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

Sci Rep. 2018 Feb 20;8(1):3357. doi: 10.1038/s41598-018-21337-6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases / deficiency
  • ADP Ribose Transferases / metabolism
  • ADP-ribosyl Cyclase 1 / deficiency
  • ADP-ribosyl Cyclase 1 / metabolism*
  • Animals
  • Apoptosis*
  • Disease Models, Animal
  • Disease Susceptibility
  • Immunologic Factors / metabolism
  • Immunosuppressive Agents / pharmacology*
  • Leukocytes / immunology
  • Lupus Erythematosus, Cutaneous / chemically induced*
  • Lupus Erythematosus, Cutaneous / pathology*
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / metabolism*
  • Mice
  • TRPM Cation Channels / metabolism*
  • Terpenes / pharmacology*

Substances

  • Immunologic Factors
  • Immunosuppressive Agents
  • Membrane Glycoproteins
  • TRPM Cation Channels
  • TRPM2 protein, mouse
  • Terpenes
  • pristane
  • ADP Ribose Transferases
  • Art2a protein, mouse
  • Cd38 protein, mouse
  • ADP-ribosyl Cyclase 1