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CD38 promotes pristane-induced chronic inflammation and increases susceptibility to experimental lupus by an apoptosis-driven and TRPM2-dependent mechanism

AuthorsGarcía-Rodríguez, Sonia ; Rosal-Vela, Antonio; Botta, Davide; Cumba García, Luz M.; Zumaquero, Esther; Prados-Maniviesa, Verónica; Cerezo-Wallis, Daniela; Lo Buono, Nicola; Robles-Guirado, José-Ángel; Guerrero, Salvador; González-Paredes, Elena; Andrés-León, Eduardo CSIC ORCID CVN ; Corbí, Angel L. ; Mack, Matthias; Koch-Nolte, Friedrich; Merino, Ramón CSIC ORCID; Zubiaur, Mercedes CSIC ORCID ; Lund, Frances E.; Sancho, Jaime CSIC ORCID
Issue Date20-Feb-2018
PublisherNature Publishing Group
CitationScientific Reports
AbstractIn 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.
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