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.