Infection of mice with Borrelia burgdorferi causes an inflammatory arthritis that peaks 3-4 wk postinfection and then spontaneously resolves. Although the recruitment of neutrophils is known to drive the development of arthritis, mechanisms of disease resolution remain unclear. Efficient clearance of apoptotic cells (AC) is likely an important component of arthritis resolution. In this article, we show the number of AC increases in the joints of B. burgdorferi-infected mice around day 21 postinfection and peaks around day 28. Injection of AC directly into the ankles of B. burgdorferi-infected mice limited ankle swelling but had no effect on spirochete clearance or arthritis severity scores. In vitro, addition of AC to bone marrow macrophage cultures decreased B. burgdorferi-induced TNF-α and KC and increased IL-10. In addition, phagocytosis of B. burgdorferi and neutrophil migration to LTB4 were inhibited by AC. Exogenous AC caused an increase in peroxisome proliferator-activated receptor-γ (PPAR-γ) expression both in vitro and in vivo during B. burgdorferi infection. The PPAR-γ agonist rosiglitazone elicited similar changes in macrophage cytokine production and neutrophil migration as exogenous AC. Addition of the PPAR-γ antagonist GW 9662 abrogated the effects of AC in vitro. Injection of rosiglitazone directly into the tibiotarsal joints of B. burgdorferi-infected mice decreased ankle swelling and immune cell recruitment, similar to the injection of AC. These results suggest that clearance of AC plays a role in the resolution of inflammation during experimental Lyme arthritis through the activation of PPAR-γ. PPAR-γ agonists, such as rosiglitazone, may therefore be effective treatments for inducing arthritis resolution.
Copyright © 2019 by The American Association of Immunologists, Inc.