Mechanisms of inflammation resolution in a murine model of Lyme arthritis
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In some patients, Lyme arthritis persists despite antibiotic clearance of Borrelia burgdorferi, indicating an underlying defect in inflammation resolution mechanisms. In the murine model of Lyme arthritis (mLA), B. burgdorferi infection of C3H/HeJ mice induces a self-limiting arthritis, allowing the study of both the development and resolution of inflammation. Our primary interest is the role of bioactive lipid mediators in mLA inflammation. Here we showed that 12/15-LO activity is required for efficient mLA resolution and that LXA4 may therapeutically ameliorate mLA by reducing edema and remodeling joint macrophage populations. We demonstrated that PGE2 is not required for mLA resolution, but mLA may instead resolve more efficiently in PGE2-deficient mPGES-1-/- mice due to enhanced bacterial control in the joint. Further, disruption of early inflammation in mPGES-1-/- mice by PGE2 addback worsened arthritis outcomes. We also designed an in vivo staining method to characterize neutrophil reverse transendothelial migration from the inflamed site. Lastly, we demonstrated that sleep fragmentation impairs B. burgdorferi clearance from the joint and prevents efficient mLA resolution. These findings strengthen our understanding of inflammation resolution and may help identify therapeutic targets to ameliorate human LA and other inflammatory diseases.
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Ph. D.