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)B4 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 LTB4 -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.
Keywords: BLT1; Lyme arthritis; efferocytosis; resolution.
© 2019 Federation of American Societies for Experimental Biology.