Uncoupled pyroptosis and IL-1β secretion downstream of inflammasome signaling

Abstract

Inflammasomes are supramolecular platforms that organize in response to various damage-associated molecular patterns and pathogen-associated molecular patterns. Upon activation, inflammasome sensors (with or without the help of ASC) activate caspase-1 and other inflammatory caspases that cleave gasdermin D and pro-IL-1β/pro-IL-18, leading to pyroptosis and mature cytokine secretion. Pyroptosis enables intracellular pathogen niche disruption and intracellular content release at the cost of cell death, inducing pro-inflammatory responses in the neighboring cells. IL-1β is a potent pro-inflammatory regulator for neutrophil recruitment, macrophage activation, and T-cell expansion. Thus, pyroptosis and cytokine secretion are the two main mechanisms that occur downstream of inflammasome signaling; they maintain homeostasis, drive the innate immune response, and shape adaptive immunity. This review aims to discuss the possible mechanisms, timing, consequences, and significance of the two uncoupling preferences downstream of inflammasome signaling. While pyroptosis and cytokine secretion may be usually coupled, pyroptosis-predominant and cytokine-predominant uncoupling are also observed in a stimulus-, cell type-, or context-dependent manner, contributing to the pathogenesis and development of numerous pathological conditions such as cryopyrin-associated periodic syndromes, LPS-induced sepsis, and Salmonella enterica serovar Typhimurium infection. Hyperactive cells consistently release IL-1β without LDH leakage and pyroptotic death, thereby leading to prolonged inflammation, expanding the lifespans of pyroptosis-resistant neutrophils, and hyperactivating stimuli-challenged macrophages, dendritic cells, monocytes, and specific nonimmune cells. Death inflammasome activation also induces GSDMD-mediated pyroptosis with no IL-1β secretion, which may increase lethality in vivo. The sublytic GSDMD pore formation associated with lower expressions of pyroptotic components, GSDMD-mediated extracellular vesicles, or other GSDMD-independent pathways that involve unconventional secretion could contribute to the cytokine-predominant uncoupling; the regulation of caspase-1 dynamics, which may generate various active species with different activities in terms of GSDMD or pro-IL-1β, could lead to pyroptosis-predominant uncoupling. These uncoupling preferences enable precise reactions to different stimuli of different intensities under specific conditions at the single-cell level, promoting cooperative cell and host fate decisions and participating in the pathogen “game”. Appropriate decisions in terms of coupling and uncoupling are required to heal tissues and eliminate threats, and further studies exploring the inflammasome tilt toward pyroptosis or cytokine secretion may be helpful.

Immune response of BV-2 microglial cells is impacted by peroxisomal beta-oxidation

“…As no IL1B secretion was detected, we wondered whether there was a maturation problem and also investigated the expression of the NLRP3/CASP1 inflammasome complex, which controls the release of IL1B and IL18 (Li and Jiang, 2023 ). Western blotting analysis confirmed the increase in pro-IL1B expression upon LPS treatment in each genotype but the absence of maturation of the protein ( Figure 2F ).…”

Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1β

“…Using IL-1β signaling to facilitate its colonization is an effective mechanism deployed by Salmonella , as multiple microbial detection apparatuses converge on processing and release of IL-1β [ 1 , 27 ]. Indeed, secretion of IL-1β can be performed even in the absence of inflammasome activation [ 1 ] and without resulting in pyroptosis [ 28 ]. This capability of different pathways to drive IL-1β secretion can also explain why mice deficient in individual components of the inflammasome have not shown the same resistance to Salmonella infection as we show here in IL-1β -/- mice [ 29 ].…”

Salvianolic Acid B Alleviates Liver Injury by Regulating Lactate-Mediated Histone Lactylation in Macrophages

“…In both RAW264.7 cells and Kupffer cells, Sal B is proven to downregulate the level of glycolysis for the data we detect in this paper. The release of LDH and the secretion of IL-1β serve as significant markers for the occurrence of pyroptosis in macrophage inflammation [ 28 ]. LDHA, an isoform of LDH, is a key rate-limiting enzyme in the final stage of cellular glycolysis, catalyzing the redox reaction of NADH and pyruvate to produce lactate and NAD+, in which the LDHA subunit plays a key role in glycolysis [ 29 ].…”