MicroRNA‑129 plays a protective role in sepsis‑induced acute lung injury through the suppression of pulmonary inflammation via the modulation of the TAK1/NF‑κB pathway

Yao,Wenjian; Xu,Lei; Jia,Xiangbo; Li,Saisai; Wei,Li

doi:10.3892/ijmm.2021.4972

MicroRNA‑129 plays a protective role in sepsis‑induced acute lung injury through the suppression of pulmonary inflammation via the modulation of the TAK1/NF‑κB pathway

Authors:
- Wenjian Yao
- Lei Xu
- Xiangbo Jia
- Saisai Li
- Li Wei
View Affiliations

Affiliations: Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, P.R. China
Published online on: May 28, 2021 https://doi.org/10.3892/ijmm.2021.4972
Article Number: 139
Copyright: © Yao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Excessive inflammatory response and apoptosis play key roles in the pathogenic mechanisms of sepsis‑induced acute lung injury (ALI); however, the molecular pathways linked to ALI pathogenesis remain unclear. Recently, microRNAs (miRNAs/miRs) have emerged as important regulators of inflammation and apoptosis in sepsis‑induced ALI; however, the exact regulatory mechanisms of miRNAs remain poorly understood. In the present study, the gene microarray dataset GSE133733 obtained from the Gene Expression Omnibus database was analyzed and a total of 38 differentially regulated miRNAs were identified, including 17 upregulated miRNAs and 21 downregulated miRNAs, in mice with lipopolysaccharide (LPS)‑induced ALI, in comparison to the normal control mice. miR‑129 was found to be the most significant miRNA, among the identified miRNAs. The upregulation of miR‑129 markedly alleviated LPS‑induced lung injury, as indicated by the decrease in lung permeability in and the wet‑to‑dry lung weight ratio, as well as the improved survival rate of mice with ALI administered miR‑129 mimic. Moreover, the upregulation of miR‑129 reduced pulmonary inflammation and apoptosis in mice with ALI. Of note, transforming growth factor activated kinase‑1 (TAK1), a well‑known regulator of the nuclear factor‑κB (NF‑κB) pathway, was directly targeted by miR‑129 in RAW 264.7 cells. More importantly, miR‑129 upregulation impeded the LPS‑induced activation of the TAK1/NF‑κB signaling pathway, as illustrated by the suppression of the nuclear phosphorylated‑p65, p‑IκB‑α and p‑IKKβ expression levels. Collectively, the findings of the present study indicate that miR‑129 protects mice against sepsis‑induced ALI by suppressing pulmonary inﬂammation and apoptosis through the regulation of the TAK1/NF‑κB signaling pathway. This introduces the basis for future research concerning the application of miR‑129 and its targets for the treatment of ALI.

View Figures

View References

1	Hoesel LM, Neff TA, Neff SB, Younger JG, Olle EW, Gao H, Pianko MJ, Bernacki KD, Sarma JV and Ward PA: Harmful and protective roles of neutrophils in sepsis. Shock. 24:40–47. 2005. View Article : Google Scholar : PubMed/NCBI
2	Villar J, Blanco J, Añón JM, Santos-Bouza A, Blanch L, Ambrós A, Gandía F, Carriedo D, Mosteiro F, Basaldúa S, et al: The ALIEN study: Incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Med. 37:1932–1941. 2011. View Article : Google Scholar : PubMed/NCBI
3	Gill SE, Taneja R, Rohan M, Wang L and Mehta S: Pulmonary microvascular albumin leak is associated with endothelial cell death in murine sepsis-induced lung injury in vivo. PLoS One. 9:e885012014. View Article : Google Scholar : PubMed/NCBI
