Maresin1通过TLR4/NF-κB/NLRP3通路抑制焦亡减轻下肢缺血再灌注损伤的机制

doi:10.3969/j.issn.1006-5725.2026.10.020

Abstract

Abstract:

Objective To investigate the mechanism by which Maresin1 reduces lower limb ischemia-reperfusion injury through the inhibition of pyroptosis. Methods This study employed a combination of in vivo and in vitro experiments. In the in vivo experiment， 27 C57BL/6 mice were randomly allocated into the Control group， the model group （LL-IRI）， and the treatment group （MaR1）. After successful modeling and drug intervention， the gastrocnemius muscle tissue of 5 mice （n = 5） from each group was collected for transcriptome sequencing and bioinformatics analysis. The remaining samples were utilized to assess histopathological damage and to detect the expression of TLR4/NF-κB p65 and NLRP3/GSDMD proteins. The MDA content and CAT activity in the serum were determined using kits. In vitro， L6 skeletal muscle cells were stimulated with LPS and ATP to establish a pyroptosis model. After modeling， ELISA was applied to measure the content of IL-1β and IL-18 in the supernatant of each group. Results Bulk RNA sequencing analysis demonstrated that， in comparison with the control group， the TLR4/NF-κB/NLRP3 signaling pathway and the expression of pyroptosis-related genes were significantly up-regulated in the LL-IRI group. Moreover， the intervention of MaR1 could reverse the above-mentioned trend， as MaR1 negatively regulated the activation of inflammasomes and the biological process associated with pyroptosis. Immunohistochemistry indicated that the expression of TLR4/NF-κB p65 and NLRP3/GSDMD was significantly enhanced in the LL-IRI group （P < 0.01）， accompanied by an increase in serum MDA content （P < 0.01） and a decrease in CAT activity （P < 0.01）. MaR1 treatment could significantly improve these pathological， molecular， and biochemical parameters. The results of in vitro experiments showed that， compared with the normal group， there was a significant increase in the release of inflammatory factors IL-1β and IL-18 at the end of pyroptosis in the LPS + ATP group （P < 0.01）. After the intervention of MaR1， the release of IL-1β and IL-18 in the LPS + ATP group was significantly reduced （P < 0.01）. Conclusion MaR1 may inhibit pyroptosis by blocking the TLR4/NF-κB/NLRP3 inflammatory cascade， thereby alleviating lower limb ischemia/reperfusion （I/R） injury in mice.

Key words: Maresin1, lower limb ischemia-reperfusion injury, pyroptosis, toll-like receptor 4

CLC Number:

R654.3

Jun LÜ,Tang DENG,Jin PENG,Xunkai WANG,Jiangpeng WU,Guiyun JIN. Mechanism of maresin1 in alleviating lower limb ischemia-reperfusion injury by inhibiting pyroptosis via the TLR4/NF-κB/NLRP3 pathway[J]. The Journal of Practical Medicine, 2026, 42(10): 1849-1857.

