Inflammasome activation and regulation: toward a better understanding of complex mechanisms

Abstract

Inflammasomes are cytoplasmic multiprotein complexes comprising a sensor protein, inflammatory caspases, and in some but not all cases an adapter protein connecting the two. They can be activated by a repertoire of endogenous and exogenous stimuli, leading to enzymatic activation of canonical caspase-1, noncanonical caspase-11 (or the equivalent caspase-4 and caspase-5 in humans) or caspase-8, resulting in secretion of IL-1β and IL-18, as well as apoptotic and pyroptotic cell death. Appropriate inflammasome activation is vital for the host to cope with foreign pathogens or tissue damage, while aberrant inflammasome activation can cause uncontrolled tissue responses that may contribute to various diseases, including autoinflammatory disorders, cardiometabolic diseases, cancer and neurodegenerative diseases. Therefore, it is imperative to maintain a fine balance between inflammasome activation and inhibition, which requires a fine-tuned regulation of inflammasome assembly and effector function. Recently, a growing body of studies have been focusing on delineating the structural and molecular mechanisms underlying the regulation of inflammasome signaling. In the present review, we summarize the most recent advances and remaining challenges in understanding the ordered inflammasome assembly and activation upon sensing of diverse stimuli, as well as the tight regulations of these processes. Furthermore, we review recent progress and challenges in translating inflammasome research into therapeutic tools, aimed at modifying inflammasome-regulated human diseases.

NOD2/RIG-I Activating Inarigivir Adjuvant Enhances the Efficacy of BCG Vaccine Against Tuberculosis in Mice

“…These data are consistent with the observation that NOD2 and RIG-I receptor stimulation induces autophagy, boosts antibacterial effect and antigen presentation, although not in the context of tuberculosis (74,75). Notably, autophagy is linked with inflammasome activation which requires caspase-1, and excessive activation of inflammasome triggers its degradation via autophagy (45,46). Finally, capsase-1 enhances the acidification of phagosomal lumen through the activation of NOX2-phagocyte oxidase (75).…”

Upregulation of Nucleotide-Binding Oligomerization Domain-, LRR- and Pyrin Domain-Containing Protein 3 in Motoneurons Following Peripheral Nerve Injury in Mice

“…In response to nerve injury, NLRP3 was not only upregulated, but also translocated to the cytoplasm of motoneurons. Increased production of active IL-1β and IL-18 on the side of the injury suggests activation of inflammasomes, since cleavage of these cytokines is one of the best readout parameters of inflammasome activity (Broz and Dixit 2016;He et al, 2016;Zheng et al, 2020). Although the classical site of assembly of inflammasomes is the cytoplasm, a recent study revealed that six out of the 20 examined NLRs were detected in the nucleus as well.…”

NLPR3 Inflammasomes and Their Significance for Atherosclerosis

“…The second version demonstrated that caspase-1 recruitment and the NLRP3 inflammasome assembly reply may be suppressed at high extracellular potassium concentrations in Thp-1 macrophages. It may propose that potassium efflux may also activate NLRP3 [27].…”