MCC950 improves lipopolysaccharide‑induced systemic inflammation in mice by relieving pyroptosis in blood neutrophils

Miao,Runfeng; Huang,Jian

doi:10.3892/etm.2023.12117

MCC950 improves lipopolysaccharide‑induced systemic inflammation in mice by relieving pyroptosis in blood neutrophils

Authors:
- Runfeng Miao
- Jian Huang
View Affiliations

Affiliations: Department of Emergency Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
Published online on: July 13, 2023 https://doi.org/10.3892/etm.2023.12117
Article Number: 417

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Sepsis is an infection‑induced systemic inflammatory response syndrome accompanied by multiple organ injury and failure. MCC950, an inhibitor of NLR family pyrin domain containing 3 (NLRP3), can alleviate the inflammatory response and relieve inflammation‑induced injury. The aim of the present study was to explore the efficacy of MCC950 in lipopolysaccharide (LPS)‑induced inflammation and elucidate the underlying mechanisms. Based on a prior study, C57BL/6 mice were divided into three groups: Control, LPS, and LPS + MCC950. The mice were administered 10 mg/kg LPS to induce sepsis and 10 mg/kg MCC950 to treat sepsis 6 h before and after LPS injection. Histopathological imaging revealed organ morphology and damage during inflammation, and MCC950 alleviated organ damage and dysfunction. MCC950 prevented LPS‑induced inflammatory responses by reducing inflammatory cytokine levels in the blood. To explore the mechanism by which MCC950 functions, blood neutrophils were isolated and a series of tests were performed. As revealed by measuring reactive oxygen species levels and Annexin V/PI staining of neutrophils, MCC950 reduced oxidative stress and programmed death induced by LPS. Western blotting was used to assess the protein levels of pyroptosis‑related markers, including GSDMD, NLRP3, and caspase‑1, in neutrophils to further explore the form of death. MCC950 reduced LPS‑induced pyroptosis in neutrophils. The results of the survival analysis revealed that MCC950 increased the survival rates of mice within 72 h of LPS injection. MCC950 may be an effective treatment for sepsis that targets neutrophil pyroptosis.

