Bcl-2 overexpression ameliorates immune complex-mediated arthritis by altering FcγRIIb expression and monocyte homeostasis

Kate E. Lawlor, Annemarie van Nieuwenhuijze, Karen L. Parker, Sarah F. Drake, Ian K. Campbell, Scott D. Smith, James E. Vince, Andreas Strasser, Ian P. Wicks

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13 Citations (Scopus)

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 Ly6Clo monocytes and increased expression of the inhibitory receptor for IgG, FcγRIIb, on leukocytes. Skewing of the myeloid cell population, increases in FcγRIIb, 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.

Original languageEnglish
Pages (from-to)585-597
Number of pages13
JournalJournal of leukocyte biology
Volume93
Issue number4
DOIs
Publication statusPublished - 1 Apr 2013
Externally publishedYes

Keywords

  • Apoptosis
  • Autoimmunity
  • Inflammation

Cite this

Lawlor, K. E., van Nieuwenhuijze, A., Parker, K. L., Drake, S. F., Campbell, I. K., Smith, S. D., Vince, J. E., Strasser, A., & Wicks, I. P. (2013). Bcl-2 overexpression ameliorates immune complex-mediated arthritis by altering FcγRIIb expression and monocyte homeostasis. Journal of leukocyte biology, 93(4), 585-597. https://doi.org/10.1189/jlb.0412190