IL‐25 Enhances B Cell Responses in Type 2 Inflammation Through IL‐17RB Receptor

Abstract

BackgroundAlarmin cytokine IL‐25 promotes type 2 inflammatory responses in disorders such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) and known targets include ILC2 and Th2 cells. However, other cellular targets for IL‐25 remain poorly defined.ObjectiveTo investigate induction and expression of IL‐25 receptor (IL‐17RB) by B cells and evaluate responsiveness of IL‐17RB‐expressing B cells to IL‐25 in vitro.MethodsIL‐17RB expression, regulation and function on B cells were evaluated in peripheral blood‐derived B cells by flow cytometry and RT‐PCR, including in response to IgE‐inducing stimuli (anti‐CD40 mAb and IL‐4). Single‐cell RNA sequencing was used to compare IL‐17RB+ and IL‐17RB‐activated peripheral blood‐derived B cells. To evaluate B cell IL‐17RB expression within type 2 inflamed tissue, B cells were compared from nasal polyps, control turbinate tissue and matched peripheral blood.ResultsActivation of B cells with anti‐CD40 and IL‐4 increased IL‐17RB expression at both protein and mRNA level, which was further upregulated by IL‐25. B cells induced to express IL‐17RB responded to IL‐25 with enhanced antibody production. Single‐cell RNA‐sequencing showed that IL17RB+ activated B cells expressed higher levels of IGHE, CCL17 and CCL22 compared to IL17RB‐ B cells. B cells from nasal polyp tissue expressed higher levels of surface IL‐17RB compared with control tissue, correlating with patient‐reported CRSwNP severity (SNOT‐22).ConclusionPeripheral blood B cells activated under IgE‐inducing conditions express surface IL‐17RB, and tissue IL‐17RB+ B cells are increased in type 2 inflammation. IL‐17RB+ cells have a distinct transcriptional profile and respond to IL‐25 with enhanced antibody production, highlighting the IL‐25/IL‐17RB pathway as a potential therapeutic target for CRSwNP and other type 2 inflammatory disorders.