Semaphorin 3E Deficiency Exacerbates Airway Inflammation, Hyperresponsiveness, and Remodeling in a Mouse Model of Allergic Asthma

Abstract

Semaphorin 3E (Sema3E) plays a crucial role in axon guidance, vascular patterning, and immune regulation. Nevertheless, the role of Sema3E in asthma is still elusive. In this study, we show that genetic ablation of Sema3E in mice results in increased lung granulocytosis, airway hyperresponsiveness, mucus overproduction, collagen deposition, and Th2/Th17 inflammation. Transfer of bone marrow progenitor cells to irradiated wild-type (WT) recipients exacerbates airway hyperresponsiveness and inflammation, whereas transfer of WT bone marrow progenitor cells ameliorates asthma pathology in recipients. mice display a higher frequency of CD11b pulmonary dendritic cells than their WT controls at the baseline and after sensitization with house dust mite. Adoptive transfer of CD11b pulmonary dendritic cells from mice into WT recipients increases house dust mite-induced Th2/Th17 inflammation in the airway. Together, these findings identify Sema3E as a novel regulatory molecule in allergic asthma that acts upstream of proallergic events and suggest that targeting this molecule could be a novel approach to treat allergic asthma.

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

“…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.…”

“…Mice heterozygous for SEMA3E expression ( Sema3e +/− ) on a mixed C57BL/6 background were used to generate Sema3e +/+ and Sema3e −/− , and Sema3e −/− was used to generate littermates. The immunophenotypic proprieties of Sema3e −/− have been described previously (Movassagh, Shan, Mohammed, et al, ). Male Sema3e −/− (20–25 g, 6–8 weeks old; IMSR Cat# KOMP:VG14098‐1‐Vlcg, RRID:IMSR_KOMP:VG14098‐1‐Vlcg) were obtained from the animal facility at the University of Manitoba and used according to the guidelines of the Canadian Council on Animal Care in science.…”

“…Semaphorins (SEMA) are secreted and membrane‐bound proteins that regulate a wide range of biological functions, from tissue morphogenesis to immune response regulation (Kruger, Aurandt, & Guan, ). The semaphorin family is composed of eight classes including semaphorin‐3E (SEMA3E), which is involved in cell trafficking and immune cell‐to‐cell interactions (Choi et al, ; Takamatsu et al, ) and controls the functions of CD11c + (Movassagh, Shan, Mohammed, et al, ). SEMA3E is also implicated in the pathogenesis of many chronic inflammatory diseases, including rheumatoid arthritis (Mangasser‐Stephan, Dooley, Welter, Mutschler, & Hanselmann, ), asthma (Movassagh, Shan, Mohammed, et al, ), atherosclerosis (Wanschel et al, ), adipose tissue inflammation, and insulin resistance (Shimizu et al, ).…”

“…The semaphorin family is composed of eight classes including semaphorin‐3E (SEMA3E), which is involved in cell trafficking and immune cell‐to‐cell interactions (Choi et al, ; Takamatsu et al, ) and controls the functions of CD11c + (Movassagh, Shan, Mohammed, et al, ). SEMA3E is also implicated in the pathogenesis of many chronic inflammatory diseases, including rheumatoid arthritis (Mangasser‐Stephan, Dooley, Welter, Mutschler, & Hanselmann, ), asthma (Movassagh, Shan, Mohammed, et al, ), atherosclerosis (Wanschel et al, ), adipose tissue inflammation, and insulin resistance (Shimizu et al, ). SEMA3E mediates anti‐proliferative and anti‐migratory functions by binding to the plexin‐D1 receptor (Gu et al, ), which is expressed by CD11c + cells (Worzfeld & Offermanns, ).…”

Neutrophilic Inflammation in the Immune Responses of Chronic Obstructive Pulmonary Disease: Lessons from Animal Models

“…It will be more appreciated if this model could clearly display a mucus hyperproduction as in the allergen-induced asthma model. If this could be realized, then a long-time self-antigen challenge should lead to the airway remodeling and emphysema-like airspace enlargement and eventually result in declined lung function, as does by allergens in the models of asthmatic airway remodeling [98, 99]. …”