View Figures

View References

1	Shen X, Cao K, Zhao Y and Du J: Targeting neutrophils in sepsis: From mechanism to translation. Front Pharmacol. 12(644270)2021.PubMed/NCBI View Article : Google Scholar
2	Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al: The Third International consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 315:801–810. 2016.PubMed/NCBI View Article : Google Scholar
3	Zhaolin Z, Guohua L, Shiyuan W and Zuo W: Role of pyroptosis in cardiovascular disease. Cell Prolif. 52(e12563)2019.PubMed/NCBI View Article : Google Scholar
4	Pronin A, Pham D, An W, Dvoriantchikova G, Reshetnikova G, Qiao J, Kozhekbaeva Z, Reiser AE, Slepak VZ and Shestopalov VI: Inflammasome activation induces pyroptosis in the retina exposed to ocular hypertension injury. Front Mol Neurosci. 12(36)2019.PubMed/NCBI View Article : Google Scholar
5	Skoglund C, Appelgren D, Johansson I, Casas R and Ludvigsson J: Increase of neutrophil extracellular traps, mitochondrial DNA and Nuclear DNA in newly diagnosed type 1 diabetes children but not in high-risk children. Front Immunol. 12(628564)2021.PubMed/NCBI View Article : Google Scholar
6	Phillipson M and Kubes P: The healing power of neutrophils. Trends Immunol. 40:635–647. 2019.PubMed/NCBI View Article : Google Scholar
7	Danielski LG, Giustina AD, Bonfante S, Barichello T and Petronilho F: The NLRP3 inflammasome and its role in sepsis development. Inflammation. 43:24–31. 2020.PubMed/NCBI View Article : Google Scholar
8	Wang J, Sahoo M, Lantier L, Warawa J, Cordero H, Deobald K and Re F: Caspase-11-dependent pyroptosis of lung epithelial cells protects from melioidosis while caspase-1 mediates macrophage pyroptosis and production of IL-18. PLoS Pathog. 14(e1007105)2018.PubMed/NCBI View Article : Google Scholar
9	Wang YC, Liu QX, Zheng Q, Liu T, Xu XE, Liu XH, Gao W, Bai XJ and Li ZF: Dihydromyricetin alleviates sepsis-induced acute lung injury through inhibiting NLRP3 inflammasome-dependent pyroptosis in mice model. Inflammation. 42:1301–1310. 2019.PubMed/NCBI View Article : Google Scholar
10	Gao YL, Zhai JH and Chai YF: Recent advances in the molecular mechanisms underlying pyroptosis in sepsis. Mediators Inflamm. 2018(5823823)2018.PubMed/NCBI View Article : Google Scholar
11	Zheng X, Chen W, Gong F, Chen Y and Chen E: The role and mechanism of pyroptosis and potential therapeutic targets in sepsis: A review. Front Immunol. 12(711939)2021.PubMed/NCBI View Article : Google Scholar
12	Zhang H, Du Y, Guo Y, Wang Z, Li H, Lv Z, Zeng L, Chen Y, Xie Z and Li R: TLR4-NLRP3-GSDMD-Mediated pyroptosis plays an important role in aggravated liver injury of CD38(-/-) sepsis mice. J Immunol Res. 2021(6687555)2021.PubMed/NCBI View Article : Google Scholar
13	Minasyan H: Sepsis: Mechanisms of bacterial injury to the patient. Scand J Trauma Resusc Emerg Med. 27(19)2019.PubMed/NCBI View Article : Google Scholar
14	Park GL, Park M, Min JK, Park YJ, Chung SW and Lee SJ: Anisomycin protects against sepsis by attenuating IκB kinase-dependent NF-κB activation and inflammatory gene expression. BMB Rep. 54:545–550. 2021.PubMed/NCBI View Article : Google Scholar
15	Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC and Reinhart K: International Forum of Acute Care Trialists. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med. 193:259–272. 2016.PubMed/NCBI View Article : Google Scholar
16	Coll RC, Hill JR, Day CJ, Zamoshnikova A, Boucher D, Massey NL, Chitty JL, Fraser JA, Jennings MP, Robertson AAB and Schroder K: MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat Chem Biol. 15:556–559. 2019.PubMed/NCBI View Article : Google Scholar
17	Sui A, Chen X, Shen J, Demetriades AM, Yao Y, Yao Y, Zhu Y, Shen X and Xie B: Inhibiting the NLRP3 inflammasome with MCC950 ameliorates retinal neovascularization and leakage by reversing the IL-1β/IL-18 activation pattern in an oxygen-induced ischemic retinopathy mouse model. Cell Death Dis. 11(901)2020.PubMed/NCBI View Article : Google Scholar
18	Garofalo AM, Lorente-Ros M, Goncalvez G, Carriedo D, Ballén-Barragán A, Villar-Fernández A, Peñuelas Ó, Herrero R, Granados-Carreño R and Lorente JA: Histopathological changes of organ dysfunction in sepsis. Intensive Care Med Exp. 7(Suppl 1)(S45)2019.PubMed/NCBI View Article : Google Scholar
19	Zhang XY, Chen X, Zhang HF, Guan S, Wen SH, Huang WQ and Liu ZM: Propofol does not reduce pyroptosis of enterocytes and intestinal epithelial injury after lipopolysaccharide challenge. Dig Dis Sci. 63:81–91. 2018.PubMed/NCBI View Article : Google Scholar
20	Ji J and Fan J: Neutrophil in reverse migration: Role in sepsis. Front Immunol. 12(656039)2021.PubMed/NCBI View Article : Google Scholar
21	Qi X, Yu Y, Sun R, Huang J, Liu L, Yang Y, Rui T and Sun B: Identification and characterization of neutrophil heterogeneity in sepsis. Crit Care. 25(50)2021.PubMed/NCBI View Article : Google Scholar
22	Kelley N, Jeltema D, Duan Y and He Y: The NLRP3 inflammasome: An overview of mechanisms of activation and regulation. Int J Mol Sci. 20(3328)2019.PubMed/NCBI View Article : Google Scholar
23	Wu X, Zhang H, Qi W, Zhang Y, Li J, Li Z, Lin Y, Bai X, Liu X, Chen X, et al: Nicotine promotes atherosclerosis via ROS-NLRP3-mediated endothelial cell pyroptosis. Cell Death Dis. 9(171)2018.PubMed/NCBI View Article : Google Scholar
24	Zhu F, Ma J, Li W, Liu Q, Qin X, Qian Y, Wang C, Zhang Y, Li Y, Jiang D, et al: The orphan receptor Nur77 binds cytoplasmic LPS to activate the non-canonical NLRP3 inflammasome. Immunity. 36:753–767.e8. 2023.PubMed/NCBI View Article : Google Scholar
25	He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, Yang ZH, Zhong CQ and Han J: Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res. 25:1285–1298. 2015.PubMed/NCBI View Article : Google Scholar
26	Tapia-Abellán A, Angosto-Bazarra D, Martínez-Banaclocha H, de Torre-Minguela C, Cerón-Carrasco JP, Pérez-Sánchez H, Arostegui JI and Pelegrin P: Addendum: MCC950 closes the active conformation of NLRP3 to an inactive state. Nat Chem Biol. 17(361)2021.PubMed/NCBI View Article : Google Scholar