Bcl-2 overexpression ameliorates immune complex-mediated arthritis by altering Fc gamma RIIb expression and monocyte homeostasis
Details
Publication Year 2013-04, Volume 93, Issue #4, Page 585-597
Journal Title
JOURNAL OF LEUKOCYTE BIOLOGY
Publication Type
Journal Article
Abstract
RA is a chronic autoimmune disease characterized by accumulation of inflammatory cells within synovial joints. RA is associated with a failure of apoptosis of infiltrating leukocytes, thought to be a result of overexpression of prosurvival Bcl-2 proteins. Overexpression of Bcl-2 in hematopoietic cells can result in spontaneous autoimmunity. We therefore hypothesized that increased Bcl-2 in the hematopoietic compartment would reduce apoptosis and thereby, exacerbate inflammatory arthritis. Paradoxically, we found that overexpression of Bcl-2 in mice (vav-bcl-2) markedly reduced pathology in antibody-dependent models of RA (CIA and K/BxN serum transfer arthritis). No such protection was observed in a model of CD4(+) T cell-dependent, B cell-independent arthritis (mBSA/IL-1-induced arthritis). In CIA, vav-bcl-2 Tg mice had lower antibody production to CII, which might explain reduced disease. However, Bcl-2 overexpression also reduced passive K/BxN serum transfer arthritis. Overexpression of Bcl-2 caused a monocytosis, with preferential expansion of Ly6C(lo) monocytes and increased expression of the inhibitory receptor for IgG, Fc gamma RIIb, on leukocytes. Skewing of the myeloid cell population, increases in Fc gamma RIIb, and reduced arthritis were independent of the hypergammaglobulinemia found in vav-bcl-2 Tg mice. These data reveal selective effects of the Bcl-2-regulated apoptotic pathway on monocyte differentiation and the expression of FcRs critical for regulation of antibody/immune complex-mediated disease. J. Leukoc. Biol. 93: 585-597; 2013.
Publisher
FEDERATION AMER SOC EXP BIOL
Keywords
COLLAGEN-INDUCED ARTHRITIS; COLONY-STIMULATING FACTOR; RHEUMATOID-ARTHRITIS; INFLAMMATORY ARTHRITIS; TRANSGENIC MICE; CELL-DEATH; ANTIINFLAMMATORY ACTIVITY; SYNOVIAL FIBROBLASTS; DENDRITIC CELLS; T-CELLS
WEHI Research Division(s)
Inflammation; Molecular Genetics Of Cancer; Cell Signalling And Cell Death
NHMRC Grants
NHMRC/1016647 NHMRC/461221
Rights Notice
© 2013 Society for Leukocyte Biology


Creation Date: 2013-04-01 12:00:00
Last Modified: 0001-01-01 12:00:00
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