Equol inhibits NLRP3 inflammasome activation in macrophages 2257578

Abstract

The intestinal microbiome produces a vast number of metabolites. Many of these metabolites have immunomodulatory properties including the ability to inhibit the NOD, LRR, and pyrin-domain containing 3 (NLRP3) inflammasome, an established driver of inflammation in many diseases including gout, psoriasis, and Alzheimer’s disease. Therefore, we developed an enzyme-linked immunosorbent assay (ELISA) based screen to identify metabolites with the potential to inhibit NLRP3 activation. Using this screen, we identified equol, a metabolite of the soy isoflavone daidzein, as a strong candidate. Additional ELISAs and caspase-1 immunoblots further validated that equol inhibits ATP dependent NLRP3 activation in murine bone marrow derived macrophages (BMDMs), evidenced by significantly decreased IL-1β secretion and caspase-1 processing after equol treatment. Our work indicates equol’s anti-inflammatory effects are specific to the NLRP3 inflammasome; treatment with equol does not alter the secretion of several other inflammatory cytokines/chemokines (TNFα, IL-6, CXCL1, MIP-1α, RANTES) or activation of the AIM2 or NLRC4 inflammasomes in BMDMs. These findings lay a strong foundation for future studies examining the immunomodulatory action of equol in mouse models of NLRP3 driven disease. This work was supported by funds from the William F. Vilas Trust Estate and the National Institutes of Health P30AG062715, R01AG070973, and R01AG083883 to TKU Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)