Recently, the research results on the mechanism of inflammation heterogeneity in chronic sinusitis by Lv Wei’s team from the Department of Otolaryngology, PUMCH in collaboration with He Wei and Zhang Jianmin’s team from the Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, were published in “Nature Immunology” (IF=31.25). The team found that ALOX15 + macrophages hold the key to influencing and regulating the development of eosinophilic chronic sinusitis with nasal polyps (eCRSwNP), and ALOX15 is expected to be a new drug target for the treatment of eCRSwNP.

The prevalence of chronic rhinosinusitis (CRS) in China is as high as 8%. The response of different patients to the standard therapeutic regimen varies greatly, hence the need for individualized treatment regimens. Of the subtypes, eCRSwNP is the most difficult one for clinical treatment, as patients often have allergic rhinitis and asthma, are very highly dependent on glucocorticoids, and are prone to relapse after discontinuation of medication as well as to recurrence of nasal polyps after endoscopic surgery.

Starting with the pathogenesis, the research team first explored the key cellular and therapeutic targets that drive the progression of the disease. Adopting single-cell RNA sequencing, the team established the world’s first nasal mucosal immune cell, epithelial cell, and mesenchymal cell atlas in normal subjects, patients with chronic sinusitis without nasal polyps, eosinophilic chronic sinusitis with nasal polyps, and non-eosinophilic chronic sinusitis with nasal polyps. The team identified key factors affecting the progression and subtype differentiation of eCRSwNP at the molecular level: impaired nasal mucosal barrier function due to overproliferation and abnormal differentiation of basal cells, and deficiency of protective cellular molecules; dysfunction of cell clusters such as fibroblasts, macrophages, vascular endothelial cells and smooth muscle cells associated with extracellular matrix remodeling; increase of TH2 cells, ILC2 cells, IL5RA + plasma cells, cytotoxic CX3CR1+CD8+ TEFF cells, and NK cells with concomitant CD8 + TRM cell deficiency; loss of NK-cDC1 immune surveillance axis function and hyperactivation of ALOX15 + cDC2-TH2 interaction axis function; enrichment of ALOX15 + macrophages, which, through secretion of chemokines, recruit eosinophils, monocytes and TH2 cells, thereby promoting type 2 immune responses and driving the progression of the airway inflammatory process.

The research team dived deeper into the pathogenesis and therapeutic targets of the disease. The results showed that ALOX15 + macrophages hold the key to influencing and regulating the development of eCRSwNP disease. A model experiment of mice with eosinophilic sinusitis revealed that the application of ALOX15 inhibitors could effectively reduce cytokines IL-4, IL-5, IL-13 and IgE levels in the blood, alleviate type 2 inflammation, and produce good efficacy in patients with eosinophilic sinusitis, suggesting that ALOX15 could potentially become a new drug target for the treatment of eCRSwNP.

Correspondent: Wang Weiqing

Reporter: Gan Dingzhu

Translator: Liu Haiyan

Editor: Wang Weiqing and Wang Yao