HIF‑1α promotes NLRP3 inflammasome activation in bleomycin‑induced acute lung injury

Huang,Jun‑Jun; Xia,Jie; Huang,Li‑Li; Li,Ya‑Chun

doi:10.3892/mmr.2019.10575

HIF‑1α promotes NLRP3 inflammasome activation in bleomycin‑induced acute lung injury

Authors:
- Jun‑Jun Huang
- Jie Xia
- Li‑Li Huang
- Ya‑Chun Li
View Affiliations

Affiliations: Department of Geriatric Rehabilitation, Geriatric Rehabilitation Hospital of Nantong, Branch of Nantong University's Affiliated Hospital, Nantong, Jiangsu 226001, P.R. China, Department of Gastroenterology, Changzhou No. 2 People's Hospital, Changzhou, Jiangsu 213164, P.R. China, Department of Anesthesiology, The Central Hospital of Songjiang, Songjiang Branch of Shanghai General Hospital Affiliated to Shanghai Jiaotong University, Shanghai 201600, P.R. China
Published online on: August 8, 2019 https://doi.org/10.3892/mmr.2019.10575
Pages: 3424-3432

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

The inflammatory response is one of the most important factors in the occurrence and development of acute lung injury (ALI). Hypoxia‑inducible factor‑1α (HIF‑1α) and the NOD‑like receptor 3 (NLRP3) inflammasome have been demonstrated to serve an important role in the pathogenesis of ALI. The objective of the present study was to investigate whether HIF‑1α could regulate activation of the NLRP3 inflammasome and its potential function and specific mechanism in bleomycin (BLM)‑induced ALI. Activation of the NLRP3 inflammasome and secretion of IL‑1β were detected following silencing of HIF‑1α or NF‑κB, respectively, in BLM‑treated A549 and RLE‑6TN cells. The results demonstrated that the NLRP3 inflammasome could be activated after BLM treatment. HIF‑1α and NF‑κB expression significantly increased in the BLM group. The levels of NF‑κB‑ and NLRP3 inflammasome‑associated proteins, including NLRP3, apoptosis‑associated speck‑like protein containing CARD and caspase‑1, markedly decreased after treating A549 and RLE‑6TN cells with HIF‑1α small interfering RNA. Activation of the NLRP3 inflammasome was also inhibited after silencing NF‑κB. Furthermore, the levels of IL‑1β markedly decreased in the cellular culture supernatants following inhibition of HIF‑1α and NF‑κB. Therefore, the present study indicated that HIF‑1α could modulate the activation of the NLRP3 inflammasome and the secretion of IL‑1β through NF‑κB signaling in BLM‑induced ALI. The current results improve understanding of the mechanism of ALI and may provide new ideas for identifying therapeutic targets of ALI.

