Na⁺/H⁺ exchanger regulatory factor 1 mediates the pathogenesis of airway inflammation in a murine model of house dust miteinduced asthma

Na⁺/H⁺ exchanger regulatory factor 1 (NHERF1), a class I PDZ-binding protein, regulates G proteincoupled receptor signaling in some cell types. NHERF1 also functions as a scaffolding protein and activates nonG proteincoupled receptor signaling pathways, thereby contributing to the pathogenesis of various diseases. Although we have previously shown that NHERF1 regulates mast cell functions, there is little information regarding the role of NHERF1 in other immune cells. How NHERF1 regulates the pathogenesis of allergic disease such as asthma also remains unknown. In the current study, we show that NHERF1 promotes allergic airway inflammation in a house dust mite extract (HDME)induced mouse model of asthma. Specifically, HDME-specific serum IgE levels, airway leukocyte numbers, and goblet cell hyperplasia were reduced in NHERF1^+/ mice as compared with NHERF1^+/+ mice. Interestingly, the gene expression of inflammatory (IL-17a, IL-25, and IL-33) as well as T helper 2 (Th2) cytokines (IL-4, IL-5, and IL-13) and several chemokines that recruit eosinophils, neutrophils, and lymphocytes were also decreased in the lungs of NHERF1^+/ mice exposed to HDME. Consistent with these observations, microRNAs regulating mucus production, inflammation, Th2 effector functions, and IL-13 expression were increased in the lungs of HDME-treated NHERF1^+/ mice. Overall, our studies reveal a unique role for NHERF1 in regulating asthma pathogenesis, and further elucidation of the mechanisms through which NHERF1 modulates allergic inflammation will lead to the development of new therapeutic strategies for asthma. The Journal of Immunology, 2021, 206: 23012311.