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Interleukin-22 ameliorated acetaminophen-induced kidney injury by inhibiting mitochondrial dysfunction and inflammatory responses

  • Applied microbial and cell physiology
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Abstract

Acetaminophen (APAP) overdose can lead to acute, severe kidney injury, which has recently attracted considerable attention among researchers and clinicians. Unfortunately, there are no well-established treatments for APAP-induced renal injury, and the molecular mechanism of APAP-induced kidney injury is still unclear. Herein, we explored the protective effects of interleukin (IL)-22 on APAP-induced renal injury and the underlying molecular basis. We found that IL-22 could significantly alleviate the accumulation of reactive oxygen species (ROS) and ameliorate mitochondrial dysfunction, reducing APAP-induced renal tubular epithelial cell (TEC) death in vitro and in vivo. Furthermore, IL-22 could downregulate the APAP-induced NLRP3 inflammasome activation and mature IL-1β release in kidney injury. Additionally, the APAP-mediated upregulation of the serum levels of IL-18, TNF-α, IL-6, and IL-1β was obviously decreased, suggesting IL-22 has inhibitory effects on inflammatory responses. Conclusively, our study demonstrated that IL-22 exerted ameliorative effects on APAP-induced kidney injury by alleviating mitochondrial dysfunction and NLRP3 inflammasome activation, suggesting that IL-22 represents a potential therapeutic approach to treat APAP-induced kidney injury.

Key Points

• IL-22 could ameliorate APAP that triggered oxidative stress and mitochondrial dysfunction.

• IL-22 could reduce APAP that caused inflammatory responses.

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References

  • Ahmad ST, Arjumand W, Nafees S, Seth A, Ali N, Rashid S, Sultana S (2012) Hesperidin alleviates acetaminophen induced toxicity in Wistar rats by abrogation of oxidative stress, apoptosis and inflammation. Toxicol Lett 208:149–161

    Article  CAS  Google Scholar 

  • Athuraliya TN, Jones AL (2009) Prolonged N,acetylcysteine therapy in late acetaminophen poisoning associated with acute liver failure-a need to be more cautious? Crit Care 13:144

    Article  Google Scholar 

  • Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (2006) Paracetamol: new vistas of an old drug. CNS Drug Rev 12:250–275

    Article  CAS  Google Scholar 

  • Bessems JG, Vermeulen NP (2001) Paracetamol (acetaminophen)-induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol 31:55–138

    Article  CAS  Google Scholar 

  • Bonavia A, Singbartl K (2018) A review of the role of immune cells in acute kidney injury. Pediatr Nephrol 33:1629–1639

    Article  Google Scholar 

  • Borghi M, De Luca A, Puccetti M, Jaeger M, Mencacci A, Oikonomou V, Pariano M, Garlanda C, Moretti S, Bartoli A, Sobel J, van de Veerdonk FL, Dinarello CA, Netea MG, Romani L (2015) Pathogenic NLRP3 Inflammasome activity during Candida infection is negatively regulated by IL-22 via activation of NLRC4 and IL-1Ra. Cell Host Microbe 18:198–209

    Article  CAS  Google Scholar 

  • Boutis K, Shannon M (2001) Nephrotoxicity after acute severe acetaminophen poisoning in adolescents. J Toxicol Clin Toxicol 39:441–445

    Article  CAS  Google Scholar 

  • Chen W, Zhang X, Fan J, Zai W, Luan J, Li Y, Wang S, Chen Q, Wang Y, Liang Y, Ju D (2017) Tethering interleukin-22 to apolipoprotein A-I ameliorates mice from acetaminophen-induced liver injury. Theranostics 7:4135–4148

    Article  CAS  Google Scholar 

  • Chen Y, ** S, Teng X, Hu Z, Zhang Z, Qiu X, Tian D, Wu Y (2018a) Hydrogen sulfide attenuates LPS-induced acute kidney injury by inhibiting inflammation and oxidative stress. Oxidative Med Cell Longev 2018:6717212

    Google Scholar 

  • Chen W, Luan J, Wei G, Zhang X, Fan J, Zai W, Wang S, Wang Y, Liang Y, Nan Y, Yin C, Li Y, Liu ML, Ju D (2018b) In vivo hepatocellular expression of interleukin-22 using penetratin-based hybrid nanoparticles as potential anti-hepatitis therapeutics. Biomaterials 187:66–80