View Figures

View References

1	ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L and Slutsky AS: Acute respiratory distress syndrome: The Berlin Definition. JAMA. 307:2526–2533. 2012.PubMed/NCBI
2	Matthay MA and Zemans RL: The acute respiratory distress syndrome: Pathogenesis and treatment. Annu Rev Pathol. 6:147–163. 2011. View Article : Google Scholar : PubMed/NCBI
3	Spragg RG, Bernard GR, Checkley W, Curtis JR, Gajic O, Guyatt G, Hall J, Israel E, Jain M, Needham DM, et al: Beyond mortality: Future clinical research in acute lung injury. Am J Respir Crit Care Med. 181:1121–1127. 2010. View Article : Google Scholar : PubMed/NCBI
4	Butt Y, Kurdowska A and Allen TC: Acute lung injury: A clinical and molecular review. Arch Pathol Lab Med. 140:345–350. 2016. View Article : Google Scholar : PubMed/NCBI
5	Qu L, Chen C, Chen Y, Li Y, Tang F, Huang H, He W, Zhang R and Shen L: High-Mobility group box 1 (HMGB1) and autophagy in acute lung injury (ALI): A review. Med Sci Monit. 25:1828–1837. 2019. View Article : Google Scholar : PubMed/NCBI
6	Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, et al: A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol. 6:97–105. 2004. View Article : Google Scholar : PubMed/NCBI
7	Bhatia M and Moochhala S: Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol. 202:145–156. 2004. View Article : Google Scholar : PubMed/NCBI
8	Schroder K and Tschopp J: The inflammasomes. Cell. 140:821–832. 2010. View Article : Google Scholar : PubMed/NCBI
9	Strowig T, Henao-Mejia J, Elinav E and Flavell R: Inflammasomes in health and disease. Nature. 481:278–286. 2012. View Article : Google Scholar : PubMed/NCBI
10	Bauernfeind F, Ablasser A, Bartok E, Kim S, Schmid-Burgk J, Cavlar T and Hornung V: Inflammasomes: Current understanding and open questions. Cell Mol Life Sci. 68:765–783. 2011. View Article : Google Scholar : PubMed/NCBI
11	Eisenbarth SC and Flavell RA: Innate instruction of adaptive immunity revisited: The inflammasome. EMBO Mol Med. 1:92–98. 2009. View Article : Google Scholar : PubMed/NCBI
12	Hosseinian N, Cho Y, Lockey RF and Kolliputi N: The role of the NLRP3 inflammasome in pulmonary diseases. Ther Adv Respir Dis. 9:188–197. 2015. View Article : Google Scholar : PubMed/NCBI
13	Kuipers MT, Aslami H, Janczy JR, van der Sluijs KF, Vlaar AP, Wolthuis EK, Choi G, Roelofs JJ, Flavell RA, Sutterwala FS, et al: Ventilator-induced lung injury is mediated by the NLRP3 inflammasome. Anesthesiology. 116:1104–1115. 2012. View Article : Google Scholar : PubMed/NCBI
14	Dai H, Pan L, Lin F, Ge W, Li W and He S: Mechanical ventilation modulates Toll-like receptors 2, 4, and 9 on alveolar macrophages in a ventilator-induced lung injury model. J Thorac Dis. 7:616–624. 2015.PubMed/NCBI
15	Vriend J and Reiter RJ: Melatonin and the von Hippel- Lindau/HIF-1 oxygen sensing mechanism: A review. Biochim Biophys Acta. 1865:176–183. 2016.PubMed/NCBI
16	Rhim T, Lee DY and Lee M: Hypoxia as a target for tissue specific gene therapy. J Control Release. 172:484–494. 2013. View Article : Google Scholar : PubMed/NCBI
17	Tang M, Tian Y, Li D, Lv J, Li Q, Kuang C, Hu P, Wang Y, Wang J, Su K and Wei L: TNF-α mediated increase of HIF-1α inhibits VASP expression, which reduces alveolar-capillary barrier function during acute lung injury (ALI). PLoS One. 9:e1029672014. View Article : Google Scholar : PubMed/NCBI
18	Jiang H, Hu R, Sun L, Chai D, Cao Z and Li Q: Critical role of toll-like receptor 4 in hypoxia-inducible factor 1α activation during trauma/hemorrhagic shocky induced acute lung injury after lymph infusion in mice. Shock. 42:271–278. 2014. View Article : Google Scholar : PubMed/NCBI
19	Suresh MV, Ramakrishnan SK, Thomas B, Machado-Aranda D, Bi Y, Talarico N, Anderson E, Yatrik SM and Raghavendran K: Activation of hypoxia-inducible factor-1α in type 2 alveolar epithelial cell is a major driver of acute inflammation following lung contusion. Crit Care Med. 42:e642–e653. 2014. View Article : Google Scholar : PubMed/NCBI
20	Sun HD, Liu YJ, Chen J, Chen MY, Ouyang B and Guan XD: The pivotal role of HIF-1α in lung inflammatory injury induced by septic mesenteric lymph. Biomed Pharmacother. 91:476–484. 2017. View Article : Google Scholar : PubMed/NCBI
21	Vohwinkel CU, Hoegl S and Eltzschig HK: Hypoxia signaling during acute lung injury. J Appl Physiol (1985). 119:1157–1163. 2015. View Article : Google Scholar : PubMed/NCBI
