2026-10-15T01:38:44Z https://data.mendeley.com/oai

oai:data.mendeley.com/6c2sbrfycw.2 2023-04-28T13:04:28Z

Xu, Bowen SAMHD1 Attenuates Acute Inflammation by Maintaining Mitochondrial Function in Macrophages via Interaction with VDAC1 Mendeley Data Abstract: Background: Over-activation of Toll-like receptor 4 (TLR4) is the key mechanism in Gram-negative bacterial infection-induced sepsis. SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) inhibits multiple virus-es , but whether it plays a role during bacterial invasion remains unelucidated. Methods: Monocyte-macrophage specific Samhd1 knockout (Samhd1−/−) mice and Samhd1−/− macrophage cell line RAW264.7 were constructed and used as research models to evaluate the role of SAMHD1 in TLR4-activated inflammation. Results: In vivo , LPS-challenged Samhd1−/− mice showed higher serum inflammatory factors, accompanied with more severe inflammation infiltration and lower survival rate. In vitro, Samhd1−/− peritoneal macrophages had more activated TLR4 pathway upon LPS-stimulation, accompanied with mitochondrial depolarization and dysfunction and a higher tendency to be M1-polarized. These results could be rescued by overexpressing full-length wild-type SAMHD1 or its phospho-mimetic T634D mutant into Samhd1−/− RAW264.7 cells, whereas the mutants, dNTP hydrolase-function-deprived H238A and phos-pho-ablative T634A, did not exert the same effect. Lastly, co-IP and immunofluorescence assays confirmed that SAMHD1 interacted with an outer mitochondrial membrane-localized protein, voltage-dependent anion channel-1 (VDAC1). Conclusion: SAMHD1 inhibits TLR4-induced acute inflammation and M1 polarization of macrophages by interacting with VDAC1 and maintaining mitochondria function, which outlines a novel regulatory mechanism of TLR signaling upon LPS stimulation. Inflammation Sepsis Mitochondrion Macrophage Dataset doi:10.17632/6c2sbrfycw.2 oai:data.mendeley.com/6c2sbrfycw.2 Creative Commons Attribution 4.0 International http://creativecommons.org/licenses/by/4.0 https://data.mendeley.com/datasets/6c2sbrfycw 2023-04-28T13:04:28Z