    Article  CAS  Google Scholar 

  • Cohen SD, Pumford NR, Khairallah EA, Boekelheide K, Pohl LR, Amouzadeh HR, Hinson JA (1997) Selective protein covalent binding and target organ toxicity. Toxicol Appl Pharmacol 143:1–12

    Article  CAS  Google Scholar 

  • Eyerich S, Eyerich K, Cavani A, Schmidt-Weber C (2010) IL-17 and IL-22: siblings, not twins. Trends Immunol 31:354–361

    Article  CAS  Google Scholar 

  • Gronke K, Hernández PP, Zimmermann J, Klose CSN, Kofoed-Branzk M, Guendel F, Witkowski M, Tizian C, Amann L, Schumacher F, Glatt H, Triantafyllopoulou A, Diefenbach A (2019) Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature 566:249–253

    Article  CAS  Google Scholar 

  • Hou Q, Ye L, Liu H, Huang L, Yang Q, Turner JR, Yu Q (2018) Lactobacillus accelerates ISCs regeneration to protect the integrity of intestinal mucosa through activation of STAT3 signaling pathway induced by LPLs secretion of IL-22. Cell Death Differ 25:1657–1670

    Article  CAS  Google Scholar 

  • Hua H, Ge X, Wu M, Zhu C, Chen L, Yang G, Zhang Y, Huang S, Zhang A, Jia Z (2018) Rotenone protects against acetaminophen-induced kidney injury by attenuating oxidative stress and inflammation. Kidney Blood Press Res 43:1297–1309

    Article  CAS  Google Scholar 

  • Jaeschke H (2018) Mechanisms of sterile inflammation in acetaminophen hepatotoxicity. Cell Mol Immunol 15:74–75

    Article  CAS  Google Scholar 

  • Kandiş H, Erkan ME, Yildirim U, Güneş H, Erbaş M, Yildirim HA, Gezer S, Kara IH (2011) Comparison of the effects of N-acetyl cysteine and erdosteine in rats with renal injury caused by paracetamol intoxication. Hum Exp Toxicol 30:1350–1358

    Article  Google Scholar 

  • Lazerow SK, Abdi MS, Lewis JH (2005) Drug-induced liver disease 2004. Curr Opin Gastroenterol 21:283–292

    Article  Google Scholar 

  • Lin Z, Wu F, Lin S, Pan X, ** L, Lu T, Shi L, Wang Y, Xu A, Li X (2014) Adiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice. J Hepatol 61:825–831

    Article  CAS  Google Scholar 

  • McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H (2012) The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest 122:1574–1583

    Article  CAS  Google Scholar 

  • Mizoguchi A (2012) Healing of intestinal inflammation by IL-22. Inflamm Bowel Dis 18:1777–1784

    Article  Google Scholar 

  • Mulay SR, Anders HJ (2017) Crystal nephropathies: mechanisms of crystal-induced kidney injury. Nat Rev Nephrol 13:226–240

    Article  CAS  Google Scholar 

  • Ngo VL, Abo H, Maxim E, Harusato A, Geem D, Medina-Contreras O, Merlin D, Gewirtz AT, Nusrat A, Denning TL (2018) A cytokine network involving IL-36γ, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage. Proc Natl Acad Sci U S A 115:E5076–E5085

    Article  CAS  Google Scholar 

  • Nikoopour E, Bellemore SM, Singh B (2015) IL-22, cell regeneration and autoimmunity. Cytokine 74:35–42

    Article  CAS  Google Scholar 

  • Reshi MS, Shrivastava S, Jaswal A, Sinha N, Uthra C, Shukla S (2017) Gold nanoparticles ameliorate acetaminophen induced hepato-renal injury in rats. Exp Toxicol Pathol 69:231–240

    Article  CAS  Google Scholar 

  • Saito C, Zwingmann C, Jaeschke H (2010) Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine. Hepatology 51:246–254

    Article  CAS  Google Scholar 

  • Shan S, Shen Z, Zhang C, Kou R, **e K, Song F (2019) Mitophagy protects against acetaminophen-induced acute liver injury in mice through inhibiting NLRP3 inflammasome activation. Biochem Pharmacol 169:113643

    Article  CAS  Google Scholar 

  • Tachiiri A, Imamura R, Wang Y, Fukui M, Umemura M, Suda T (2003) Genomic structure and inducible expression of the IL-22 receptor alpha chain in mice. Genes Immun 4:153–159

    Article  CAS  Google Scholar 

  • Ulinski T, Guigonis V, Dunan O, Bensman A (2004) Acute renal failure after treatment with non-steroidal anti-inflammatory drugs. Eur J Pediatr 163:148–150

