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 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.

The Role of CD38 on the Function of Regulatory B Cells in a Murine Model of Lupus

“…The low proportion of pDCs correlated with lower amounts of IFN-α detected in the peritoneal lavage fluids of the Cd38 −/− mice as compared with that in WT and Art2 −/− mice ( Figure 4 c). Indeed, these data are in agreement with our previous study where pristane-treated Cd38 −/− mice showed reduced autoantibody, type I IFN signature, and kidney pathology compared to WT and Art2 −/− mice [ 17 ].…”

“…Although the mechanism is still not fully understood, it seems that IL-10 protects against pristane-induced lung injury by interacting with IL-10R on alveolar macrophages or bone marrow-derived cells [ 16 ]. Cd38 −/− mice develop a milder pristane-induced lupus disease than WT and Art2 −/− mice [ 17 ]. Our data demonstrate that CD38 promotes pristane-induced chronic inflammation and increases susceptibility to experimental lupus by an apoptosis-driven and Transient Receptor Potential Melastatin 2 (TRPM2)-dependent mechanism [ 17 ].…”

“…Cd38 −/− mice develop a milder pristane-induced lupus disease than WT and Art2 −/− mice [ 17 ]. Our data demonstrate that CD38 promotes pristane-induced chronic inflammation and increases susceptibility to experimental lupus by an apoptosis-driven and Transient Receptor Potential Melastatin 2 (TRPM2)-dependent mechanism [ 17 ]. On the other hand, NAD-induced cell death (NICD), which acts through the mono-ADP-ribosyltransferase 2(ART2)-P2X purinoreceptor 7 (P2X7) pathway [ 18 , 19 ], is regulated by CD38.…”

Is There a Future for Anti-CD38 Antibody Therapy in Systemic Autoimmune Diseases?

“…Furthermore, CD38 deficiency protected mice from the onset of the disease by reducing the number of intraperitoneal apoptotic cells, which are pathogenic in this murine model of SLE. The results of this study suggest that the enzymatic activity of CD38 is important for the regulation of apoptosis in immune cells [27].…”

CD38, CD157, and RAGE as Molecular Determinants for Social Behavior

“…Thus, these KO experiments revealed that both CD38 and TRPM2 are involved in the cADPR-and heat-induced facilitation of OT release in vivo. Furthermore, now, cooperative roles of TRPM2 and CD38 were reported in natural killer cells [72], mesenchymal stem cells [73], pancreatic beta cells [74], neutrophil granulocytes [75], and inflammatory monocytes [76]…”