AIM2 positively regulates B cell activation and function through the SNX9-PI3K-WASP axis.

AIM2, an inflammasome sensor, has been extensively investigated for its ability to induce pyroptosis in macrophages. However, its role in the adaptive immune system remains poorly studied, particularly in B cells. AIM2 knockout mice had decreased follicular (FO) and marginal zone (MZ) B cell subsets and impaired IgG3 switching. The activation of B cells enhanced the co-localization of AIM2 and BCR. Interestingly, AIM2 exerts dual regulatory effects on BCR signaling transduction by positively regulating the PI3K-AKT signaling axis and negatively regulating the BTK-NFκB signaling axis. Through immunoprecipitation-mass spectrometry (IP-MS) analysis, SNX9 was identified as a critical molecule that promotes downstream signaling by facilitating the association of PI3K with CD19 in an AIM2-dependent manner. Furthermore, AIM2 is involved in the endocytosis of BCR and CD19 and the subsequent antigen uptake and presentation processes via SNX9-WASP interaction. In AIM2 knockout mice, this dual regulation leads to reduced overall BCR signaling characterized by decreased calcium signaling and reduced antibody production following RBD immunization. Conversely, AIM2 is overexpressed in B cells of Kawasaki disease patients, contributing to the development of this autoimmune disease. In summary, our study has unveiled a novel positive regulatory role of AIM2 in B cell receptor activation, endocytosis, and humoral response, focusing on AIM2-associated signaling pathways in B cells.