Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors

Loss of function polymorphisms of phospholipase D3 and D4 are associated with inflammatory diseases and their function is unclear. Here the authors show that PLD3/4 function as RNAses and deletion of these proteins in mice leads to accumulation of ssRNA which exacerbates inflammation through TLR signalling. 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)-gamma. Pathology is rescued in Unc93b1(3d/3d)Pld3(-/-)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-gamma made a minor contribution to pathology. Elevated type I IFN and some other remaining perturbations in Unc93b1(3d/3d)Pld3(-/-)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.

Automated summary

Loss of function polymorphisms in phospholipase D3 and D4 are linked to inflammatory diseases, and this study reveals that these proteins function as RNAses and their deletion in mice leads to the accumulation of ssRNA, exacerbating inflammation through TLR signaling pathways. This suggests that both endosomal TLR and cytoplasmic/STING nucleic acid sensing pathways are regulated by PLD3 and PLD4, offering potential implications for treating nucleic acid-driven inflammatory diseases.