4	Jiang C, Ting AT and Seed B: PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 391:82–86. 1998. View Article : Google Scholar : PubMed/NCBI
5	Strieter RM, Belperio JA and Keane MP: Cytokines in innate host defense in the lung. J Clin Invest. 109:699–705. 2002. View Article : Google Scholar : PubMed/NCBI
6	Hoesel B and Schmid JA: The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 12:862013. View Article : Google Scholar
7	Jiang T, Tian F, Zheng H, Whitman SA, Lin Y, Zhang Z, Zhang N and Zhang DD: Nrf2 suppresses lupus nephritis through inhibition of oxidative injury and the NF-κB-mediated inflammatory response. Kidney Int. 85:333–343. 2014. View Article : Google Scholar
8	Gross CM, Kellner M, Wang T, Lu Q, Sun X, Zemskov EA, Noonepalle S, Kangath A, Kumar S, Gonzalez-Garay M, et al: LPS-induced acute lung injury involves NF-κB-mediated down- regulation of SOX18. Am J Respir Cell Mol Biol. 58:614–624. 2018. View Article : Google Scholar :
9	Yang H, Lv H, Li H, Ci X and Peng L: Oridonin protects LPS-induced acute lung injury by modulating Nrf2-mediated oxidative stress and Nrf2-independent NLRP3 and NF-κB pathways. Cell Commun Signal. 17:622019. View Article : Google Scholar
10	Yang KY, Arcaroli JJ and Abraham E: Early alterations in neutrophil activation are associated with outcome in acute lung injury. Am J Respir Crit Care Med. 167:1567–1574. 2003. View Article : Google Scholar : PubMed/NCBI
11	Schwartz MD, Moore EE, Moore FA, Shenkar R, Moine P, Haenel JB and Abraham E: Nuclear factor-kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome. Crit Care Med. 24:1285–1292. 1996. View Article : Google Scholar : PubMed/NCBI
12	Yang S, Yu Z, Yuan T, Wang L, Wang X, Yang H, Sun L, Wang Y and Du G: Therapeutic effect of methyl salicylate 2-O-β-d-lactoside on LPS-induced acute lung injury by inhibiting TAK1/NF-kappaB phosphorylation and NLRP3 expression. Int Immunopharmacol. 40:219–228. 2016. View Article : Google Scholar : PubMed/NCBI
13	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
14	Guo Z, Gu Y, Wang C, Zhang J, Shan S, Gu X, Wang K, Han Y and Ren T: Enforced expression of miR-125b attenuates LPS-induced acute lung injury. Immunol Lett. 162:18–26. 2014. View Article : Google Scholar : PubMed/NCBI
15	Zhang Y, Xie Y, Zhang L and Zhao H: MicroRNA-155 participates in smoke-inhalation-induced acute lung injury through inhibition of SOCS-1. Molecules. 25:10222020. View Article : Google Scholar :
16	Wan G, An Y, Tao J, Wang Y, Zhou Q, Yang R and Liang Q: MicroRNA-129-5p alleviates spinal cord injury in mice via suppressing the apoptosis and inflammatory response through HMGB1/TLR4/NF-κB pathway. Biosci Rep. 40:BSR201933152020. View Article : Google Scholar
17	Li XQ, Chen FS, Tan WF, Fang B, Zhang ZL and Ma H: Elevated microRNA-129-5p level ameliorates neuroinflammation and blood-spinal cord barrier damage after ischemia-reperfusion by inhibiting HMGB1 and the TLR3-cytokine pathway. J Neuroinflammation. 14:2052017. View Article : Google Scholar : PubMed/NCBI
18	Zeng Z, Liu Y, Zheng W, Liu L, Yin H, Zhang S, Bai H, Hua L, Wang S, Wang Z, et al: MicroRNA-129-5p alleviates nerve injury and inflammatory response of Alzheimer's disease via downregulating SOX6. Cell cycle. 18:3095–3110. 2019. View Article : Google Scholar : PubMed/NCBI
