PGRN Inhibits Early B‐cell Activation and IgE Production Through the IFITM3‐STAT1 Signaling Pathway in Asthma

Progranulin (PGRN) plays a critical role in bronchial asthma and the function of various immune cells. However, the mechanisms by which PGRN influences B‐cell receptor (BCR) signaling and immunoglobulin E(IgE) production are not fully understood. The study aimed to elucidate the molecular mechanisms through which PGRN affects BCR signaling, B‐cell differentiation, and IgE production. A PGRN knockout mouse model, along with techniques including flow cytometry, the creation of a bone marrow chimeric mouse model, total internal reflection fluorescence (TIRF), and Western blot (WB) analysis is employed, to investigate the link between PGRN and various aspects of B‐cell biology. It is discovered that the absence of PGRN in mice alters peripheral B‐cell subpopulations, promotes IgE class switching in a cell‐intrinsic manner, and affects B‐cell subpopulations. Additionally, PGRN modulates B‐cell functions by regulating BCR signaling pathways, metabolic processes, and the actin cytoskeleton during early B‐cell activation. Significantly, PGRN deficiency results in diminished production of NP‐specific antibodies. Moreover, it is found that PGRN inhibits B‐cell activation and IgE production through the PGRN‐IFITM3‐STAT1 signaling pathway. The findings provide new strategies for the targeted treatment of bronchial asthma, highlighting the crucial role of PGRN in B‐cell signaling and IgE production. Progranulin (PGRN) influences B‐cell receptor (BCR) signaling and immunoglobulin E (IgE) production, crucial in bronchial asthma. This study reveals that PGRN deficiency alters B‐cell subpopulations, enhances IgE class switching, and modulates BCR signaling via the PGRN‐IFITM3‐STAT1 pathway. These findings suggest potential therapeutic targets for asthma treatment.