AIM2 deficiency in B cells ameliorates systemic lupus erythematosus by regulating Blimp-1–Bcl-6 axis-mediated B-cell differentiation

• Published in: Signal transduction and targeted therapy Vol. 6; no. 1; pp. 341 - 11
• Main Authors: Yang, Ming, Long, Di, Hu, Longyuan, Zhao, Zhidan, Li, Qianwen, Guo, Yunkai, He, Zhenghao, Zhao, Ming, Lu, Liwei, Li, Fen, Long, Hai, Wu, Haijing, Lu, Qianjin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.09.2021; Nature Publishing Group
• Subjects: 692/699/1670; 692/699/249; Adenoids - metabolism; Adenoids - pathology; Animals; Antigens, CD19 - genetics; Bcl-6 protein; Cancer Research; CD19 antigen; Cell Biology; Cell differentiation; Cell Differentiation - genetics; Demethylation; Disease Models, Animal; DNA Methylation - genetics; DNA-Binding Proteins - genetics; Germinal Center - immunology; Humans; Immunity, Innate - genetics; Immunoglobulin G; Immunological memory; Inflammasomes; Interleukin 10; Internal Medicine; Lupus; Lupus Erythematosus, Systemic - blood; Lupus Erythematosus, Systemic - chemically induced; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lymph nodes; Lymph Nodes - metabolism; Lymph Nodes - pathology; Lymphocytes B; Medicine; Medicine & Public Health; Melanoma; Memory B Cells - immunology; Memory cells; Mice; Oncology; Pathology; Patients; Plasma cells; Positive Regulatory Domain I-Binding Factor 1 - genetics; Pristane; Proto-Oncogene Proteins c-bcl-6 - genetics; Skin diseases; Skin lesions; Spleen - immunology; Spleen - metabolism; Systemic lupus erythematosus; Terpenes - toxicity; Tonsil
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-021-00725-x

Absent in melanoma 2 (AIM2) has been reported to be a component of inflammasomes in innate immune cells. Surprisingly, AIM2 is expressed by B cells, and higher AIM2 expression is observed in the B cells from lupus patients. To date, the inflammasome-independent function of AIM2 in B cells remains unclear. Here, we report increased expression of AIM2 in human tonsil memory and germinal center (GC) B cells and in memory B cells and plasma cells from the circulation and skin lesions of lupus patients. Conditional knockout of AIM2 in B cells reduces the CD19 + B-cell frequency in lymph nodes and spleens, and dampens KLH-induced IgG1-antibody production. In a pristane-induced mouse model of lupus, AIM2 deficiency in B cells attenuates lupus symptoms and reduces the frequency of GC B cells, T follicular helper (Tfh) cells, plasmablast cells, and plasma cells. Furthermore, the loss of AIM2 in human B cells leads to the increased expression of Blimp-1 and reduces the expression of Bcl-6. However, the silencing of Blimp-1 and Bcl-6 has no significant effect on AIM2 expression, indicating that AIM2 might be the upstream regulator for Blimp-1 and Bcl-6. In addition, IL-10 is found to upregulate AIM2 expression via DNA demethylation. Together, our findings reveal that AIM2 is highly expressed in the B cells of lupus patients and promotes B-cell differentiation by modulating the Bcl-6–Blimp-1 axis, providing a novel target for SLE treatment.