NLRP3

A forum investigating the similarities between COVID-19 and fluoride poisoning, thyroid dysfunction and Gq/11 pathways.
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NLRP3

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NLRP3
©2022 - 2024 PFPC

NLRP3 = nucleotide-binding domain and leucine-rich repeat containing proteins 3
The NLRP3 inflammasome consists of NLRP3, ASC and pro-caspase 1 proteins. With NLRP3 activation, pro-caspase 1 converts into caspase 1, which leads to release proinflammatory cytokines like IL-1α, IL-1β, IL-18 and TNF-α.


The NLRP3 pathways is activated by both inorganic and organic fluoride compounds (PFAS). It is down-regulated by T3.

COVID-19

Jiang Q, Li G, Wang H, Chen W, Liang F, Kong H, Chen TSR, Lin L, Hong H, Pei Z - "SARS-CoV-2 spike S1 protein induces microglial NLRP3-dependent neuroinflammation and cognitive impairment in mice" Exp Neurol 115020 (2024). doi: 10.1016/j.expneurol.2024.115020
https://www.sciencedirect.com/science/a ... 8624003467 (NOTE: S1 used in this study likely contaminated with endotoxin. Thanks to Geoff Payne for info.)
"We found that S1 protein injection led to cognitive impairment, neuronal loss, and neuroinflammation by activating NLRP3 inflammation...These results reveal a distinct mechanism through which the SARS-CoV-2 spike S1 protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses."

Sciacchitano S, De Vitis C, D'Ascanio M, Giovagnoli S, De Dominicis C, Laghi A, Anibaldi P, Petrucca A, Salerno G, Santino I, Amodeo R, Simmaco M, Napoli C, Tafuri A, Di Napoli A, Sacconi A, Salvati V, Ciliberto G, Fanciulli M, Piaggio G, de Latouliere L, Ricci A, Mancini R - "Gene signature and immune cell profiling by high-dimensional, single-cell analysis in COVID-19 patients, presenting Low T3 syndrome and coexistent hematological malignancies" J Transl Med 19(1):139 (2021) doi: 10.1186/s12967-021-02805-6
Image


Fluoride

Zhang Q, Li T, Shi R, Qi R, Hao X, Ma B - "Fluoride promotes the secretion of inflammatory factors in microglia through NLRP3/Caspase-1/GSDMD pathway" Environ Sci Pollut Res Int. 2024 Feb 17. doi: 10.1007/s11356-024-32443-6
https://link.springer.com/article/10.10 ... 24-32443-6
https://pubmed.ncbi.nlm.nih.gov/38367109/
"NaF could induced BV2 cells injury in a dose-dependent fashion through disrupting the integrity of cell membranes and increasing IL-1β via upregulating NLRP3, Caspase-1, and its downstream protein GSDMD...our results suggested that NLRP3/Caspase-1/GSDMD-mediated classical pyroptosis pathway was involved in fluoride-induced BV2 microglia damage."

Li W, Ma Z, Su C, Liu F, Yan N, Duan X, Sun Z, Wang H, Ma Y, Wang Z, Ren F - "The hepatoprotective effect of sodium butyrate on hepatic inflammatory injury mediated by the NLRP3 inflammatory pathway in subchronic fluoride-exposed mice" Mol Biol Rep 51(1):1022 (2024). doi: 10.1007/s11033-024-09926-3
https://pmc.ncbi.nlm.nih.gov/articles/PMC11438657/

Chen R, Xu W, Sun Y, Zhi R, Xie P, Zhi Z, Tang X, Zhang C - "2-BFI Provides Neuroprotection Against Fluorosis by Stabilizing Endoplasmic Reticulum-Mitochondria Contact Sites and Inhibiting Activation of the NLRP3 Inflammasome" Neurochem Res 48(2):591-603 (2024). doi: 10.1007/s11064-022-03781-z.
https://link.springer.com/article/10.10 ... 22-03781-z


PFAS

Wang LQ, Liu T, Yang S, Sun L, Zhao ZY, Li LY, She YC, Zheng YY, Ye XY, Bao Q, Dong GH, Li CW, Cui J - "Perfluoroalkyl substance pollutants activate the innate immune system through the AIM2 inflammasome" Nat Commun 12(1):2915 (2021). doi: 10.1038/s41467-021-23201-0
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131593/
"Mechanistically, PFOS activates the AIM2 inflammasome in a process involving mitochondrial DNA release through the Ca2+-PKC-NF-κB/JNK-BAX/BAK axis..." NOTE: Here, PFOS induced caspase-1 activation - but not through NLRP3, but AIM2. In liver, PFOS acts via NLRP3, see Qin et al., 2022)

Shi B, Zhang Z, Xing J, Liu Q, Cai J, Zhang Z - "Perfluorooctane sulfonate causes pyroptosis and lipid metabolism disorders through ROS-mediated NLRP3 inflammasome activation in grass carp hepatocyte" Aquat Toxicol 267:106839 (2024). doi: 10.1016/j.aquatox.2024.106839
https://linkinghub.elsevier.com/retriev ... 24)00010-9
"This research demonstrated that PFOS drives NLRP3 inflammasome activation through oxidative stress induced by reactive oxygen species overload. This in turn leads to pyroptosis and lipid metabolism disorders."

Wang T, Xu H, Guo Y, Guo Y, Guan H, Wang D - "Perfluorodecanoic acid promotes high-fat diet-triggered adiposity and hepatic lipid accumulation by modulating the NLRP3/caspase-1 pathway in male C57BL/6J mice" Food Chem Toxicol 178:113943 (2023). doi: 10.1016/j.fct.2023.113943
https://www.sciencedirect.com/science/a ... 1523003459
"PFDA may enhance HFD-induced adiposity and hepatic lipid accumulation through the NLRP3/caspase-1 pathway. This contaminant may be a key risk factor for obesity development in individuals consuming high-fat foods, particularly Western diet."

