Preventing pores and inflammation

doi:10.1126/science.abe0917

GSTDTAP > 气候变化

DOI	10.1126/science.abe0917
	Preventing pores and inflammation
	Robert J. Pickering; Clare E. Bryant
	2020-09-25
发表期刊	Science
出版年	2020
英文摘要	Inflammation is a tightly regulated process that is essential for host protection against infections. When it is dysregulated, however, inflammation becomes damaging, causing many common diseases such as sepsis, arthritis, asthma, and diabetes. Some programmed cell death pathways, such as pyroptosis and necroptosis, induce inflammation in response to pathogens or sterile stimuli. The pyroptosis executioner protein gasdermin D is cleaved by the cysteine protease caspases 1, 4, 5, or 11 ([ 1 ][1], [ 2 ][2]). This produces a toxic amino-terminal fragment that forms pores in membranes, which lyses cells and releases inflammatory mediators ([ 3 ][3]). On page 1633 of this issue, Humphries et al. ([ 4 ][4]) reveal a switch whereby dimethyl fumarate (DMF), a drug that is used to treat inflammatory conditions such as multiple sclerosis, succinates critical cysteine residues in gasdermin D to prevent its cleavage, inhibit pyroptosis, and protect against severe inflammation in mice. Gasdermin D is cleaved by caspases through the action of macromolecular inflammatory protein signaling complexes called inflammasomes ([ 1 ][1]). Canonical inflammasomes are formed when a cytosolic receptor such as a NOD-like receptor (NLR)—for example, NLRP3—binds to a ligand (pathogenic or endogenous), leading to the formation of a signaling platform that activates caspase 1 through proximity-induced dimerization ([ 5 ][5]). This process cleaves gasdermin D but also results in the cleavage of pro–interleukin 1β (pro–IL-1β) and pro–IL-18 into their mature forms ([ 1 ][1]). Gasdermin D pore formation, and the subsequent pyroptotic lysis of the cells, allows the release of these mature cytokines and a number of other damaging molecules to perpetuate inflammation ([ 6 ][6]). Noncanonical inflammasomes, activated by the binding of the bacterial lipid lipopolysaccharide to caspase 4 or 5 (in humans) or 11 (in mice), also results in gasdermin D cleavage, and this in turn leads to activation of NLRP3 and canonical inflammasome formation ([ 5 ][5]). ![Figure][7] Inflammatory cell death Upon inflammasome activation, caspases are released that cleave gasdermin D (GSDMD) and produce an amino-terminal fragment (GSDMD-NT). This fragment forms pores in the cellular membrane, inducing pyroptosis and release of inflammatory cytokines such as interleukin 18 (IL-18) and IL-1β. GRAPHIC: C. BICKEL/ SCIENCE Canonical NLRP3 inflammasome formation is linked to many chronic inflammatory diseases, including type 2 diabetes, Alzheimer's disease, and gout, so inhibition of this pathway is of considerable therapeutic interest ([ 7 ][8]). Inhibition of noncanonical inflammasome activation protects against sepsis and associated systemic inflammation ([ 7 ][8]), conditions that occur when the host response against infection (bacterial or viral) is dysregulated and becomes hyperactive. Sepsis is often intractable—for example, in severe coronavirus disease 2019 (COVID-19) ([ 8 ][9])—and despite multiple clinical trials, no successful treatments for sepsis have been developed. This has resulted in, understandably, waning enthusiasm by the pharmaceutical industry to develop drugs to treat sepsis. Inhibiting gasdermin D activation could represent a new strategy to target inflammatory conditions, especially because it is downstream of both canonical and noncanonical inflammasomes ([ 9 ][10]). Disulpharim, a drug already in clinical use for alcohol addiction, covalently modifies human Cys191 and mouse Cys192 in gasdermin D, resulting in prevention of pore formation but not its cleavage, protecting against sepsis in rodents ([ 10 ][11]). This drug is being tested in the DISCO clinical trial for patients with severe COVID-19 infections (NCT04485130). Humphries et al. show that succination of the same cysteines by DMF inhibits both gasdermin D processing and pore formation, reducing inflammatory conditions in mice (see the figure). These data confirm that inhibiting gasdermin D is promising, even for severe inflammatory conditions, and maybe this will tempt pharmaceutical companies, particularly in the context of the severe COVID-19 systemic inflammation syndrome, to revisit sepsis as an unmet medical need. Immunometabolism studies clearly show that metabolic reprogramming of cells underpins the anti-inflammatory effects of a number of therapeutic molecules ([ 11 ][12]). A number of important posttranslational modifications by endogenous metabolites modulate inflammatory pathways ([ 11 ][12]). DMF and its clinically relevant metabolite monomethyl fumarate, for example, succinate glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to inactivate its enzyme activity, down-regulating aerobic glycolysis to prevent immune activation. This shifts the balance from inflammatory toward regulatory cell types ([ 12 ][13]). Fumarate, from which DMF is derived, is a metabolic intermediate of the Krebs cycle (downstream of glycolysis), and so its inactivation of GAPDH may be an endogenous negative feedback loop ([ 12 ][13]). The identification of gasdermin D as another target of fumarate-mediated succination expands the repertoire of fumarate substrates and helps to explain some of the immunomodulatory effects of DMF. The intersection between metabolism and regulation of inflammasome biology is now well established, with metabolites regulating IL-1β production and multiple links between mitochondrial metabolism and NLRP3 activity ([ 13 ][14]). Many bacteria and viruses activate diverse inflammasomes, with pyroptosis thought to be an important aspect of the response to control infections ([ 6 ][6]). Efficient release of IL-1β and IL-18 from the cell requires gasdermin D pores ([ 6 ][6]), which makes it challenging to precisely differentiate between what is a pyroptotic-dependent or proinflammatory cytokine-dependent process. Pyroptosis is only one of a diverse array of cell death pathways that are increasingly linked to important functions in infection and immunity. The close interrelationship between cell death pathways, particularly those associated with caspase activity, probably arises because cell death is an essential process, and so redundancy is required if one pathway is lost or dysfunctional. In a Salmonella infection model, for example, ablation of caspases 1, 11, 12, and 8 as well as RIPK3 (receptor-interacting serine/threonine-protein kinase 3)—which limits pyroptosis, necroptosis, and apoptosis—is required to see a profound deficit in the ability of the host to control bacterial load ([ 14 ][15]). How these pathways are regulated and potential hierarchies in caspase activity are beginning to emerge, with caspase 8 being a key player and possibly controlled from a PANoptosome multiprotein cell death complex ([ 15 ][16]). How inhibiting, as opposed to genetically ablating, one cell death pathway affects the activity of another remains to be determined. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/296476
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Robert J. Pickering,Clare E. Bryant. Preventing pores and inflammation[J]. Science,2020.
APA	Robert J. Pickering,&Clare E. Bryant.(2020).Preventing pores and inflammation.Science.
MLA	Robert J. Pickering,et al."Preventing pores and inflammation".Science (2020).