Abrogation of lysophosphatidic acid receptor 1 ameliorates murine vasculitis

Lysophosphatidic acid (LPA), generated by autotaxin (ATX), is a bioactive lipid mediator that binds to the receptors (LPA_1-6), and serves as an important mediator in inflammation. Previous studies have demonstrated that LPA-LPA₁ cascade contributes to arthritis and skin sclerosis. In this study, we examined the role of LPA signals in murine Candida albicans water-soluble fraction (CAWS)-induced vasculitis.

ATX and LPA receptor expressions were analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. Effects of LPA₁ inhibition on CAWS-induced vasculitis were evaluated in LPA₁-deficient mice or using an LPA₁ antagonist, LA-01. Migration activity was assessed using a chemotaxis chamber. The number of migrated fluorescently labeled neutrophils, which were transferred into the vasculitis mice, was counted in the aortic wall. CXCL1 and IL-8 concentrations were determined by enzyme-linked immunosorbent assay.

ATX and LPA₁ were highly expressed in the inflamed region of CAWS-induced vasculitis. Severity of the vasculitis in LPA₁-deficient mice was suppressed. The LPA₁ antagonist, LA-01, also ameliorated the CAWS-induced vasculitis. LPA induced neutrophil migration, which was inhibited by LA-01 in vitro. Infiltration of transferred neutrophils from LPA₁-deficient mice into the coronary arteries was suppressed. LA-01 also inhibited the infiltration of wild-type neutrophils. Expression of CXCL1 and IL-8 in human endothelial cells was enhanced by LPA, but was inhibited by LA-01. ATX and LPA₁ expression levels were higher in the affected skin region of vasculitis patients than in healthy controls.

These results suggest that LPA-LPA₁ signaling contributes to the development of vasculitis via chemoattractant production from endothelial cells followed by neutrophil recruitment. Thus, LPA₁ has potential as a novel target for vasculitis therapies.