{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n A wealth of studies has established that nucleotide‐binding domain, leucine‐rich repeat–containing protein 3 (LRRC3), more commonly known as NLRP3, functions as a central intracellular sensor of both pathogen‐associated and damage‐associated molecular patterns. Upon activation by diverse stimuli – such as extracellular histones, high‐mobility group box 1 (HMGB1), reactive oxygen species, mitochondrial DNA, and other endogenous stress signals – NLRP3 forms a multiprotein complex (the NLRP3 inflammasome) by recruiting the adaptor ASC and pro–caspase‐1. This assembly leads to caspase‐1 activation, facilitating the cleavage and secretion of proinflammatory cytokines interleukin (IL)–1β and IL–18 as well as the induction of inflammatory cell death (pyroptosis)."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n This signaling cascade not only drives innate immune responses during infections but also underpins sterile inflammatory injuries—as demonstrated in hepatic ischemia/reperfusion and in acute glaucoma—as well as in chronic conditions including neuroinflammation, atherosclerosis, diabetic nephropathy, and even in the modulation of platelet activation in sickle cell disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, additional regulators – including factors such as TRIM25, BRD4, and various pattern recognition receptors and kinases – modulate NLRP3 inflammasome activity, thereby influencing inflammatory cytokine production, cell death, and tissue damage in multiple disease models. In turn, these insights have spurred progress toward therapeutic interventions that either directly target NLRP3 or modulate its upstream activators to mitigate detrimental inflammation in disorders ranging from cardiovascular disease and neurodegeneration to metabolic and ischemic injuries."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, LRRC3/NLRP3 operates as a pivotal inflammasome component that bridges cellular stress sensing to inflammatory effector responses. Its activation not only contributes to the onset and amplification of tissue injury and immune dysregulation in various experimental models but also offers a promising therapeutic target for controlling excessive inflammation in a broad spectrum of acute and chronic human diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hai Huang, Hui-Wei Chen, John Evankovich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Histones activate the NLRP3 inflammasome in Kupffer cells during sterile inflammatory liver injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1202733"}], "href": "https://doi.org/10.4049/jimmunol.1202733"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23904166"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23904166"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Wei Chi, Hongrui Chen, Fei Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HMGB1 promotes the activation of NLRP3 and caspase-8 inflammasomes via NF-κB pathway in acute glaucoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neuroinflammation (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12974-015-0360-2"}], "href": "https://doi.org/10.1186/s12974-015-0360-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26224068"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26224068"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Aritz Lopategi, Roger Flores-Costa, Bibiana Rius, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Frontline Science: Specialized proresolving lipid mediators inhibit the priming and activation of the macrophage NLRP3 inflammasome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Leukoc Biol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/JLB.3HI0517-206RR"}], "href": "https://doi.org/10.1002/JLB.3HI0517-206RR"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29601102"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29601102"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Weizhe Zhong, Zhuqing Rao, Jianhua Rao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aging aggravated liver ischemia and reperfusion injury by promoting STING-mediated NLRP3 activation in macrophages."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Aging Cell (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/acel.13186"}], "href": "https://doi.org/10.1111/acel.13186"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32666684"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32666684"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Wei Ye, Yingfeng Lei, Mengmeng Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NLRP3 inflammasome is responsible for Hantavirus inducing interleukin-1β in THP-1 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijmm.2015.2162"}], "href": "https://doi.org/10.3892/ijmm.2015.2162"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25847326"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25847326"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Dan-Shu Wang, Liu-Yan Yan, De-Zhi Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Formononetin ameliorates myocardial ischemia/reperfusion injury in rats by suppressing the ROS-TXNIP-NLRP3 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2020.02.147"}], "href": "https://doi.org/10.1016/j.bbrc.2020.02.147"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32145915"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32145915"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Hai Huang, Samer Tohme, Ahmed B Al-Khafaji, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hepatology (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/hep.27841"}], "href": "https://doi.org/10.1002/hep.27841"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25855125"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25855125"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Hong-Su Park, Yao Lu, Kannupriya Pandey, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NLRP3 Inflammasome Activation Enhanced by TRIM25 is Targeted by the NS1 Protein of 2009 Pandemic Influenza A Virus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Microbiol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fmicb.2021.778950"}], "href": "https://doi.org/10.3389/fmicb.2021.778950"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34867921"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34867921"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yi Zhou, Yang Gu, Jianming Liu "}, {"type": "b", "children": [{"type": "t", "text": "BRD4 suppression alleviates cerebral ischemia-induced brain injury by blocking glial activation via the inhibition of inflammatory response and pyroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2019.07.097"}], "href": "https://doi.org/10.1016/j.bbrc.2019.07.097"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31530390"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31530390"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Zhenning Liu, Xiaokai Wang, Yu Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NLRP3 inflammasome activation regulated by NF-κB and DAPK contributed to paraquat-induced acute kidney injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunol Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12026-017-8901-7"}], "href": "https://doi.org/10.1007/s12026-017-8901-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28215032"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28215032"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Oscar J Lara-Guzman, Jorge H Tabares-Guevara, Yudy M Leon-Varela, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Proatherogenic macrophage activities are targeted by the flavonoid quercetin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pharmacol Exp Ther (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/jpet.112.196147"}], "href": "https://doi.org/10.1124/jpet.112.196147"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22869926"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22869926"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Gloria Lopez-Castejon "}, {"type": "b", "children": [{"type": "t", "text": "Control of the inflammasome by the ubiquitin system."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS J (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/febs.15118"}], "href": "https://doi.org/10.1111/febs.15118"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31679183"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31679183"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Sebastian Vogel, Sayuri Kamimura, Taruna Arora, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NLRP3 inflammasome and bruton tyrosine kinase inhibition interferes with upregulated platelet aggregation and in vitro thrombus formation in sickle cell mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2021.03.115"}], "href": "https://doi.org/10.1016/j.bbrc.2021.03.115"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33831782"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33831782"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Sebastian Vogel, Taruna Arora, Xunde Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The platelet NLRP3 inflammasome is upregulated in sickle cell disease via HMGB1/TLR4 and Bruton tyrosine kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood Adv (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/bloodadvances.2018021709"}], "href": "https://doi.org/10.1182/bloodadvances.2018021709"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30333099"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30333099"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Sharifa Alzahrani, Sawsan A Zaitone, Eman Said, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Protective effect of isoliquiritigenin on experimental diabetic nephropathy in rats: Impact on Sirt-1/NFκB balance and NLRP3 expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int Immunopharmacol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.intimp.2020.106813"}], "href": "https://doi.org/10.1016/j.intimp.2020.106813"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32707499"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32707499"}]}]}]}