19	Chen ZX, He D, Mo QW, Xie LP, Liang JR, Liu L and Fu WJ: MiR-129-5p protects against myocardial ischemia-reperfusion injury via targeting HMGB1. Eur Rev Med Pharmacol Sci. 24:4440–4450. 2020.PubMed/NCBI
20	Xu Z, Zhang C, Cheng L, Hu M, Tao H and Song L: The microRNA miR-17 regulates lung FoxA1 expression during lipopolysaccharide-induced acute lung injury. Biochem Biophys Res Commun. 445:48–53. 2014. View Article : Google Scholar : PubMed/NCBI
21	Carbone L, Carbone ET, Yi EM, Bauer DB, Lindstrom KA, Parker JM, Austin JA, Seo Y, Gandhi AD and Wilkerson JD: Assessing cervical dislocation as a humane euthanasia method in mice. J Am Assoc Lab Anim Sci. 51:352–356. 2012.PubMed/NCBI
22	Li C, Yang D, Cao X, Wang F, Jiang H, Guo H, Du L, Guo Q and Yin X: LFG-500, a newly synthesized flavonoid, attenuates lipopolysaccharide-induced acute lung injury and inflammation in mice. Biochem Pharmacol. 113:57–69. 2016. View Article : Google Scholar : PubMed/NCBI
23	Lei C, Jiao Y, He B, Wang G, Wang Q and Wang J: RIP140 down-regulation alleviates acute lung injury via the inhibition of LPS-induced PPARγ promoter methylation. Pulm Pharmacol Ther. 37:57–64. 2016. View Article : Google Scholar : PubMed/NCBI
24	Ayaz G, Halici Z, Albayrak A, Karakus E and Cadirci E: Evaluation of 5-HT7 receptor trafficking on in vivo and in vitro model of lipopolysaccharide (LPS)-induced inflammatory cell injury in rats and LPS-treated A549 cells. Biochem Genet. 55:34–47. 2017. View Article : Google Scholar
25	Shao L, Meng D, Yang F, Song H and Tang D: Irisin-mediated protective effect on LPS-induced acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells. Biochem Biophys Res Commun. 487:194–200. 2017. View Article : Google Scholar : PubMed/NCBI
26	Wang Z, Yan J, Yang F, Wang D, Lu Y and Liu L: MicroRNA-326 prevents sepsis-induced acute lung injury via targeting TLR4. Free Radic Res. 54:408–418. 2020. View Article : Google Scholar : PubMed/NCBI
27	Bian B, Yu XF, Wang GQ and Teng TM: Role of miRNA-1 in regulating connexin 43 in ischemia-reperfusion heart injury: A rat model. Cardiovasc Pathol. 27:37–42. 2017. View Article : Google Scholar : PubMed/NCBI
28	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
29	Moitra J, Sammani S and Garcia JG: Re-evaluation of evans blue dye as a marker of albumin clearance in murine models of acute lung injury. Transl Res. 150:253–265. 2007. View Article : Google Scholar : PubMed/NCBI
30	Villar J, Cabrera-Benitez NE, Valladares F, García-Hernández S, Ramos-Nuez Á, Martín-Barrasa JL, Muros M, Kacmarek RM and Slutsky AS: Tryptase is involved in the development of early ventilator-induced pulmonary fibrosis in sepsis-induced lung injury. Crit Care. 19:1382015. View Article : Google Scholar : PubMed/NCBI
31	Varghese F, Bukhari AB, Malhotra R and De A: IHC Profiler: An open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS One. 9:e968012014. View Article : Google Scholar : PubMed/NCBI
32	Wu G, Li X, Li M and Zhang Z: Long non-coding RNA MALAT1 promotes the proliferation and migration of Schwann cells by elevating BDNF through sponging miR-129-5p. Exp Cell Res. 390:1119372020. View Article : Google Scholar : PubMed/NCBI
33	Ju M, Liu B, He H, Gu Z, Liu Y, Su Y, Zhu D, Cang J and Luo Z: MicroRNA-27a alleviates LPS-induced acute lung injury in mice via inhibiting inflammation and apoptosis through modulating TLR4/MyD88/NF-κB pathway. Cell Cycle. 17:2001–2018. 2018. View Article : Google Scholar :
