Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/6616
CD38 promotes pristane-induced chronic inflammation and increases susceptibility to experimental lupus by an apoptosis-driven and TRPM2-dependent mechanism
García-Rodríguez, Sonia | Rosal-Vela, Antonio | Botta, Davide | Cumba Garcia, Luz M | Zumaquero, Esther | Prados-Maniviesa, Verónica | Cerezo Wallis, Daniela CNIO | Lo Buono, Nicola | Robles-Guirado, José-Ángel | Guerrero, Salvador | González-Paredes, Elena | Andrés-León, Eduardo | Corbí, Ángel | Mack, Matthias | Koch-Nolte, Friedrich | Merino, Ramón | Zubiaur, Mercedes | Lund, Frances E | Sancho, Jaime
Sci Rep. 2018; 8(1):3357.
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.
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