Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors, including endolysosomal TLRs and a STING dependent sensing pathway.

Abstract

Abstract We have studied the biochemistry and genetics of Phospholipase D3 (PLD3) and PLD4 because polymorphisms of these proteins have been associated with several important inflammatory and autoimmune diseases, including rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus and Alzheimer’s disease. We found that both PLD3 and PLD4 are 5’ exonucleases able to degrade both ssDNA and ssRNA. Deficiency in PLD3, PLD4 or both results in a variety of inflammatory defects, with the most serious being lethal hemophagocytic lymphohistiocytosis (HLH) in double knockout mice. Pld3−/−Pld4−/− mice represent a unique spontaneous model of HLH apparently independent of microbes, whereas Pld4−/− mice develop a range of phenotypes depending upon genetic background ranging from macrophage activation syndrome to lupus like disease. Evidence will be presented showing that the diseases in these mice result from autorecognition of nucleic acids and can be reversed by mutation of nucleic acid sensing pathways. PLD3 and PLD4 tend to limit TLR9 recognition but have a more complex effect on recognition by TLR7 and TLR8. Unc93b13d/3dPld3−/−Pld4−/− mice spontaneously signal through STING suggesting that PLD3 and PLD4 also may regulate cytoplasmic nucleic acid sensing. Supported by NIH grants R01 AI142945 and R56AG070775