A murine model of eosinophilic chronic rhinosinusitis using the topical application of a vitamin D3 analog

Abstract

Background Eosinophilic chronic rhinosinusitis (ECRS) is a chronic inflammatory disease, characterized by eosinophilic infiltration, T‐helper type 2 (Th2‐type) response, and olfactory dysfunction. A master regulator of Th2‐type inflammation, thymic stromal lymphopoietin (TSLP), is important for basophil activation. TSLP‐elicited basophils are a key factor in the pathogenesis of ECRS. Methods In order to elucidate the mechanisms of ECRS in humans, we aimed to establish a murine model of ECRS based on TSLP production in response to the topical application of MC903 (a vitamin D3 analog) and the subsequent TSLP‐induced basophil activation. Histological analyses were performed to assess immune cell infiltration into the nasal mucosa and to explore the impact of eosinophilic inflammation on the olfactory epithelium. The status of Th2‐type inflammation was evaluated by quantitative real‐time PCR and enzyme‐linked immunosorbent assay (ELISA). Results Eosinophils, basophils, and M2 macrophages increased significantly in the nasal mucosa of the mice treated with MC903 and ovalbumin (OVA), compared to those treated with OVA alone or the controls. Quantitative real‐time PCR and ELISA revealed elevated expression of interleukin (IL)‐4, IL‐5, IL‐13, TSLP, the chemokine CCL11, and CCL24 in the nasal mucosa of the ECRS mice. In parallel, thinned olfactory epithelium and decreased mature olfactory sensory neurons were observed in the ECRS mice. Conclusions Our model of ECRS displayed Th2‐type inflammation in the sinonasal region, including both eosinophil infiltration and basophil infiltration. Additionally, olfactory epithelium turned out to be affected by eosinophilic inflammation. These features are consistent with the characteristics of the human ECRS.

Highlights in the advances of chronic rhinosinusitis

“…20 This may be the result of mast cell and eosinophil infiltration into olfactory mucosa and impaired renewal of olfactory neurons. 21,22 Type 2 CRSwNP is also more commonly associated with adult early-onset or late-onset asthma, which tends to also exhibit type 2 inflammation. 23 F I G U R E 1 Updated classification of chronic rhinosinusitis, adapted from EPOS2020.…”

“…Clinically, this endotype tends to be associated with loss of smell 20 . This may be the result of mast cell and eosinophil infiltration into olfactory mucosa and impaired renewal of olfactory neurons 21,22 . Type 2 CRSwNP is also more commonly associated with adult early‐onset or late‐onset asthma, which tends to also exhibit type 2 inflammation 23 …”

Thymic Stromal Lymphopoietin in Cutaneous Immune-Mediated Diseases

“…However, TSLPR expression on basophils is minimally associated with asthma severity, indicating a limited role for basophils in TSLP-induced inflammation ( 17 , 38 , 47 ). Based on these findings, basophils are involved in the polarization, expansion, and progression of Th2 polarization and appear to be critical in the pathogenesis of AD, allergic asthma and rhinitis, and eosinophilic chronic rhinosinusitis ( 48 ). However, the mechanism of the activation of basophils by TSLP under these abnormal conditions warrants additional investigations.…”

Activation of STAT6 by intranasal allergens correlated with the development of eosinophilic chronic rhinosinusitis in a mouse model

“…This was consistent with Kagoya R’s report. 34 The thinning of the olfactory mucosa and the loss of olfactory cells may lead to hyposmia. However, SEB alone could not significantly induce two cardinal features of ECRS, based on the polyp-like lesions and eosinophilic inflammation accompanied by Th2-type immunity.…”