J Immunol. 2026 Apr 15;215(4):vkag051. doi: 10.1093/jimmun/vkag051.
ABSTRACT
Folate receptor beta (FRβ), encoded by FOLR2, is selectively expressed in monocytes and macrophages, yet its function in innate immune signaling remains poorly defined. Here, we identify FRβ 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 severely impaired caspase-1 activation, gasdermin D cleavage, and IL-1β release in response to multiple NLRP3 stimuli, without altering pro-IL-1β induction. These defects were not rescued by exogenous folate and were independent of extracellular folate concentrations. Mechanistically, FOLR2/FRβ appears to potentiate potassium efflux and the expression of multiple potassium channel-encoding genes. Single-cell RNA sequencing revealed broad transcriptional repression in FRβ-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 FRβ promotes NLRP3 activation in a folate-independent manner potentially by regulating DNA methylation, gene transcription, and K+ efflux in macrophages. These findings uncover a previously unrecognized immunoregulatory function for FRβ, positioning it as a potential modulator of macrophage-driven inflammation in contexts such as host defense, autoimmunity, and tissue-specific immune responses at the tumor and maternal-fetal interface.
PMID:41984502 | DOI:10.1093/jimmun/vkag051