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Inflammasome Activation and Regulation Zheng et al. Cell Discovery (2020) 6:36 Cell Discovery https://doi.org/10.1038/s41421-020-0167-x www.nature.com/celldisc REVIEW ARTICLE Open Access Inflammasome activation and regulation: toward a better understanding of complex mechanisms Danping Zheng1,2,TimurLiwinski1,3 and Eran Elinav 1,4 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. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction (DAMPs), which are signals of host cellular distress. Inflammation is a vital physiological response triggered PAMPs and DAMPs are sensed by an increasingly by noxious agents in all metazoan organisms. Virtually appreciated variety of pattern recognition receptors any challenge to the body’s homeostasis may elicit an (PRRs) and cells of innate and adaptive immunity2,3. inflammatory response at the local or systemic levels1. Upon encounter of a pathogenic agent or tissue injury, The innate immune system’s task is to generate a pro- the innate immune system is challenged to integrate a tective response against signals of danger including both wealth of signals to initiate a proper response. In addition pathogenic microorganisms and sterile incursions such as to Toll-like receptors (TLR)4, Lectin receptors5, RIG-I- trauma, cancer, ischemia, and metabolic perturbations. like receptors6, and oligoadenylate synthase (OAS)-like Technically, factors eliciting an innate inflammatory receptor7,inflammasomes emerged in the last decade to response can be classified as pathogen-associated mole- constitute fundamental processing units contributing to cular patterns (PAMPs), conserved compounds of infec- PAMP and DAMP sensing, which actively participate in tious agents, and damage-associated molecular patterns integration of their downstream signaling3,8. The term “inflammasome” has originally been coined by Martinon et al.8 in a seminal report in 2002 that described the Correspondence: Eran Elinav ([email protected]) 1Immunology Department, Weizmann Institute of Science, Rehovot 7610001, assembly of these supramolecular structures in the cyto- Israel plasm of activated immune cells, thereby leading to pro- 2 fi Department of Gastroenterology, The First Af liated Hospital, Sun Yat-sen teolytic activation of proinflammatory caspases, which University, Guangzhou, China Full list of author information is available at the end of the article drives subsequent systemic immune responses and These authors contributed equally: Danping Zheng, Timur Liwinski © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Zheng et al. Cell Discovery (2020) 6:36 Page 2 of 22 inflammation. Importantly, while inflammasome signaling Inflammasome activation and assembly has been shown to be critical to host defense, the elicited As an important arm of innate immunity, one of the immune response needs to be tightly regulated in order to most outstanding functions of inflammasomes is to limit collateral damage to the host. This implies that detect and sense a variety of endogenous or exogenous, appropriate regulation of inflammasomes is intrinsic to the sterile or infectious stimuli that are encountered within control circuit of the associated inflammatory processes. the cell, and to induce cellular responses and effector Several cytoplasmic PRRs are able to assemble into an mechanisms. The assembly of the inflammasome plat- inflammasome complex and are classified by their protein form is a critical and well-organized process involving domain structures. For example, the NBD leucine-rich several core parts: the upstream sensors recognizing repeat-containing receptor (NLR) family implicates sub- activating signals, the adapters and the downstream families distinguishable by their N-terminal effector effectors (Fig. 1). domains. There are four recognizable NLR N-terminal domains: the acidic transactivation domain, pyrin domain, Pathogen-derived activating signals caspase recruitment domain (CARD), and baculoviral A plethora of PAMPs play key roles in initiating acti- inhibitory repeat (BIR)-like domains9. Another class of vation of various inflammasomes, among which the most inflammasome assembling PRRs is represented by PYHIN well-studied are bacteria-associated signals. Pathogenic protein family members, such as absent in melanoma 2 activators of the NLRC4 inflammasome are mainly (AIM2), which contain HIN200 and pyrin domains10. derived from Gram-negative bacteria namely Salmonella, Inflammasome-assembling PRRs are expressed in many Legionella, Shigella, and Pseudomonas spp. These bacteria cell types, including macrophages, dendritic cells (DCs), possess flagellin, or a type III (T3SS) or type IV (T4SS) neutrophils, and epithelial cells11. The final common secretion system rod proteins that are recognized by the pathway of inflammasome signaling is inflammatory NAIP proteins, constituting unique binding partners of caspase-activation. This task is achieved by the assembly of NLRC417. The murine NLRP1b inflammasome detects a hetero-oligomeric complex based on a scaffold protein, Bacillus anthracis lethal toxin in the cytoplasm18. The such as NOD-like receptor-pyrin-containing proteins NLRP3 inflammasome can be activated by the pore- (NLRP) or AIM2 protein, and in some inflammasomes the forming activity of a wide array of Gram-positive and additional recruitment of adapter and effector partners, Gram-negative bacteria, including Staphylococcus aureus, such as apoptosis-associated speck-like protein containing Streptococcus pneumoniae, enterohemorrhagic Escherichia + a CARD (ASC)12. The activation of caspases results in the coli and others, mainly through triggering potassium (K ) – proteolytic activation of the proinflammatory cytokines eflux19 21. NLRP6 inflammasome can sense lipoteichoic interleukin-1β (IL-1β) and/or interleukin-18 (IL-18). In acid derived from Gram-positive pathogens like Listeria particular, IL-1β is considered a gatekeeper cytokine which monocytogenes22. In human macrophages, the NLRP7 is critically involved in many events related to activation inflammasome recognizes acylated lipopeptides, a and regulation of inflammation13. microbial cell wall components23. Free cytosolic DNA Considering the potency of the inflammasome- released from a variety of bacteria species, including but dependent immune responses, it is not surprising that not limited to Francisella novicida, is required to activate dysregulated inflammasome activity is associated with a the inflammasome-forming DNA sensor AIM224. Mod- number of inflammatory disorders or of multi-factorial ification and inactivation of the Rho GTPases by bacterial diseases involving an inflammatory component, toxins, for example the Clostridium difficile cytotoxin including autoinflammatory disorders, cardiometabolic TcdB, and Clostridium botulinum ADP-ribosylating C3 diseases, infection, cancer and neurological dis- toxin, are important to activate the Pyrin inflammasome, – orders12,14 16. Therefore, regulation of inflammasome dependent on their enzymatic activities25. In addition, activity and therapeutic interventions targeting struc- intracellular lipopolysaccharide (LPS) from Gram- tures related to inflammasome signaling constitute negative bacteria is known to be recognized by the promising areas of basic and translational
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