Neuroimmune semaphorin 4D is necessary for optimal lung allergic inflammation

Abstract

Neuroimmune semaphorin 4D (Sema4D) was found to be expressed and function in the nervous and immune systems. In the immune system, Sema4D is constitutively expressed on T cells and regulates T cell priming. In addition, it displays a stimulatory function on macrophages, DC, NK cells, and neutrophils. As all these cells are deeply involved in asthma pathology, we hypothesized that Sema4D plays a critical non-redundant regulatory role in allergic airway response. To test our hypothesis, we exposed Sema4D−/− and WT mice to OVA injections and challenges in the well-defined mouse model of OVA-induced experimental asthma. We observed a significant decrease in eosinophilic airway infiltration in allergen-treated Sema4D−/− mice relative to WT mice. This reduced allergic inflammatory response was associated with decreased BAL IL-5, IL-13, TGFβ1, IL-6, and IL-17A levels. In addition, T cell proliferation in OVA323–339 - restimulated Sema4D−/− cell cultures was downregulated. We also found increased Treg numbers in spleens of Sema4D−/− mice. However, airway hyperreactivity (AHR) to methacholine challenges was not affected by Sema4D deficiency in either acute or chronic experimental disease setting. Surprisingly, lung DC number and activation were not affected by Sema4D deficiency. These data provide a new insight into Sema4D biology and define Sema4D as an important regulator of Th2-driven lung pathophysiology and as a potential target for a combinatory disease immunotherapy.

Semaphorin 4A Stabilizes Human Regulatory T Cell Phenotype via Plexin B1

“…In contrast, Sema4D 2/2 mice demonstrated reduced allergic lung inflammatory cell infiltration, lung Th2 and proinflammatory cytokine contents, and humoral anti-allergen responses (20). The exacerbated inflammatory lung response in Sema4A 2/2 mice was accompanied by the significantly lower numbers of Treg cells in spleens and lungs, whereas this was the opposite for Sema4D 2/2 mice (19,20). Treatment of Sema4A 2/2 mice with recombinant Sema4A (rSema4A) resulted in not only significantly reduced allergic airway responses but also increased numbers of lung Treg cells (21).…”

“…We previously investigated the roles of two neuroimmune Sema, Sema4A and Sema4D, in allergic asthma in vivo. We demonstrated that these two distinct members of the class IV Sema family of proteins display opposite effects on asthma severity (19,20). Sema4A 2/2 mice exhibited an exacerbated response to allergen challenge that included increases in eosinophilic airway infiltration, lung local Th2 cytokine secretion, bronchial epithelial cell hyperplasia, airway hyperresponsiveness to methacholine challenges, and allergen-specific Ab content in serum (19).…”

“…Sema4A 2/2 mice exhibited an exacerbated response to allergen challenge that included increases in eosinophilic airway infiltration, lung local Th2 cytokine secretion, bronchial epithelial cell hyperplasia, airway hyperresponsiveness to methacholine challenges, and allergen-specific Ab content in serum (19). In contrast, Sema4D 2/2 mice demonstrated reduced allergic lung inflammatory cell infiltration, lung Th2 and proinflammatory cytokine contents, and humoral anti-allergen responses (20). The exacerbated inflammatory lung response in Sema4A 2/2 mice was accompanied by the significantly lower numbers of Treg cells in spleens and lungs, whereas this was the opposite for Sema4D 2/2 mice (19,20).…”

Semaphorin 4C Protects against Allergic Inflammation: Requirement of Regulatory CD138+ Plasma Cells

“…Nkyimbeng-Takwi et al (42) found that Sema4a 2/2 mice had higher baseline AHR and were hyperresponsive to OVA challenge. Sema4d 2/2 mice had low airway eosinophilia, normal basal AHR, and modest decreases in airway inflammation (43).…”

Semaphorin 4D is expressed constitutively by human eosinophils

“…It affected T cell activation and function suggesting its positive costimulatory role. 12 Further studies are required to define the function of eosinophil-expressed sema4D in lung allergic inflammation. Letter to the Editor / Allergology International xxx (2015) 1e3…”