    Article  CAS  Google Scholar 

  • Vivoli E, Cappon A, Milani S, Piombanti B, Provenzano A, Novo E, Masi A, Navari N, Narducci R, Mannaioni G, Moneti G, Oliveira CP, Parola M, Marra F (2016) NLRP3 inflammasome as a target of berberine in experimental murine liver injury: interference with P2X7 signalling. Clin Sci 130:1793–1806

    Article  CAS  Google Scholar 

  • Wang S, Li Y, Fan J, Zhang X, Luan J, Bian Q, Ding T, Wang Y, Wang Z, Song P, Cui D, Mei X, Ju D (2017) Interleukin-22 ameliorated renal injury and fibrosis in diabetic nephropathy through inhibition of NLRP3 inflammasome activation. Cell Death Dis 8:e2937

    Article  CAS  Google Scholar 

  • Wang S, Fan J, Mei X, Luan J, Li Y, Zhang X, Chen W, Wang Y, Meng G, Ju D (2019) Interleukin-22 attenuated renal tubular injury in aristolochic acid nephropathy via suppressing activation of NLRP3 inflammasome. Front Immunol 10:2277

    Article  CAS  Google Scholar 

  • Wolk K, Sabat R (2006) Interleukin-22: a novel T-cell and NK cell derived cytokine that regulates the biology of tissue cells. Cytokine Factor Rev 17:367–380

    Article  CAS  Google Scholar 

  • Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R (2004) IL-22 increases the innate immunity of tissues. Immunity 21:241–254

    Article  CAS  Google Scholar 

  • Woolbright BL, Jaeschke H (2017) The impact of sterile inflammation in acute liver injury. J Clin Transl Res 3(Suppl 1):170–188

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xu MJ, Feng D, Wang H, Guan Y, Yan X, Gao B (2014) IL-22 ameliorates renal ischemia-reperfusion injury by targeting proximal tubule epithelium. J Am Soc Nephrol 25:967–977

    Article  CAS  Google Scholar 

  • Yan M, Huo Y, Yin S, Hu H (2018) Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions. Redox Biol 17:274–283

    Article  CAS  Google Scholar 

  • Zai W, Chen W, Luan J, Fan J, Zhang X, Wu Z, Ding T, Ju D, Liu H (2018) Dihydroquercetin ameliorated acetaminophen-induced hepatic cytotoxicity via activating JAK2/STAT3 pathway and autophagy. Appl Microbiol Biotechnol 102:1443–1453

    Article  CAS  Google Scholar 

  • Zhang C, Feng J, Du J, Zhuo Z, Yang S, Zhang W, Wang W, Zhang S, Iwakura Y, Meng G, Fu YX, Hou B, Tang H (2018) Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity. Cell Mol Immunol 15:973–982

    Article  CAS  Google Scholar 

Download references

Funding

The study was supported by grants from the National Nature Science Foundation of China (31872746), National Nature Science Foundation of China (81773620), and Scientific Research Projects of Shanghai Municipal Commission of Health and Family Planning (201740140).

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Author notes

  1. Yilan Shen, **n **, Wei Chen and Congrong Gao contributed equally to this work.

Authors and Affiliations

  1. Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China

    Yilan Shen, Qi Bian, Zhiyong Guo & **aobin Mei

  2. Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China

    **n **, Wei Chen, Jiajun Fan, **gyun Luan, Zhonglian Cao, Yuting Gu, Hongrui Liu & Dianwen Ju

  3. Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA

    Wei Chen

  4. Department of Geratology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China

    Congrong Gao

Authors
  1. Yilan Shen
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  3. Wei Chen
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Contributions

**aobin Mei and Dianwen Ju designed the study; Yilan Shen, **n **, Wei Chen, Congrong Gao, Qi Bian, Jiajun Fan, and **gyun Luan carried out experiments; Congrong Gao, Zhiyong Guo, Hongrui Liu, and Zhonglian Cao analysed the data; Yilan Shen and Wei Chen drafted and revised the paper; all authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Dianwen Ju or **aobin Mei.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal experiments were conducted with the approval of the Ethics Committee of Fudan University School of Pharmacy.

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Shen, Y., **, X., Chen, W. et al. Interleukin-22 ameliorated acetaminophen-induced kidney injury by inhibiting mitochondrial dysfunction and inflammatory responses. Appl Microbiol Biotechnol 104, 5889–5898 (2020). https://doi.org/10.1007/s00253-020-10638-4

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