Folate Receptor Beta Regulates Macrophage NLRP3 Inflammasome Activation and Pyroptosis in a Folate-Independent Manner

Here, we identify FRb as a novel regulator of NLRP3 inflammasome activation and pyroptosis in human THP-1 macrophages. Using CRISPR/Cas9-mediated gene deletion, we show that loss of FOLR2 impairs caspase-1 activation, gasdermin D cleavage, and IL-1b release in response to multiple NLRP3 stimuli, without altering pro-IL-1 b induction.

These defects were not rescued by exogenous folate and were independent of extracellular folate concentrations. Mechanistically, FOLR2 deletion reduced potassium efflux and downregulated multiple potassium channel genes. Single-cell RNA sequencing revealed broad transcriptional repression in FRb-deficient macrophages, including genes involved in inflammasome signaling and ion transport.