Semaphorins were originally identified as neural guidance factors. It has been demonstrated that these proteins play pleiotropic functions in immune regulation, angiogenesis, tumor metastasis, and bone metabolism. We here present the pathological implications of Semaphorin 4D (SEMA4D) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and show the novel regulatory mechanisms of neutrophils through neutrophil-endothelium interactions to maintain immunological homeostasis , providing basic and clinical implications.
Inappropriate activation of neutrophils plays a pathological role in AAV . S erum levels of soluble SEMA4D were elevated in AAV patients and correlated with disease activity scores. Cell surface expression of SEMA4D was downregulated in neutrophils from AAV patients, a consequence of proteolytic cleavage of membrane SEMA4D. Membranous SEMA4D on neutrophils bound to plexin B2 on endothelial cells, and this interaction decreased NET formation . Recombinant plexin B2 suppressed neutrophil Rac1 activation through SEMA4D’s intracellular domain, and inhibited pathogen- or ANCA-induced oxidative burst and NET formation .
Collectively, these findings indicate that neutrophil surface SEMA4D functions as a negative regulator of neutrophil activation (an immune check point for neutrophils) and imply that SEMA4D is a promising biomarker and potential therapeutic target for AAV.