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

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-indepe ndent functi on of AIM2 in B cells remai ns un clear.Here,we report in creased expressi on 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 lgG1-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 silendng 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.