICs. Stalling in maturation-defective organelles facilitated leakage of DNA-ICs into the cytosol, promoting activation of the TBK1/STING pathway. Genetic deletion of STING and STING and cGAS chemical inhibitors abolished IFN production and rescued systemic activation of IFN-stimulated genes in vivo. These data unveil the contribution of cytosolic self–nucleic acid sensing in WAS and underscore the importance of WASp-mediated endosomal actin remodeling in preventing innate activation.
Highlights
The link between innate sensing of endogenous nucleic acid (NA) and autoimmune manifestations has become clear in several monogenic diseases and in common autoimmune diseases such as systemic lupus erythematosus (SLE)
DCs from Wiskott-Aldrich syndrome protein (WASp)-KO (WKO) animals activated Ifnb gene transcription at the lowest concentration of DNA in immune complex with autoantibodies (DNA-immune complexes (ICs)), whereas WT cells failed to respond to the highest dose of ICs tested (Figure 1D)
To discriminate whether enhanced responsiveness to DNA-ICs is a cell-intrinsic property of WASp-null cells, we generated a WASp-deficient DC line (WKOCAS) by genome editing [29] (Figure 1G and Supplemental Figure 2A)
Summary
The link between innate sensing of endogenous nucleic acid (NA) and autoimmune manifestations has become clear in several monogenic diseases and in common autoimmune diseases such as systemic lupus erythematosus (SLE). More recent evidence suggests that the cytosolic cGAS/STING sensing system plays a critical role in recognition of self-DNA in systemic autoimmunity [4,5,6]. In Aicardi-Goutières syndrome (AGS) and AGS animal models [4], dysregulated activation of the cGAS/STING pathway results from defects in the enzymes that degrade cytosolic DNA, such as the cytosolic exonuclease TREX1, leading to constitutive activation of IFN-stimulated genes (ISGs) and severe inflammation. Defects in lysosomal DNase II may lead to accumulation of undigested self-DNA in lysosomes, leakage to the cytosol, and severe autoinflammation in a cGAS/STING-dependent fashion [9,10,11,12,13]. Partner proteins binding to selfDNA or alteration in endosomal maturation may promote leakage of ingested material into the cytosol, inducing activation of cytosolic innate pathways [14,15,16,17]
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