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

ABSTRACT: Folate receptor beta (FRb), encoded by FOLR2, is selectively expressed in monocytes and macrophages, yet its function in innate immune signaling remains poorly defined. 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. Genome-wide methylation profiling showed increased CpG hypermethylation in FOLR2-deficient cells, consistent with reduced transcriptional activity. Our findings indicate that FRb promotes NLRP3 activation in a folate-independent manner by regulating transcription and K⁺ efflux in macrophages. These data reveal a previously unrecognized immunoregulatory role for FRb with implications for host defense, autoimmunity, and macrophage function in tissue microenvironments such as the tumor or placenta.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301541 | GEO | 2026/04/15

REPOSITORIES: GEO

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