Mechanisms of inflammasome mediated IL-1β production in germinal center B cells 2543

Description Influenza infected mice with a B cell-specific interleukin-1β (IL-1β) deficiency exhibit significant reduction in germinal center (GC) B cells, T follicular helper cells (TFH), and impaired trafficking of TFH cells into the B cell follicles, delineating a role of B cell-derived IL-1β in the GC reaction. Two signals drive IL-1β production - 1) NFkB mediated pro-IL1β expression and 2) activation of inflammasomes to cleave pro-IL1β into the active IL-1β. Extracellular ATP, ROSs, and ion fluxes within the GC suggest the activation of the NOD-like receptor-3 (NLRP3) inflammasome. We hypothesized that NLRP3 activity mediates IL-1β production in GC B cells. Our data show that GC B cells had significantly higher expression of NLRP3 than non-GC (nGC) and naïve B cells. B cell-specific ablation of NLRP3, but not of other inflammasome sensor proteins, showed significant reductions in GC B cell and TFH cell numbers. Mechanisms underpinning NLRP3 activity, like active caspase-1 (aCasp-1) and caspase-8 (aCasp-8) are upregulated in GC B cells. However, coexpression analysis showed significantly higher coexpression of aCasp-1 with IL-1β compared to aCasp-8 with IL-1β in GC vs. nGC B cells, suggesting aCasp-1 is mediating IL-1β activation. Similar to murine B cells, human activated GC B cells from the palatine tonsils showed IL-1β production, mediated by aCasp-1 and NLRP3 inflammasome activity. Our findings expose novel molecular targets to enhance the GC response, post influenza infection.