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

Autor: Hilliard KA; Department of Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA., Blaho VA; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA, USA., Jackson CD; Department of Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA., Brown CR; Department of Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2020 Feb; Vol. 34 (2), pp. 2840-2852. Date of Electronic Publication: 2019 Dec 24.
DOI: 10.1096/fj.201902014R
Abstrakt: 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 4 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 4 -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.
(© 2019 Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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