Addition of apoptotic cells alters immune cell function and reduces ankle swelling in experimental Lyme arthritis

Abstract

Abstract Experimental Lyme arthritis is induced by the infection of C3H mice with the spirochete, Borrelia burgdorferi, (Bb), and is a valuable model to study the regulation of inflammation during bacterial infection. We are interested in understanding the role that apoptotic cells (AC) play in inflammation resolution during murine Lyme arthritis. We show the number of AC within infected ankle joints significantly increases during arthritis resolution. Additionally, injection of AC into the tibio-tarsal joints of Bb infected mice reduces ankle swelling compared to control animals. In vitro studies using bone marrow derived macrophages (BMDM) co-cultured with Bb demonstrates the addition of AC decreases TNFα and KC production, while increasing IL-10 and PGE2 levels. The presence of AC in BMDM and also bone marrow neutrophils (BMN) cultures, decreases Bb phagocytosis, and also decreases BMN migration to LTB4. To further explore this mechanism, we measured expression of PPAR-γ (peroxisome proliferator-activated receptor gamma), which is known to regulate cytokine expression. Addition of AC to BMDM/Bb co-cultures increased PPAR-γ transcription in vitro, and also within infected ankle joints compared to mock treated mice in vivo. We also found AC themselves can produce PGE2, a bioactive lipid which activates PPAR-γ, setting up a positive feedback loop for the production PGE2. These results suggest AC can alter macrophage and neutrophil effector functions and may play a role in downregulating inflammatory responses, perhaps via activation of PPAR-γ. In addition, injection of AC into infected joints may limit inflammatory responses or induce their resolution.