Figures/Tables 7

Fig.1

Fig.2

Fig.3

Fig.4

Fig.5

Fig.6

Fig.7

References 27

[1]	CARMON L， PETERS A A， LABAN N， et al. Part I： Acute lower limb ischemia-reperfusion injury： Pathophysiology and experimental interventions［J］. Vasc Endovascular Surg， 2026， 60（3）： 255-270. doi：10.1177/15385744251387771 . doi: 10.1177/15385744251387771
[2]	刘洋，何春水，张丽峰，等. 机械性血栓清除术治疗急性下肢动脉缺血中应用AngioJet的疗效及预后［J］. 实用医学杂志， 2022， 38（10）： 1255-1259. doi：10.3969/j.issn.1006-5725.2022.10.016 . doi: 10.3969/j.issn.1006-5725.2022.10.016
[3]	DENG T， PENG J， YE B， et al. Near-infrared fluorogenic probe enables real-time imaging of HOCl to reveal MAR1-mediated suppression of pyroptosis in limb ischemia-reperfusion injury［J］. Anal Chem， 2025， 97（48）： 26599-26606. doi：10.1021/acs.analchem.5c04923 . doi: 10.1021/acs.analchem.5c04923
[4]	ZHANG M， GUO B， ZHANG X， et al. IFP35， a novel DAMP， aggravates neuroinflammation following acute ischemic stroke via TLR4/NF-κB/NLRP3 signaling［J］. J Neuroinflammation， 2025， 22（1）： 164. doi：10.1186/s12974-025-03492-6 . doi: 10.1186/s12974-025-03492-6
[5]	GOUCHOE D A， ZHANG Z， KIM J L， et al. Improving lung allograft function in the early post-operative period through the inhibition of pyroptosis［J］. Med Rev， 2024， 4（5）： 384-394. doi：10.1515/mr-2023-0066 . doi: 10.1515/mr-2023-0066
[6]	周文洋，廖烨晖，田明昊，等. NLRP3炎性小体在脊髓损伤后小胶质细胞中的作用［J］. 中国组织工程研究， 2025， 29（13）： 2849-2860. doi：10.12307/2025.035 . doi: 10.12307/2025.035
[7]	宋行行，刘鑫源，李虹霖，等. 细胞焦亡在脑缺血再灌注损伤中作用机制的研究进展［J］. 生命科学， 2025， 37（3）： 296-303. doi：10.13376/j.cbls/2025030 . doi: 10.13376/j.cbls/2025030
[8]	AL-KHARASHI L， ATTIA H， ALSAFFI A， et al. Pentoxifylline and thiamine ameliorate rhabdomyolysis-induced acute kidney injury in rats via suppressing TLR4/NF-κB and NLRP-3/caspase-1/gasdermin mediated-pyroptosis［J］. Toxicol Appl Pharmacol， 2023， 461： 116387. doi：10.1016/j.taap.2023.116387 . doi: 10.1016/j.taap.2023.116387
[9]	武禹佳，武文印，李艳，等. 隐丹参酮调节TLR4/NF-κB/NLRP3信号通路对高糖诱导的心肌细胞焦亡的影响［J］. 中西医结合心脑血管病杂志， 2024， 22（14）： 2553-2558. doi：10.12102/j.issn.1672-1349.2024.14.010 . doi: 10.12102/j.issn.1672-1349.2024.14.010
[10]	谷岩，何菊，侯骊坤，等. 急性下肢缺血再灌注损伤机制的研究进展［J］. 齐齐哈尔医学院学报， 2020， 41（12）： 1521-1522. doi：10.3969/j.issn.1002-1256.2020.12.025 . doi: 10.3969/j.issn.1002-1256.2020.12.025
[11]	SAITO-SASAKI N， SAWADA Y， NAKAMURA M. Maresin-1 and inflammatory disease［J］. Int J Mol Sci， 2022， 23（3）： 1367. doi：10.3390/ijms23031367 . doi: 10.3390/ijms23031367
[12]	WU H， WANG Y， FU H， et al. Maresin1 ameliorates sepsis-induced microglial neuritis induced through blocking TLR4-NF-κ B-NLRP3 signaling pathway［J］. J Pers Med， 2023， 13（3）： 534. doi：10.3390/jpm13030534 . doi: 10.3390/jpm13030534
[13]	ZHANG Q， WANG L， WANG S， et al. Signaling pathways and targeted therapy for myocardial infarction［J］. Signal Transduct Target Ther， 2022， 7（1）： 78. doi：10.1038/s41392-022-00925-z . doi: 10.1038/s41392-022-00925-z
[14]	刘慧玲，吴传新，龙贤梨，等. LPS与ATP共同诱导小鼠原代腹腔巨噬细胞焦亡模型的建立［J］. 中国免疫学杂志， 2023， 39（10）： 2028-2033. doi：10.3969/j.issn.1000-484X.2023.10.003 . doi: 10.3969/j.issn.1000-484X.2023.10.003
