The role of apoptosis during inflammation resolution in Lyme arthritis

Abstract

Experimental Lyme arthritis is induced by the infection of C3H mice with the spirochete, Borrelia burgdorferi, and is a valuable model to study the regulation of inflammation during bacterial infection. While the lab has previously focused on how inflammation is initiated, this thesis focuses on the role of apoptotic cells during inflammation resolution in Lyme arthritis. We show administration of apoptotic cells can be used to initiate earlier resolution in B. burgdorferi-infected mice by decreased neutrophil recruitment, and this may be due to increased PPAR-[gamma] activation. Additionally, the PPAR-[gamma] agonist, rosiglitazone, can be used as a cell-free treatment to elicit a similar effect as the apoptotic cells. We also define the role of various eicosanoids during inflammation resolution. If apoptosis or efferocytosis, the phagocytosis of apoptotic cells, is dysregulated, it can cause exacerbated inflammation and arthritis. BLT1-/- neutrophils have a defect in apoptosis and efferocytosis recognition to due decreased DISC formation. This is a result of increased cAMP in BLT1-/- neutrophils due to the inability for LTB4/BLT1 signaling to downregulate cAMP. Additionally, macrophages must be able to produce PGE2 to be affected by and efferocytose apoptotic cells efficiently. Deficiencies in either of these eicosanoid signaling pathways results in increased cellular infiltrate during arthritis resolution, prolonging inflammation. We also show apoptotic cells actively secrete mediators to aid in their alteration of the inflammatory response. These results demonstrate the importance of apoptosis and efferocytosis during inflammation resolution in Lyme arthritis and several mechanisms involved.