BAD inactivation exacerbates rheumatoid arthritis pathology by promoting survival of sublining macrophages

Elife. 2020 Dec 3;9:e56309. doi: 10.7554/eLife.56309.

Abstract

The resistance of synovial sublining macrophages to apoptosis has a crucial role in joint inflammation and destruction in rheumatoid arthritis (RA). However, the underlying mechanism is incompletely understood. Here we report that inactivation of the pro-apoptotic BCL-2 family protein BAD is essential for survival of synovial sublining macrophage in RA. Genetic disruption of Bad leads to more severe joint inflammation and cartilage and bone damage with reduced apoptosis of synovial sublining macrophages in collagen-induced arthritis (CIA) and TNFα transgenic (TNF-Tg) mouse models. Conversely, Bad3SA/3SA mice, in which BAD can no longer be inactivated by phosphorylation, are protected from collagen-induced arthritis. Mechanistically, phosphorylation-mediated inactivation of BAD specifically protects synovial sublining macrophages from apoptosis in highly inflammatory environment of arthritic joints in CIA and TNF-Tg mice, and in patients with RA, thereby contributing to RA pathology. Our findings put forward a model in which inactivation of BAD confers the apoptosis resistance on synovial sublining macrophages, thereby contributing to the development of arthritis, suggesting that BAD may be a potential therapeutic target for RA.

Keywords: BAD; apoptosis; human; immunology; inflammation; macrophages; mouse; rheumatoid arthritis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / metabolism*
  • Bone Marrow Transplantation
  • Collagen / toxicity
  • Female
  • Humans
  • Macrophages / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Osteoarthritis / chemically induced*
  • Osteoarthritis / metabolism
  • bcl-Associated Death Protein / genetics
  • bcl-Associated Death Protein / metabolism*

Substances

  • BAD protein, human
  • Bad protein, mouse
  • bcl-Associated Death Protein
  • Collagen