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Inflammasomes are cytosolic multiprotein platforms with pivotal roles in infectious diseases. Activation of inflammasomes results in proinflammatory cytokine signaling and pyroptosis. Sexually transmitted infections (STIs) are a major health problem worldwide, yet few studies have probed the impact of inflammasome signaling during these infections. Due to the dearth of appropriate infection models, our current understanding of inflammasomes in STIs is mostly drawn from results obtained in vitro, from distant infection sites, or from related microbial strains that are not sexually transmitted. Understanding how inflammasomes influence the outcome of STIs may lead to the development of novel and effective strategies to control disease and prevent transmission. Here we discuss and highlight the recent progress in this field., Trends Distinct inflammasomes can be activated during sexually transmitted infections (STIs), often in discrete cell compartments. The crosstalk between multiple inflammasome sensors is central to maintaining tissue homeostasis. Contrary to popular belief, inflammasome activation can generate detrimental inflammatory responses during STIs in vivo. The outcome of inflammasome activity is governed by the complex host–pathogen interaction in the infected tissue. Inflammasome effector molecules can yield disparate functional consequences in different tissues, suggesting the need to employ appropriate infection models. Ligand internalization is not a necessary prerequisite for cytosolic NLRP3 activation. Engagement of certain plasma membrane-localized receptors by sexually transmitted pathogens or their ligands elicits both priming and activation signals for the NLRP3 inflammasome.

The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K(+) efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome.