Inosine: A broad-spectrum anti-inflammatory against SARS-CoV-2 infection-induced acute lung injury via suppressing TBK1 phosphorylation

Ningning Wang; Entao Li; Huifang Deng; Lanxin Yue; Lei Zhou; Rina Su; Baokun He; Chengcai Lai; Gaofu Li; Yuwei Gao; Wei Zhou; Yue Gao

doi:10.1016/j.jpha.2022.10.002

Volume 13 Issue 1

Jan. 2023

Turn off MathJax

Article Contents

Article Navigation > Journal of Pharmaceutical Analysis > 2023 > 13(1): 11-23

Ningning Wang, Entao Li, Huifang Deng, Lanxin Yue, Lei Zhou, Rina Su, Baokun He, Chengcai Lai, Gaofu Li, Yuwei Gao, Wei Zhou, Yue Gao. Inosine: A broad-spectrum anti-inflammatory against SARS-CoV-2 infection-induced acute lung injury via suppressing TBK1 phosphorylation[J]. Journal of Pharmaceutical Analysis, 2023, 13(1): 11-23. doi: 10.1016/j.jpha.2022.10.002

Citation:

Ningning Wang, Entao Li, Huifang Deng, Lanxin Yue, Lei Zhou, Rina Su, Baokun He, Chengcai Lai, Gaofu Li, Yuwei Gao, Wei Zhou, Yue Gao. Inosine: A broad-spectrum anti-inflammatory against SARS-CoV-2 infection-induced acute lung injury via suppressing TBK1 phosphorylation[J]. Journal of Pharmaceutical Analysis, 2023, 13(1): 11-23. doi: 10.1016/j.jpha.2022.10.002

Citation:

Ningning Wang, Entao Li, Huifang Deng, Lanxin Yue, Lei Zhou, Rina Su, Baokun He, Chengcai Lai, Gaofu Li, Yuwei Gao, Wei Zhou, Yue Gao. Inosine: A broad-spectrum anti-inflammatory against SARS-CoV-2 infection-induced acute lung injury via suppressing TBK1 phosphorylation[J]. Journal of Pharmaceutical Analysis, 2023, 13(1): 11-23. doi: 10.1016/j.jpha.2022.10.002

PDF( 4999 KB)

Inosine: A broad-spectrum anti-inflammatory against SARS-CoV-2 infection-induced acute lung injury via suppressing TBK1 phosphorylation

doi: 10.1016/j.jpha.2022.10.002

Ningning Wang^a,b,
Entao Li^c,
Huifang Deng^a,
Lanxin Yue^a,
Lei Zhou^a,
Rina Su^c,d,
Baokun He^e,
Chengcai Lai^a,
Gaofu Li^a,
Yuwei Gao^{c
,
,},
Wei Zhou^{a
,
,},
Yue Gao^{a,b
,
,}

a. Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China;
b. Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China;
c. Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, China;
d. College of Veterinary Medicine, Jilin Agricultural University, Changchun, 130022, China;
e. Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China

Funds:

This work was supported by grants from the Young Elite Scientists Sponsorship Program by CAST (Grant No.: 2021-QNRC1-03) and the National Key Research and Development Program of China (Grant No.: 2020YFC0845400). We thank Prof. Hui P. Chen for providing advice on the experiments.

Received Date: Jun. 28, 2022
Accepted Date: Oct. 17, 2022
Rev Recd Date: Oct. 14, 2022
Publish Date: Oct. 22, 2022

Abstract

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storms constitute the primary cause of coronavirus disease 19 (COVID-19) progression, severity, criticality, and death. Glucocorticoid and anti-cytokine therapies are frequently administered to treat COVID-19, but have limited clinical efficacy in severe and critical cases. Nevertheless, the weaknesses of these treatment modalities have prompted the development of anti-inflammatory therapy against this infection. We found that the broad-spectrum anti-inflammatory agent inosine downregulated proinflammatory interleukin (IL)-6, upregulated anti-inflammatory IL-10, and ameliorated acute inflammatory lung injury caused by multiple infectious agents. Inosine significantly improved survival in mice infected with SARS-CoV-2. It indirectly impeded TANK-binding kinase 1 (TBK1) phosphorylation by binding stimulator of interferon genes (STING) and glycogen synthase kinase-3β (GSK3β), inhibited the activation and nuclear translocation of the downstream transcription factors interferon regulatory factor (IRF3) and nuclear factor kappa B (NF-κB), and downregulated IL-6 in the sera and lung tissues of mice infected with lipopolysaccharide (LPS), H1N1, or SARS-CoV-2. Thus, inosine administration is feasible for clinical anti-inflammatory therapy against severe and critical COVID-19. Moreover, targeting TBK1 is a promising strategy for inhibiting cytokine storms and mitigating acute inflammatory lung injury induced by SARS-CoV-2 and other infectious agents.
- Cytokine storm,
- Interleukin 6 (IL-6),
- Inosine,
- SARS-CoV-2,
- TANK-binding kinase 1 (TBK1)

FullText(HTML)

References(43)

References

A. Martinez Mesa, E. Cabrera Cesar, E. Martin-Montanez, et al., Acute Lung Injury Biomarkers in the Prediction of COVID-19 Severity: Total Thiol, Ferritin and Lactate Dehydrogenase, Antioxidants (Basel Switzerland). 10 (2021) 1221

A.M. Edwards, R.S. Baric, E.O. Saphire, et al., Stopping pandemics before they start: Lessons learned from SARS-CoV-2, Science. 375 (2022) 1133-1139

W. Zhou, Y. Liu, D. Tian, et al., Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia, Signal Transduct Target Ther. 5 (2020) 18

