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CD38 promotes pristane-induced chronic inflammation and increases susceptibility to experimental lupus by an apoptosis-driven and TRPM2-dependent mechanism. CD38 promotes pristane-induced chronic inflammation and increases susceptibility to experimental lupus by an apoptosis-driven and TRPM2-dependent mechanism. S. García-Rodríguez, A. Rosal-Vela, D. Botta, L.M. Cumba-García, E. Zumaquero, V. Prados-Maniviesa, D. Cerezo-Wallis, N. Lo Buono, J.A. Robles-Guirado, S. Guerrero, E. González-Paredes, E. Andrés-León, A. Corbí, M. Mack, F. Koch-Nolte, R. Merino, M. Zubia2018-02-19T23:00:00Z<p>​<strong class="ms-rteFontSize-2" style="text-align:justify;">Abstract:</strong></p><p style="text-align:justify;"><span class="ms-rteFontSize-2">In this study, we investigated the role of CD38 in a pristane-induced murine model of lupus. CD38-</span></p><p style="text-align:justify;"><span class="ms-rteFontSize-2">deficient (<em>Cd38</em><sup>-/-</sup>) but not ART2-deficient (<em>Art2</em><sup>-/-</sup>) mice developed less severe lupus compared to</span></p><p style="text-align:justify;"><span class="ms-rteFontSize-2">wild type (WT) mice, and their protective phenotype consisted of (i) decreased IFN-I-stimulated gene expression, (ii) decreased numbers of peritoneal CCR2</span><sup class="ms-rteFontSize-2">hi</sup><span class="ms-rteFontSize-2">Ly6C</span><sup class="ms-rteFontSize-2">hi</sup><span class="ms-rteFontSize-2">inflammatory monocytes, TNF-α- producing Ly6G</span><sup class="ms-rteFontSize-2">+</sup><span class="ms-rteFontSize-2">neutrophils and Ly6C</span><sup class="ms-rteFontSize-2">lo</sup><span class="ms-rteFontSize-2">monocytes/macrophages, (iii) decreased production of anti-single-stranded DNA and anti-nRNP autoantibodies, and (iv) ameliorated glomerulonephritis. </span><em class="ms-rteFontSize-2">Cd38</em><sup class="ms-rteFontSize-2">-/-</sup><span class="ms-rteFontSize-2">pristane-elicited peritoneal exudate cells had defective CCL2 and TNF-αsecretion following TLR7 stimulation. However, </span><em class="ms-rteFontSize-2">Tnf-</em><em class="ms-rteFontSize-2">α</em><span class="ms-rteFontSize-2">and </span><em class="ms-rteFontSize-2">Cxcl12</em><em class="ms-rteFontSize-2"> </em><span class="ms-rteFontSize-2">gene expression in </span><em class="ms-rteFontSize-2">Cd38</em><sup class="ms-rteFontSize-2">-/-</sup><span class="ms-rteFontSize-2">bone marrow (BM) cells was intact, suggesting a CD38-independent TLR7/TNF-α/CXCL12 axis in the BM. Chemotactic responses of </span><em class="ms-rteFontSize-2">Cd38</em><sup class="ms-rteFontSize-2">-/-</sup><span class="ms-rteFontSize-2">Ly6C</span><sup class="ms-rteFontSize-2">hi</sup><span class="ms-rteFontSize-2">monocytes and Ly6G</span><sup class="ms-rteFontSize-2">+</sup><span class="ms-rteFontSize-2">neutrophils were not impaired. However, </span><em class="ms-rteFontSize-2">Cd38</em><sup class="ms-rteFontSize-2">-/-</sup><span class="ms-rteFontSize-2">Ly6C</span><sup class="ms-rteFontSize-2">hi</sup><span class="ms-rteFontSize-2">monocytes and Ly6C</span><sup class="ms-rteFontSize-2">lo</sup><span class="ms-rteFontSize-2">monocytes/macrophages had defective apoptosis-mediated cell death. Importantly, mice lacking the cation channel TRPM2 (</span><em class="ms-rteFontSize-2">Trpm2</em><sup class="ms-rteFontSize-2">-/-</sup><span class="ms-rteFontSize-2">) exhibited very similar protection, with decreased numbers of PECs, and apoptotic Ly6C</span><sup class="ms-rteFontSize-2">hi</sup><span class="ms-rteFontSize-2">monocytes and Ly6C</span><sup class="ms-rteFontSize-2">lo</sup><span class="ms-rteFontSize-2">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.</span><br></p><p><a href="https://www.nature.com/articles/s41598-018-21337-6">​Sci. Rep. 2018, 8:3357. doi: 10.1038/s41598-018-21337-6.</a><br></p>171