[15]	BROUWERS K， VAN GEEL S R W M， VAN MIDDEN D， et al. Added value of histological evaluation of muscle biopsies in porcine vascularized composite allografts［J］. J Clin Med， 2024， 13（17）： 5167. doi：10.3390/jcm13175167 . doi: 10.3390/jcm13175167
[16]	WANG H， SHI M J， HU Z Q， et al. Effect of miR-206 on lower limb ischemia-reperfusion injury in rat and its mechanism［J］. Sci Rep， 2023， 13（1）： 21574. doi：10.1038/s41598-023-48858-z . doi: 10.1038/s41598-023-48858-z
[17]	PENG J， DENG T， WANG X， et al. Advances in the treatment of lower-extremity ischemia-reperfusion injury［J］. Front Pharmacol， 2025， 16： 1576091. doi：10.3389/fphar.2025.1576091 . doi: 10.3389/fphar.2025.1576091
[18]	LORNE E， DUPONT H， ABRAHAM E. Toll-like receptors 2 and 4： Initiators of non-septic inflammation in critical care medicine？［J］. Intensive Care Med， 2010， 36（11）： 1826-1835. doi：10.1007/s00134-010-1983-5 . doi: 10.1007/s00134-010-1983-5
[19]	施佳君，杨钦钦，富丹婷，等. 冠心宁片抑制NLRP3/ASC/Caspase-1通路改善阿霉素诱导的扩张型心肌病大鼠心肌细胞焦亡［J］. 中国实验动物学报， 2024， 32（3）： 337-346. doi：10.3969/j.issn.1005-4847.2024.03.007 . doi: 10.3969/j.issn.1005-4847.2024.03.007
[20]	SHEN S， WANG Z， SUN H， et al. Role of NLRP3 inflammasome in myocardial ischemia-reperfusion injury and ventricular remodeling［J］. Med Sci Monit， 2022， 28： e934255. doi：10.12659/MSM.934255 . doi: 10.12659/MSM.934255
[21]	DE OLIVEIRA T H C， GONÇALVES G K N. Liver ischemia reperfusion injury： Mechanisms， cellular pathways， and therapeutic approaches［J］. Int Immunopharmacol， 2025， 150： 114299. doi：10.1016/j.intimp.2025.114299 . doi: 10.1016/j.intimp.2025.114299
[22]	SHIH Y V， TAO H， GILPIN A， et al. Specialized pro-resolving mediator Maresin 1 attenuates pain in a mouse model of osteoarthritis［J］. Osteoarthritis Cartilage， 2025， 33（3）： 341-350. doi：10.1016/j.joca.2024.10.018 . doi: 10.1016/j.joca.2024.10.018
[23]	CHEN Y， WU X， LI J， et al. The mechanisms of specialized pro-resolving mediators in pain relief： Neuro-immune and neuroglial regulations［J］. Front Immunol， 2025， 16： 1634724. doi：10.3389/fimmu.2025.1634724 . doi: 10.3389/fimmu.2025.1634724
[24]	XIAO H， LIU J， CAI Q， et al. Maresin 1 alleviates myocardial ischemia-reperfusion injury in rats by suppressing inflammation［J］. Eur J Histochem， 2025， 69（4）： 4254. doi：10.4081/ejh.2025.4254 . doi: 10.4081/ejh.2025.4254
[25]	史秀丽，陈嘉琪，朱璠，等. miR-143-3p靶向调控TLR2/NF-κB/NLRP3通路对溃疡性结肠炎细胞焦亡的影响［J］. 实用医学杂志， 2024， 40（15）： 2056-2062. doi：10.3969/j.issn.1006-5725.2024.15.003 . doi: 10.3969/j.issn.1006-5725.2024.15.003
[26]	CAI Q， ZHAO C， XU Y， et al. Qingda granule alleviates cerebral ischemia/reperfusion injury by inhibiting TLR4/NF-κB/NLRP3 signaling in microglia［J］. J Ethnopharmacol， 2024， 324： 117712. doi：10.1016/j.jep.2024.117712 . doi: 10.1016/j.jep.2024.117712
[27]	CHANG S Y， LI Y T， ZHU H Y， et al. Buyang Huanwu Decoction stabilizes atherosclerotic vulnerable plaques by regulating intestinal flora， TLR4-NF-κB-NLRP3 inflammatory pathway and mitophagy［J］. Phytomedicine， 2025， 142： 156751. doi：10.1016/j.phymed.2025.156751 . doi: 10.1016/j.phymed.2025.156751

