SEMA4D Exacerbates Eosinophilic CRS in Humans, Mice

by Amy E. Hamaker •

What are the pathological functions and therapeutic potential of semaphorin 4D (SEMA4D) in eosinophilic chronic rhinosinusitis (ECRS)?

Bottom line: Eosinophil-derived SEMA4D aggravates ECRS, and serum SEMA4D levels reflect disease severity. Anti-SEMA4D antibody has therapeutic potential as an ECRS treatment.

Commentary: “Eosinophilic chronic rhinosinusitis is a type of airway disease involving nasal inflammation. Many studies have attempted to understand the molecular-based pathogenesis of recurrent ECRS; none have provided a clear explanation, until now.” —Subinoy Das, MD

Background: ECRS is characterized by intractable nasal polyps with eosinophilic infiltration. It is becoming clear that semaphorins play key roles in immune regulation and inflammatory diseases. Blocking therapy of soluble SEMA4D has been proposed as a treatment for several diseases, but no study has examined the diagnostic or therapeutic potential of SEMA4D in allergic disease.

Study design: Human clinical/in vitro and mouse in vivo study of serum soluble SEMA4D levels in 126 patients with paranasal sinus disease treated between 2014 and 2018. 

Setting: Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Hospital, Osaka, Japan.

Synopsis: Serum soluble SEMA4D levels were significantly higher in patients with ECRS than in healthy donors or patients with other paranasal diseases, and serum SEMA4D levels were positively correlated with ECRS clinical features. SEMA4D levels on eosinophils were significantly lower in ECRS patients than in healthy donors. Membrane-bound SEMA4D on eosinophils was cleaved, contributing to the increase in serum soluble SEMA4D levels in ECRS patients. Matrix metalloproteinase (MMP-9) induced a decrease in SEMA4D cell surface expression on eosinophils, concomitant with soluble SEMA4D release. Tissue-infiltrated eosinophils in nasal polyps from ECRS patients stained strongly with anti-SEMA4D antibody. Treatment with SEMA4D increased endothelial cell permeability and increased basophil migration. SEMA4D exacerbated inflammation by eliciting eosinophil infiltration into local tissue, increasing nasal epithelial cell permeability, and inducing epithelial production of the cytokine IL-6. Paranasal inflammation was less severe, and neutrophils, eosinophils, and inflammatory cytokines were reduced in SEMA4D2/2 mice. Mice treated with anti-SEMA4D antibody exhibited significantly reduced eosinophilic inflammation in sinus tissues. Limitations included partially blinded polyp scoring, some in vitro experimental settings that were too focused, and an artificially induced allergic reaction in mice that may not accurately reflect intrinsic allergic disorders.

Citation: Tsuda T, Nishide M, Maeda Y, et al. Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis. J Allergy Clin Immunol. 2020;145:843-854.