Leukotriene B4 receptor BLT1 signaling is critical for neutrophil apoptosis and resolution of experimental Lyme arthritis.

Eicosanoids are powerful mediators of inflammation and are known to drive both the progression and regression of arthritis. We previously reported the infection of C3H 5-lipoxygenase (LO)-deficient mice with Borrelia burgdorferi results in prolonged nonresolving Lyme arthritis. Here we define the role of the 5-LO metabolite leukotriene (LT)B and its high-affinity receptor, BLT1, in this response. C3H and C3H BLT1 mice were infected with B. burgdorferi and arthritis progression was monitored by ankle swelling over time. Similar to 5-LO mice, BLT1 mice developed nonresolving Lyme arthritis characterized by increased neutrophils in the joint at later time points than WT mice, but with fewer apoptotic (caspase-3 ) neutrophils. In vitro, BLT1 neutrophils were defective in their ability to undergo apoptosis due to the lack of LTB -mediated down-regulation of cAMP, subsequent failure to induce Death-Inducing Signaling Complex (DISC) components, and decreased FasL and CD36 expression. Inhibition of adenylyl cyclase with SQ 22,536 restored BLT1 BMN apoptosis, FasL and CD36 expression, and clearance by macrophages. We conclude that LTB4/BLT1 signaling has an unexpected critical role in mediating neutrophil apoptosis via the down-regulation of cAMP. Loss of BLT1 signaling led to defective clearance of neutrophils from the inflamed joint and failed arthritis resolution.