Qin Y, Gu T, Ling J, Luo J, Zhao J, Hu B, Hua L, Wan C, Jiang S - "PFOS facilitates liver inflammation and steatosis: An involvement of NLRP3 inflammasome-mediated hepatocyte pyroptosis" J Appl Toxicol 42(5):806-817 (2022). doi: 10.1002/jat.4258
https://analyticalsciencejournals.onlin ... 2/jat.4258


Gq/11

Kong R, Peng L, Bao H, Sun L, Feng Y, Li H, Wang D - "The role of Gαq in regulating NLRP3 inflammasome activation" Inflamm Res. 2024 Oct 26. doi: 10.1007/s00011-024-01961-x
https://pubmed.ncbi.nlm.nih.gov/39455437/
"Our results indicate that Gαq regulates NLRP3 inflammasome activation by modulating mitochondrial ROS production. Our research provides new mechanistic insight into the activation of NLRP3 inflammasome. As it has been proved that NLRP3 inflammasome plays an important role in the pathogenesis many diseases such as Alzheimer's disease, cancer, and inflammatory bowel disease, Gαq might become a novel drug target for these diseases in future."

Xu M, Jiang Z, Wang C, Li N, Bo L, Zha Y, Bian J, Zhang Y, Deng X - "Acetate attenuates inflammasome activation through GPR43-mediated Ca2+-dependent NLRP3 ubiquitination" Exp Mol Med 51(7):1-13 (2019). doi: 10.1038/s12276-019-0276-5
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802670/
"Here, we demonstrate that acetate attenuates inflammasome activation via GPR43 in a Ca2+-dependent manner. Through binding to GPR43, acetate activates the Gq/11 subunit and subsequent phospholipase C-IP3 signaling to decrease Ca2+ mobilization...Collectively, our research demonstrates that acetate regulates the NLRP3 inflammasome via GPR43 and Ca2+-dependent mechanisms, which reveals the mechanism of metabolite-mediated NLRP3 inflammasome attenuation and highlights acetate as a possible therapeutic strategy for NLRP3 inflammasome-related diseases."


Thyroid

Dong X, Yang H, Li C, Liu Q, Bai Q, Zhang Z - "Triiodothyronine alleviates alcoholic liver disease injury through the negative regulation of the NLRP3 signaling pathway" Exp Ther Med 16(3):1866-1872 (2018). doi: 10.3892/etm.2018.6409
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122124/
"T3 negatively regulates the NLRP3-Caspase-1-pro-IL-1β-IL-1β signaling pathway and the NLRP3-TGF-β1 signaling pathway."

Głombik K, Detka J, Budziszewska B - "Venlafaxine and L-Thyroxine Treatment Combination: Impact on Metabolic and Synaptic Plasticity Changes in an Animal Model of Coexisting Depression and Hypothyroidism" Cells 10(6):1394 (2021). doi: 10.3390/cells10061394
https://pubmed.ncbi.nlm.nih.gov/34198731/
"...an unfavorable change caused by the lack of thyroid hormones was an increase in the caspase-1 level..."

Ma B, Chen D, Liu Y, Zhao Z, Wang J, Zhou G, Xu K, Zhu T, Wang Q, Ma C -"Yanghe Decoction Suppresses the Experimental Autoimmune Thyroiditis in Rats by Improving NLRP3 Inflammasome and Immune Dysregulation" Front Pharmaco 12:645354 (2021). doi: 10.3389/fphar.2021.645354
https://pubmed.ncbi.nlm.nih.gov/34234669/

Sahin E, Bektur E, Baycu C, Burukoglu Dönmez D, Kaygısız B - "Hypothyroidism Increases Expression of Sterile Inflammation Proteins in Rat Heart Tissue" Acta Endocrinol (Buchar) 5(1):39-45 (2019). doi: 10.4183/aeb.2019.39
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535312/

Sun YJ, Zhang YF, Xu HM, Ma YT, Li C, Nie CH, Zhao M - "Morin Improves Experimental Autoimmune Thyroiditis in Rats via NLRP3/Caspase-1 Pathway" Sichuan University. Medical Science Edition 52(2):229-234 (2021). Chinese. doi: 10.12182/20210160507
https://pubmed.ncbi.nlm.nih.gov/33829696/

Tahmineh Mokhtari, AymanEl-Meghawry El-Kenawy, Li Hu - "Intraventricular T3 reverses chronic restraint stress-induced depressive-like behaviors: Inhibition of NF-κB/NLRP3 inflammasome pathway in the hippocampus" (2021)
https://www.researchsquare.com/article/rs-226593/v1
Image

Vargas R, Videla LA - "Thyroid hormone suppresses ischemia-reperfusion-induced liver NLRP3 inflammasome activation: Role of AMP-activated protein kinase" Immunol Lett 184:92-97(2017). doi: 10.1016/j.imlet.2017.01.007
https://www.sciencedirect.com/science/a ... 7816302747


Resveratrol

Bartra C, Yuan Y, Vuraić K, Valdés-Quiroz H, Garcia-Baucells P, Slevin M, Pastorello Y, Suñol C, Sanfeliu C - "Resveratrol Activates Antioxidant Protective Mechanisms in Cellular Models of Alzheimer's Disease Inflammation" Antioxidants (Basel) 13(2):177 (2024. doi: 10.3390/antiox13020177.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10886200/



SEE also: LPS - Endotoxin
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