Neutrophil-Derived Semaphorin 4D Induces Inflammatory Cytokine Production of Endothelial Cells via Different Plexin Receptors in Kawasaki Disease

Abstract

Inflammation of endothelial cells (ECs) plays an important role in the pathogenesis of coronary artery lesions (CALs) in Kawasaki disease (KD). Semaphorin 4D (Sema4D) is the first semaphorin shown to have immunoregulatory functions by interacting with its receptors—plexin Bs. Recently, Sema4D has been reported to exert a proinflammatory effect on the endothelium and to be involved in cardiovascular disease. However, the role of Sema4D in KD remains unknown. This study was aimed at revealing the change of soluble Sema4D (sSema4D) in the serum of patients with KD and the effect of the sSema4D-plexin axis on the production of proinflammatory cytokines from human coronary endothelial cells (HCAECs) stimulated with sera from KD patients. Our results showed that serum sSema4D levels were specifically elevated in KD patients, especially in those with CALs, and correlated positively with disease severity and serum concentrations of interleukin- (IL-) 1β, IL-6, and IL-8. The disintegrin and metalloproteinase domain 17- (AMAM17-) mediated Sema4D shedding from neutrophils contributed to the elevation of sSema4D in the serum of KD patients. Furthermore, we found that Sema4D induced IL-1β production of HCAECs via plexin B2, whereas it promoted IL-6 and IL-8 production via plexin B1. Moreover, the expression of both plexin B1 and plexin B2 was upregulated in HCAECs treated with KD sera, and silencing of the two plexin receptors suppressed the overexpression of IL-1β, IL-6, and IL-8 in KD serum-treated HCAECs. Thus, our findings indicated that sSema4D released from neutrophils participates in the pathogenesis of KD-CALs by promoting inflammatory cytokine production of ECs via both plexin B1 and plexin B2, and Sema4D may be a novel predictor for KD-CALs and a candidate therapeutic target for anti-inflammatory strategies of KD.

Overexpressed Neuropilin-1 in Endothelial Cells Promotes Endothelial Permeability through Interaction with ANGPTL4 and VEGF in Kawasaki Disease

“…In this study, we also found that albumin concentrations were decreased in the KD group, indicating these KD patients presented a status of vascular leakage. Sera from patients with KD have recently been used as a stimulator to achieve KD vasculitis in vitro [ 12 , 16 – 18 ]. KD serum can induce dysfunction and inflammation of HCAECs by activating Ca2+/nuclear factor of activated T cell signaling pathway, which leads to the proliferation and angiogenesis of endothelial cells [ 16 ]; and in our previous study, we showed that sera from KD patients can stimulate HCAECs to upregulate some cell-membrane molecules, such as plexin Bs [ 12 ].…”

“…Sera from patients with KD have recently been used as a stimulator to achieve KD vasculitis in vitro [ 12 , 16 – 18 ]. KD serum can induce dysfunction and inflammation of HCAECs by activating Ca2+/nuclear factor of activated T cell signaling pathway, which leads to the proliferation and angiogenesis of endothelial cells [ 16 ]; and in our previous study, we showed that sera from KD patients can stimulate HCAECs to upregulate some cell-membrane molecules, such as plexin Bs [ 12 ]. Here, for the first time, we treated HCAEC monolayers with KD sera and investigated the effect of KD sera on EC permeability.…”

“…Human coronary artery endothelial cells (HCAECs) were purchased from SCIENCELL (CA, USA) and cultured as previously described [ 12 ]. For the human serum stimulation assay, HCAECs were cultured in RPMI-1640 media containing 20% KD serum or HC serum for 6 hours.…”

Essential role of Rnd1 in innate immunity during viral and bacterial infections

“…Their role as receptors for immune guidance molecules has recently been identified. Reports indicate that Type-B plexins are abundant in lung epithelium [ 16 ], and their activation induces pro-inflammatory cytokine production [ 17 , 18 ]. Although the exact mechanism is unclear, it is thought that Rnd1 interaction with plexin-B1 regulates Rho GTPases either through their intrinsic RhoGAP activity or through PDZ-RhoGEF to induce cytokine expression [ 15 , 19 , 20 ].…”

Molecular mechanisms of endothelial dysfunction in Kawasaki-disease-associated vasculitis

“…Besides, the expression of Sema4D disturbs the cellular function of CD15+ neutrophils and correlates with the shedding proteinase, ADAM17, which interacts with endothelial cells and is associated with cardiovascular disease. Sema4D also promotes the production of cytokines in HCAECs in a dose-dependent manner through the Sema4D-plexin B axis ( 35 ) ( Figure 1 ).…”