34	Li P, Yao Y, Ma Y and Chen Y: MiR-150 attenuates LPS-induced acute lung injury via targeting AKT3. Int Immunopharmacol. 75:1057942019. View Article : Google Scholar : PubMed/NCBI
35	Xie W, Lu Q, Wang K, Lu J, Gu X, Zhu D, Liu F and Guo Z: miR-34b-5p inhibition attenuates lung inflammation and apoptosis in an LPS-induced acute lung injury mouse model by targeting progranulin. J Cell Physiol. 233:6615–6631. 2018. View Article : Google Scholar :
36	Yan Y, Lou Y and Kong J: MiR-155 expressed in bone marrow-derived lymphocytes promoted lipopolysaccharide-induced acute lung injury through Ang-2-Tie-2 pathway. Biochem Biophys Res Commun. 510:352–357. 2019. View Article : Google Scholar : PubMed/NCBI
37	Vaporidi K, Vergadi E, Kaniaris E, Hatziapostolou M, Lagoudaki E, Georgopoulos D, Zapol WM, Bloch KD and Iliopoulos D: Pulmonary microRNA profiling in a mouse model of ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol. 303:L199–L207. 2012. View Article : Google Scholar : PubMed/NCBI
38	Ma R, Chen X, Ma Y, Bai G and Li DS: MiR-129-5p alleviates myocardial injury by targeting suppressor of cytokine signaling 2 after ischemia/reperfusion. Kaohsiung J Med Sci. 36:599–606. 2020. View Article : Google Scholar : PubMed/NCBI
39	Huang X, Hou X, Chuan L, Wei S, Wang J, Yang X and Ru J: miR-129-5p alleviates LPS-induced acute kidney injury via targeting HMGB1/TLRs/NF-kappaB pathway. Int Immunopharmacol. 89:1070162020. View Article : Google Scholar : PubMed/NCBI
40	Fang Y, Gao F, Hao J and Liu Z: microRNA-1246 mediates lipopolysaccharide-induced pulmonary endothelial cell apoptosis and acute lung injury by targeting angiotensin-converting enzyme 2. Am J Transl Res. 9:1287–1296. 2017.PubMed/NCBI
41	Tianzhu Z and Shumin W: Esculin inhibits the inflammation of LPS-induced acute lung injury in mice via regulation of TLR/NF-κB pathways. Inflammation. 38:1529–1536. 2015. View Article : Google Scholar : PubMed/NCBI
42	Mei SH, McCarter SD, Deng Y, Parker CH, Liles WC and Stewart DJ: Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med. 4:e2692007. View Article : Google Scholar : PubMed/NCBI
43	Cheng KT, Xiong S, Ye Z, Hong Z, Di A, Tsang KM, Gao X, An S, Mittal M, Vogel SM, et al: Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury. J Clin Invest. 127:4124–4135. 2017. View Article : Google Scholar : PubMed/NCBI
44	Liu H, Lin Z and Ma Y: Suppression of Fpr2 expression protects against endotoxin-induced acute lung injury by interacting with Nrf2-regulated TAK1 activation. Biomed Pharmacother. 125:1099432020. View Article : Google Scholar : PubMed/NCBI
45	Gao D, Wang R, Li B, Yang Y, Zhai Z and Chen DY: WDR34 is a novel TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-kappaB activation pathway. Cell Mol Life Sci. 66:2573–2584. 2009. View Article : Google Scholar : PubMed/NCBI
46	Chen Q, Wu S, Wu Y, Chen L and Pang Q: MiR-149 suppresses the inflammatory response of chondrocytes in osteoarthritis by down-regulating the activation of TAK1/NF-κB. Biomed Pharmacother. 101:763–768. 2018. View Article : Google Scholar : PubMed/NCBI
47	Nan CC, Zhang N, Cheung KCP, Zhang HD, Li W, Hong CY, Chen HS, Liu XY, Li N and Cheng L: Knockdown of lncRNA MALAT1 alleviates LPS-induced acute lung injury via inhibiting apoptosis through the miR-194-5p/FOXP2 axis. Front Cell Dev Biol. 8:5868692020. View Article : Google Scholar : PubMed/NCBI
