Inhibition of G Protein ?? Subunit Signaling Abrogates Nephritis in Lupus-Prone Mice.

ABSTRACT: Despite considerable advances in the understanding of systemic lupus erythematosus (SLE), there is still an urgent need for new and more targeted treatment approaches. We previously demonstrated that small-molecule blockade of G protein ?? subunit (G??) signaling inhibits acute inflammation through inhibition of chemokine receptor signal transduction. We undertook this study to determine whether inhibition of G?? signaling ameliorates disease in a mouse model of SLE.Lupus-prone (NZB × NZW)F1 female mice were prophylactically or therapeutically treated with the small-molecule G?? inhibitor gallein. Tissue samples were analyzed by flow cytometry and immunohistochemistry. The development and extent of nephritis were assessed by monitoring proteinuria and by immunohistochemical analysis. Serum immunoglobulin levels were measured by enzyme-linked immunosorbent assay, and total IgG and anti-double-stranded DNA (anti-dsDNA) antibody-secreting cells were measured by enzyme-linked immunospot assay.Gallein inhibited accumulation of T cells and germinal center (GC) B cells in the spleen. Both prophylactic and therapeutic treatment reduced GC size, decreased antibody-secreting cell production in the spleen, and markedly decreased accumulation of autoreactive anti-dsDNA antibody-secreting cells in kidneys. Gallein also reduced immune complex deposition in kidneys. Finally, gallein treatment dramatically inhibited kidney inflammation, prevented glomerular damage, and decreased proteinuria. Mechanistically, gallein inhibited immune cell migration and signaling in response to chemokines in vitro, which suggests that its mechanisms of action in vivo are inhibition of migration of immune cells to sites of inflammation and inhibition of immune cell maturation.Overall, these data demonstrate the potential use of gallein or novel inhibitors of G?? signaling in SLE treatment.

SUBMITTER: Rangel-Moreno J 

PROVIDER: S-EPMC5001921 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature