Abstract
Phospholipase D3 (PLD3) and PLD4 polymorphisms have been associated with several important inflammatory diseases. Here, we show that PLD3 and PLD4 digest ssRNA in addition to ssDNA as reported previously. Moreover, Pld3−/−Pld4−/− mice accumulate small ssRNAs and develop spontaneous fatal hemophagocytic lymphohistiocytosis (HLH) characterized by inflammatory liver damage and overproduction of Interferon (IFN)-γ. Pathology is rescued in Unc93b13d/3dPld3−/−Pld4−/− mice, which lack all endosomal TLR signaling; genetic codeficiency or antibody blockade of TLR9 or TLR7 ameliorates disease less effectively, suggesting that both RNA and DNA sensing by TLRs contributes to inflammation. IFN-γ made a minor contribution to pathology. Elevated type I IFN and some other remaining perturbations in Unc93b13d/3dPld3−/−Pld4−/− mice requires STING (Tmem173). Our results show that PLD3 and PLD4 regulate both endosomal TLR and cytoplasmic/STING nucleic acid sensing pathways and have implications for the treatment of nucleic acid-driven inflammatory disease.
Highlights
Phospholipase D3 (PLD3) and PLD4 polymorphisms have been associated with several important inflammatory diseases
Because IFN-γ is a signature cytokine of HLH15,31, we first tested the extent to which Ifng−/−Pld3−/−Pld4−/− mice were protected from the disease compared to Pld3−/−Pld4−/− mice
As the 3d mutation blocks endosomal TLR signaling and the phenotype of Unc93b13d/3dPld3−/−Pld4−/− mice was milder than that of Tlr9−/−Pld3−/−Pld4thss/thss mice, collectively, the results suggested that endolysosomal TLR sensing of RNA contributes significantly to the pathology caused by deficiency in both PLD3 and PLD4
Summary
Phospholipase D3 (PLD3) and PLD4 polymorphisms have been associated with several important inflammatory diseases. Pld3−/−Pld4−/− mice accumulate small ssRNAs and develop spontaneous fatal hemophagocytic lymphohistiocytosis (HLH) characterized by inflammatory liver damage and overproduction of Interferon (IFN)-γ. Our results show that PLD3 and PLD4 regulate both endosomal TLR and cytoplasmic/STING nucleic acid sensing pathways and have implications for the treatment of nucleic acid-driven inflammatory disease. Nucleic acid sensing is important in host responses to infection, tissue damage, and tumors[1,2], promoting activation of a variety of cell types and the production of IFNs and inflammatory cytokines. PLD3 and PLD4 are endolysosomal ssDNA exonucleases that limit TLR9 responses[30] and that Pld3−/−Pld4−/− double-deficient mice developed a spontaneous, fatal HLH-like disease[16,30]
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