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- W4313366179 abstract "Abstract Leukocyte sensing of microbial genetic material often elicits beneficial proinflammatory cytokines, but dysregulated responses can cause severe pathogenesis. Genome-wide association studies have linked Phospholipase D3 (PLD3) to Alzheimer’s disease and PLD4 to rheumatoid arthritis and systemic sclerosis. PLD3 and PLD4 are endolysosomal proteins with no detectable phospholipase activity. PLD4 deficient mice have a mild inflammatory disease, marked by elevated interferon-γ (IFN γ) and splenomegaly. These phenotypes were traced to an altered responsiveness of PLD4-deficient dendritic cells to ligands of the single-stranded DNA (ssDNA) sensor Toll-like receptor 9 (TLR9). Thioglycolate elicited peritoneal macrophages from PLD3-deficient mice also had exaggerated TLR9 responses to particular ligands. Although PLD4 and PLD3 were presumed to be phospholipases, we found that they are 5′-ssDNA exonucleases that break down TLR9 ligands. Mice deficient in both PLD3 and PLD4 died pre-weaning from an inflammatory disease with many similarities to primary hemophagocytic lymphohistiocytosis (HLH). The levels of IFN γ, IL-6, TNF α, IL-10 and ferritin were markedly elevated in the serum of Pld3−/−Pld4−/− mice. Low blood platelets, severe anemia, liver steatosis, and hemophagocytosis were evident in Pld3−/−Pld4−/− mice. The lethal inflammation in PLD3 and PLD4 deficient animals was only marginally improved by IFN γ deficiency, however inactivation of UNC93B1 rescues their survival, revealing excessive endosomal TLR signaling is responsible for driving the disease." @default.
- W4313366179 created "2023-01-06" @default.
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- W4313366179 date "2019-05-01" @default.
- W4313366179 modified "2023-09-27" @default.
- W4313366179 title "The ssDNA exonucleases PLD3 and PLD4 are required to prevent lethal primary HLH-like disease in mice" @default.
- W4313366179 doi "https://doi.org/10.4049/jimmunol.202.supp.187.6" @default.
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