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

Abstract

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 CCR2^hiLy6C^hi inflammatory monocytes, TNF-α-producing Ly6G⁺ neutrophils and Ly6C^lo 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^−/− Ly6C^hi monocytes and Ly6G⁺ neutrophils were not impaired. However, Cd38^−/− Ly6C^hi monocytes and Ly6C^lo 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 Ly6C^hi monocytes and Ly6C^lo 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.