Mechanism of maresin1 in alleviating lower limb ischemia-reperfusion injury by inhibiting pyroptosis via the TLR4/NF-κB/NLRP3 pathway

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 7

References 27

Related Articles 14

Recommended Articles

Metrics

Comments

[1]	Kehan YIN,Biyu WU,Qianqian WANG,Shengliang CHEN. The role of β2AR-mediated macrophage pyroptosis in psychological stress-induced duodenal inflammation in mice [J]. The Journal of Practical Medicine, 2026, 42(8): 1322-1331.
[2]	Yufen LU,Xiaoming ZHENG,Shaojuan WEI,Liqin CHEN,Tongtong XU,Xiangwei. LÜ. Effects of miR⁃483⁃3p on hypoxia/reoxygenation⁃induced apoptosis and pyroptosis in cardiomyocytes [J]. The Journal of Practical Medicine, 2025, 41(3): 339-346.
[3]	Qiang JIANG,Yu DING,Zhili DING,Jiaheng. HAN. Exploring the mechanism of acupotomy intervention on radicular inflammation in rabbit LDH model through ROS/NLRP3/Caspase⁃1 pyroptosis pathway [J]. The Journal of Practical Medicine, 2025, 41(14): 2167-2173.
[4]	Fei GAO,Jing LI,Hongjian. LI. MAPK improves intestional obstruction in pregnancy through inhibiting TLR4/Myd88/NF⁃κB pathway [J]. The Journal of Practical Medicine, 2024, 40(8): 1095-1100.
[5]	Yujun YI,Xiaoming ZHAI,Huiling LIU,Jin. TAO. The role of PTTG1 in colonic inflammation by regulating intestinal epithelial cells pyroptosis [J]. The Journal of Practical Medicine, 2024, 40(5): 632-638.
[6]	Zhenghao ZHANG,Fang MA,Qing ZHANG,Tongtong XIA,Honglin LIU,Zhigang BAI,Guanjun LU,Jingwen ZHANG,Hongjian PENG,Yideng JIANG,Shengchao. MA. Effect of LncRNA SNHG1 on homocysteine⁃induced podocytespyrophosis [J]. The Journal of Practical Medicine, 2024, 40(4): 476-482.
[7]	Xiao XIAO,Fangyi LONG,Gang. WANG. Dual role and new strategies of pyroptosis in cancer therapy [J]. The Journal of Practical Medicine, 2024, 40(23): 3419-3426.
[8]	Xiuli SHI,Jiaqi CHEN,Fan ZHU,Juan ZENG,Na. WU. The effect of miR⁃143⁃3p on pyroptosis of ulcerative colitis cells by regulating TLR2/NF⁃κB/NLRP3 [J]. The Journal of Practical Medicine, 2024, 40(15): 2056-2062.
[9]	Di WANG,Jian YANG,Xiang HE. Dexmedetomidine alleviates propofol induced learning and memory impairment in rats at developmental stage by regulating AKAP150 [J]. The Journal of Practical Medicine, 2024, 40(12): 1619-1624.
[10]	Xuan QIU,Yishajiang SHAREZATI,Yulan CHEN,Mengmeng WANG,Yu LI,Tulahong GULINAZI,Abuhan ZUBAIDAN,Abulizi ALIYA,Xingchen WANG. Effect of transient receptor potential channel 5 on myocardial pyroptosis in intermittent hypoxia [J]. The Journal of Practical Medicine, 2024, 40(12): 1637-1642.
[11]	Dan XIE,Shi. OUYANG. Effect of Yinchenhao Decoction combined with exosomes derived from umbilical cord mesenchymal stem cells on acute liver failure and hepatocyte pyroptosis [J]. The Journal of Practical Medicine, 2023, 39(23): 3034-3042.
[12]	Jiashan LI,Debin YANG,Zhifeng. PENG. Effect of chronic high fat diet on brain injury in ischemia/reperfusion rats and its mechanisms [J]. The Journal of Practical Medicine, 2023, 39(20): 2579-2583.
[13]	Sha YI,Nan HU,Yue LI,Lin YANG,Yuting ZHANG,Xia XIONG,Guishu ZHONG,Yan. CHEN. Role of peroxisome proliferator⁃activated receptors⁃γ in modulating P. acnes⁃induced pyroptosis， cell proliferation and apoptosis in human keratinocytes [J]. The Journal of Practical Medicine, 2023, 39(16): 2043-2049.
[14]	. Amygdalin reduces coronary endothelial pyroptosis and ameliorates atherosclerotic plaque formation in ApoE-/- mice [J]. The Journal of Practical Medicine, 2023, 39(14): 1746-1755.