48	Zhang J, Ding C, Shao Q, Liu F, Zeng Z, Nie C and Qian K: The protective effects of transfected microRNA-146a on mice with sepsis-induced acute lung injury in vivo. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 27:591–594. 2015.In Chinese. PubMed/NCBI
49	Cao X, Zhang C, Zhang X, Chen Y and Zhang H: MiR-145 negatively regulates TGFBR2 signaling responsible for sepsis-induced acute lung injury. Biomed Pharmacother. 111:852–858. 2019. View Article : Google Scholar : PubMed/NCBI
50	Li L, Wu W, Huang W, Hu G, Yuan W and Li W: NF-κB RNAi decreases the Bax/Bcl-2 ratio and inhibits TNF-α-induced apoptosis in human alveolar epithelial cells. Inflamm Res. 62:387–397. 2013. View Article : Google Scholar : PubMed/NCBI
51	Gong Y, Lan H, Yu Z, Wang M, Wang S, Chen Y, Rao H, Li J, Sheng Z and Shao J: Blockage of glycolysis by targeting PFKFB3 alleviates sepsis-related acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells. Biochem Biophys Res Commun. 491:522–529. 2017. View Article : Google Scholar : PubMed/NCBI
52	Albertine KH, Soulier MF, Wang Z, Ishizaka A, Hashimoto S, Zimmerman GA, Matthay MA and Ware LB: Fas and fas ligand are up-regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome. Am J Pathol. 161:1783–1796. 2002. View Article : Google Scholar : PubMed/NCBI
53	Kawasaki M, Kuwano K, Hagimoto N, Matsuba T, Kunitake R, Tanaka T, Maeyama T and Hara N: Protection from lethal apoptosis in lipopolysaccharide-induced acute lung injury in mice by a caspase inhibitor. Am J Pathol. 157:597–603. 2000. View Article : Google Scholar : PubMed/NCBI
54	Yang R, Cai X, Li J, Liu F and Sun T: Protective effects of MiR-129-5p on acute spinal cord injury rats. Med Sci Monit. 25:8281–8288. 2019. View Article : Google Scholar : PubMed/NCBI
55	Du X, Tian D, Wei J, Yan C, Hu P, Wu X and Yang W: MEG3 alleviated LPS-induced intestinal injury in sepsis by modulating miR-129-5p and surfactant protein D. Mediators Inflamm. 2020:82327342020. View Article : Google Scholar : PubMed/NCBI
56	Chen Z, Zhang D, Li M and Wang B: Costunolide ameliorates lipoteichoic acid-induced acute lung injury via attenuating MAPK signaling pathway. Int Immunopharmacol. 61:283–289. 2018. View Article : Google Scholar : PubMed/NCBI
57	Fan C, Wu LH, Zhang GF, Xu F, Zhang S, Zhang X, Sun L, Yu Y, Zhang Y and Ye RD: 4′-Hydroxywogonin suppresses lipopolysaccharide-induced inflammatory responses in RAW 264.7 macrophages and acute lung injury mice. PLoS One. 12:e01811912017. View Article : Google Scholar
58	Cai PC, Shi L, Liu VW, Tang HW, Liu IJ, Leung TH, Chan KK, Yam JW, Yao KM, Ngan HY and Chan DW: Elevated TAK1 augments tumor growth and metastatic capacities of ovarian cancer cells through activation of NF-κB signaling. Oncotarget. 5:7549–7562. 2014. View Article : Google Scholar : PubMed/NCBI
59	Meng Q, Wu W, Pei T, Xue J, Xiao P, Sun L, Li L and Liang D: miRNA-129/FBW7/NF-κB, a novel regulatory pathway in inflammatory bowel disease. Mol Ther Nucleic Acids. 19:731–740. 2020. View Article : Google Scholar : PubMed/NCBI
60	Liu AH, Wu YT and Wang YP: MicroRNA-129-5p inhibits the development of autoimmune encephalomyelitis-related epilepsy by targeting HMGB1 through the TLR4/NF-kB signaling pathway. Brain Res Bull. 132:139–149. 2017. View Article : Google Scholar : PubMed/NCBI