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oai:repisalud.isciii.es:20.500.12105/66162024-11-29T21:41:45Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc García-Rodríguez, Sonia author Rosal-Vela, Antonio author Botta, Davide author Cumba Garcia, Luz M author Zumaquero, Esther author Prados-Maniviesa, Verónica author Cerezo Wallis, Daniela author Lo Buono, Nicola author Robles-Guirado, José-Ángel author Guerrero, Salvador author González-Paredes, Elena author Andrés-León, Eduardo author Corbí, Ángel author Mack, Matthias author Koch-Nolte, Friedrich author Merino, Ramón author Zubiaur, Mercedes author Lund, Frances E author Sancho, Jaime author 2018-02-20 In this study, we investigated the role of CD38 in a pristane-induced murine model of lupus. CD38-deficient (Cd38-/-) but not ART2-deficient (Art2-/-) mice developed less severe lupus compared to wild type (WT) mice, and their protective phenotype consisted of (i) decreased IFN-I-stimulated gene expression, (ii) decreased numbers of peritoneal CCR2hiLy6Chi inflammatory monocytes, TNF-α-producing Ly6G+ neutrophils and Ly6Clo monocytes/macrophages, (iii) decreased production of anti-single-stranded DNA and anti-nRNP autoantibodies, and (iv) ameliorated glomerulonephritis. Cd38-/- pristane-elicited peritoneal exudate cells had defective CCL2 and TNF-α secretion following TLR7 stimulation. However, Tnf-α and Cxcl12 gene expression in Cd38-/- bone marrow (BM) cells was intact, suggesting a CD38-independent TLR7/TNF-α/CXCL12 axis in the BM. Chemotactic responses of Cd38-/- Ly6Chi monocytes and Ly6G+ neutrophils were not impaired. However, Cd38-/- Ly6Chi monocytes and Ly6Clo monocytes/macrophages had defective apoptosis-mediated cell death. Importantly, mice lacking the cation channel TRPM2 (Trpm2-/-) exhibited very similar protection, with decreased numbers of PECs, and apoptotic Ly6Chi monocytes and Ly6Clo monocytes/macrophages compared to WT mice. These findings reveal a new role for CD38 in promoting aberrant inflammation and lupus-like autoimmunity via an apoptosis-driven mechanism. Furthermore, given the implications of CD38 in the activation of TRPM2, our data suggest that CD38 modulation of pristane-induced apoptosis is TRPM2-dependent. Sci Rep. 2018; 8(1):3357. 10.1038/s41598-018-21337-6 2045-2322 2045-2322 Scientific reports 29463868 http://hdl.handle.net/20.500.12105/6616 CYCLIC ADP-RIBOSE CELL-SURFACE-PROTEINS TIME PCR DATA T-CELLS I INTERFERON GM-CSF POLY(ADP-RIBOSE) GLYCOHYDROLASE OXIDATIVE STRESS IMMUNE-RESPONSES DENDRITIC CELLS CD38 promotes pristane-induced chronic inflammation and increases susceptibility to experimental lupus by an apoptosis-driven and TRPM2-dependent mechanism