22	Nicholas SA, Bubnov VV, Yasinska IM and Sumbayev VV: Involvement of xanthine oxidase and hypoxia-inducible factor 1 in Toll-like receptor 7/8-mediated activation of caspase 1 and interleukin-1β. Cell Mol Life Sci. 68:151–158. 2011. View Article : Google Scholar : PubMed/NCBI
23	Tian R, Zhu Y, Yao J, Meng X, Wang J, Xie H and Wang R: NLRP3 participates in the regulation of EMT in bleomycin-induced pulmonary fibrosis. Exp Cell Res. 357:328–334. 2017. View Article : Google Scholar : PubMed/NCBI
24	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 : PubMed/NCBI
25	Grebe A, Hoss F and Latz E: NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis. Circ Res. 122:1722–1740. 2018. View Article : Google Scholar : PubMed/NCBI
26	Sarvestani ST and McAuley JL: The role of the NLRP3 inflammasome in regulation of antiviral responses to influenza A virus infection. Antiviral Res. 148:32–42. 2017. View Article : Google Scholar : PubMed/NCBI
27	Sciuto AM, Clapp DL, Hess ZA and Moran TS: The temporal profile of cytokines in the bronchoalveolar lavage fluid in mice exposed to the industrial gas phosgene. Inhal Toxicol. 15:687–700. 2003. View Article : Google Scholar : PubMed/NCBI
28	Wang P, Ye XL, Liu R, Chen HL, Liang X, Li WL, Zhang XD, Qin XJ, Bai H, Zhang W, et al: Mechanism of acute lung injury due to phosgene exposition and its protection by cafeic acid phenethyl ester in the rat. Exp Toxicol Pathol. 65:311–318. 2013. View Article : Google Scholar : PubMed/NCBI
29	Toma C, Higa N, Koizumi Y, Nakasone N, Ogura Y, McCoy AJ, Franchi L, Uematsu S, Sagara J, Taniguchi S, et al: Pathogenic Vibrio activate NLRP3 inflammasome via cytotoxins and TLR/nucleotide-binding oligomerization domain-mediated NF-kappa B signaling. J Immunol. 184:5287–5297. 2010. View Article : Google Scholar : PubMed/NCBI
30	Gross O, Poeck H, Bscheider M, Dostert C, Hannesschläger N, Endres S, Hartmann G, Tardivel A, Schweighoffer E, Tybulewicz V, et al: Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature. 459:433–436. 2009. View Article : Google Scholar : PubMed/NCBI
31	Thomas PG, Dash P, Aldridge JR Jr, Ellebedy AH, Reynolds C, Funk AJ, Martin WJ, Lamkanfi M, Webby RJ, Boyd KL, et al: The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity. 30:566–575. 2009. View Article : Google Scholar : PubMed/NCBI
32	Martinon F, Petrilli V, Mayor A, Tardivel A and Tschopp J: Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 440:237–241. 2006. View Article : Google Scholar : PubMed/NCBI
33	Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA and Latz E: Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 9:847–856. 2008. View Article : Google Scholar : PubMed/NCBI
34	Semenza GL: Hypoxia-inducible factors in physiology and medicine. Cell. 148:399–408. 2012. View Article : Google Scholar : PubMed/NCBI
35	Palazon A, Goldrath AW, Nizet V and Johnson RS: HIF transcription factors, inflammation, and immunity. Immunity. 41:518–528. 2014. View Article : Google Scholar : PubMed/NCBI
36	Rohwer N, Zasada C, Kempa S and Cramer T: The growing complexity of HIF-1α's role in tumorigenesis: DNA repair and beyond. Oncogene. 32:3569–3576. 2013. View Article : Google Scholar : PubMed/NCBI
37	Koyasu S, Kobayashi M, Goto Y, Hiraoka M and Harada H: Regulatory mechanisms of hypoxia-inducible factor 1 activity: Two decades of knowledge. Cancer Sci. 109:560–571. 2018. View Article : Google Scholar : PubMed/NCBI
38	Ouyang X, Ghani A, Malik A, Wilder T, Colegio OR, Flavell RA, Cronstein BN and Mehal WZ: Adenosine is required for sustained inflammasome activation via the A₂A receptor and the HIF-1α pathway. Nat Commun. 4:29092013. View Article : Google Scholar : PubMed/NCBI
39	Li YC, Yeh CH, Yang ML and Kuan YH: Luteolin suppresses inflammatory mediator expression by blocking the Akt/NFκB pathway in acute lung injury induced by lipopolysaccharide in mice. Evid Based Complement Alternat Med. 2012:3836082012. View Article : Google Scholar : PubMed/NCBI
40	Niu X, Hu H, Li W, Li Y, Huang H, Mu Q, Yao H and Li H: Protective effect of total alkaloids on lipopolysaccharide-induced acute lung injury. J Surg Res. 189:126–134. 2014. View Article : Google Scholar : PubMed/NCBI
41	Luo M, Hu L, Li D, Wang Y, He Y, Zhu L and Ren W: MD-2 regulates LPS-induced NLRP3 inflammasome activation and IL-1beta secretion by a MyD88/NF-κB-dependent pathway in alveolar macrophages cell line. Mol Immunol. 90:1–10. 2017. View Article : Google Scholar : PubMed/NCBI
42	D'Ignazio L and Rocha S: Hypoxia Induced NF-κB. Cells. 5(pii): E102016. View Article : Google Scholar : PubMed/NCBI