Chemorepellent Semaphorin 3E Negatively Regulates Neutrophil Migration In Vitro and In Vivo

Abstract

Neutrophil migration is an essential step in leukocyte trafficking during inflammatory responses. Semaphorins, originally discovered as axon guidance cues in neural development, have been shown to regulate cell migration beyond the nervous system. However, the potential contribution of semaphorins in the regulation of neutrophil migration is not well understood. This study examines the possible role of a secreted chemorepellent, Semaphorin 3E (Sema3E), in neutrophil migration. In this study, we demonstrated that human neutrophils constitutively express Sema3E high-affinity receptor, PlexinD1. Sema3E displayed a potent ability to inhibit CXCL8/IL-8-induced neutrophil migration as determined using a microfluidic device coupled to real-time microscopy and a transwell system in vitro. The antimigratory effect of Sema3E on human neutrophil migration was associated with suppression of CXCL8/IL-8-mediated Ras-related C3 botulinum toxin substrate 1 GTPase activity and actin polymerization. We further addressed the regulatory role of Sema3E in the regulation of neutrophil migration in vivo. Allergen airway exposure induced higher neutrophil recruitment into the lungs of Sema3e mice compared with wild-type controls. Administration of exogenous recombinant Sema3E markedly reduced allergen-induced neutrophil recruitment into the lungs, which was associated with alleviation of allergic airway inflammation and improvement of lung function. Our data suggest that Sema3E could be considered an essential regulatory mediator involved in modulation of neutrophil migration throughout the course of neutrophilic inflammation.

Semaphorin‐3E attenuates intestinal inflammation through the regulation of the communication between splenic CD11C+ and CD4+CD25− T‐cells

“…Interestingly, rec‐SEMA3E treatment ameliorated the development of colitis and decreased the level of colonic pro‐inflammatory cytokines not only in colitic Sema3e −/− but also in colitic Sema3e +/+ mice. Our findings are consistent with a recent study that showed an improved allergic airway inflammation in mice treated with exogenous rec‐SEMA3E (Movassagh, Saati, et al, ; Movassagh, Shan, Duke‐Cohan, et al, ; Movassagh, Shan, Mohammed, et al, ). Therefore, the present study highlights the immune‐modulatory role of SEMA3E during the pathogenesis of colitis.…”

“…In the brain, SEMA3E is mainly produced by specific neurons (Gu & Giraudo, ; Schmidt & Moore, ; Zhou, Gunput, & Pasterkamp, ), therefore, it is possible that the destruction of enteric neurons during the colonic inflammation (Lakhan & Kirchgessner, ; Lomax et al, ; Zhou et al, ) can result in the reduction of colonic levels of SEMA3E. Furthermore, reduced levels of SEMA3E are associated with various inflammatory conditions (Movassagh, Saati, et al, ; Movassagh, Shan, Mohammed, et al, ), and genetic ablation of Sema3e in a mouse model of allergic asthma results in an aggravated inflammation associated with a massive recruitment of immune cells into the inflamed tissue (Movassagh, Shan, Mohammed, et al, ). Furthermore, we reported that colonic Sema3E level is not higher in colitic Sema3e +/+ mice compared to Sema3e −/− mice in the same condition; this could be explained by the possibility that the recombinant protein reached a maximum level in the colon and passed into the blood stream.…”

Semaphorin 3F signaling actively retains neutrophils at sites of inflammation

“…SEMA3E, another class 3 semaphorin, signals independently of NRP coreceptor expression, unlike SEMA3F (33). More recently, Movassagh et al identified that SEMA3E was a chemorepellent and modulator of neutrophil migration in the context of chronic allergen-driven lung inflammation, in a whole animal Sema3e -/murine model (34). Our work both extends the role of class 3 semaphorins in regulating neutrophil movement to include SEMA3F and raises the concept of active neutrophil retention within the inflamed site.…”

Immunomodulatory Functions of Neuronal Guidance Proteins

“…Thus, the disruption of PlexinD1 expression in these macrophages and of adipose tissue p53 expression led to downregulation of Sema3E with reduced adipose tissue inflammation. By contrast, Sema3E reduced the infiltration of neutrophils through PlexinD1 in a model of allergic airway inflammation [28]. Sema4A is an important regulator of Th2-driven lung pathophysiology, where it markedly reduces the severity of allergic airway inflammation.…”