R. Dal-Re, S.L. Becker, E. Bottieau, et al., Availability of oral antivirals against SARS-CoV-2 infection and the requirement for an ethical prescribing approach, Lancet Infect Dis. 22 (2022) e231-e238

R. Karki, B.R. Sharma, S. Tuladhar, et al., Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes, Cell. 184 (2021) 149-168.e17

R.Q. Cron, R. Caricchio, W.W. Chatham, Calming the cytokine storm in COVID-19, Nat Med. 27 (2021) 1674-1675

P.F. Dequin, N. Heming, F. Meziani, et al., Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial, JAMA. 324 (2020) 1298-1306

B.M. Tomazini, I.S. Maia, A.B. Cavalcanti, et al., Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial, JAMA. 324 (2020) 1307-1316

R. Huang, C. Zhu, W. Jian, et al., Corticosteroid therapy is associated with the delay of SARS-CoV-2 clearance in COVID-19 patients, Eur J Pharmacol. 889 (2020), 173556

D.C. Fajgenbaum, C.H. June, Cytokine Storm, New England Journal of Medicine. 383 (2020) 2255-2273

W. Zhou, Y. Liu, B. Xu, et al., Early identification of patients with severe COVID-19 at increased risk of in-hospital death: a multicenter case-control study in Wuhan, J Thorac Dis. 13 (2021) 1380-1395

L.Y.C. Chen, R.L. Hoiland, S. Stukas, et al., Confronting the controversy: interleukin-6 and the COVID-19 cytokine storm syndrome, European Respiratory Journal. 56 (2020), 2003006

O.J. McElvaney, G.F. Curley, S. Rose-John, et al., Interleukin-6: obstacles to targeting a complex cytokine in critical illness, Lancet Respir Med. 9 (2021) 643-654

S.A. Jones, C.A. Hunter, Is IL-6 a key cytokine target for therapy in COVID-19?, Nat Rev Immunol. 21 (2021) 337-339

Z. Zhou, X. Zhang, X. Lei, et al., Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection, Signal Transduct Target Ther. 6 (2021) 382

N. Sugimoto, H. Mitoma, T. Kim, et al., Helicase proteins DHX29 and RIG-I cosense cytosolic nucleic acids in the human airway system, Proceedings of the National Academy of Sciences. 111 (2014) 7747-7752

Y. Yu, Y. Liu, W. An, et al., STING-mediated inflammation in Kupffer cells contributes to progression of nonalcoholic steatohepatitis, Journal of Clinical Investigation. 129 (2019) 546-555

A. Park, A. Iwasaki, Type I and Type III Interferons-Induction, Signaling, Evasion, and Application to Combat COVID-19, Cell Host Microbe. 27 (2020) 870-878

S. Khan, M.S. Shafiei, C. Longoria, et al., SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-kappaB pathway, Elife. 10 (2021), 68563

A.K. Rana, S.N. Rahmatkar, A. Kumar, et al., Glycogen synthase kinase-3: A putative target to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, Cytokine Growth Factor Rev. 58 (2021) 92-101

A. Marineau, K.A. Khan, M.J. Servant, Roles of GSK-3 and β-Catenin in Antiviral Innate Immune Sensing of Nucleic Acids, Cells. 9 (2020) 897

S. Yum, M. Li, Y. Fang, et al., TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections, Proceedings of the National Academy of Sciences. 118 (2021), e2100225118

S. Srinivasan, A.G. Torres, L. Ribas de Pouplana, Inosine in Biology and Disease, Genes (Basel). 12 (2021) 600

L. Liaudet, J.G. Mabley, P. Pacher, et al., Inosine exerts a broad range of antiinflammatory effects in a murine model of acute lung injury, Ann Surg. 235 (2002) 568-578

L. Liaudet, J.G. Mabley, F.G. Soriano, et al., Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture, Am J Respir Crit Care Med. 164 (2001) 1213-1220

L.P. Chen, Y.M. Cai, J.S. Li, Medication rules of famous veteran traditional Chinese medicine doctor in treatment of chronic bronchitis based on implicit structure model, Zhongguo Zhong Yao Za Zhi. 42 (2017) 1609-1616

C. Ding, Z. Song, A. Shen, et al., Small molecules targeting the innate immune cGAS-STING-TBK1 signaling pathway, Acta Pharm Sin B. 10 (2020) 2272-2298

Y. Liu, W. Liu, Z. Liang, Endophytic bacteria from Pinellia ternata, a new source of purine alkaloids and bacterial manure, Pharm Biol. 53 (2015) 1545-1548

M. Ogasawara, K. Yoshii, J. Wada, et al., Identification of guanine, guanosine, and inosine for α-amylase inhibitors in the extracts of the earthworm Eisenia fetida and characterization of their inhibitory activities against porcine pancreatic α-amylase, Enzyme Microb Technol. 142 (2020), 109693

L. Zhu, P. Yang, Y. Zhao, et al., Single-Cell Sequencing of Peripheral Mononuclear Cells Reveals Distinct Immune Response Landscapes of COVID-19 and Influenza Patients, Immunity. 53 (2020) 685-696 e683

X. Ren, W. Wen, X. Fan, et al., COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas, Cell. 184 (2021) 1895-1913.e19

N.G. Ravindra, M.M. Alfajaro, V. Gasque, et al., Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium identifies target cells, alterations in gene expression, and cell state changes, PLoS Biol. 19 (2021), e3001143

R.T. Huang, D. Wu, A. Meliton, et al., Experimental Lung Injury Reduces Kruppel-like Factor 2 to Increase Endothelial Permeability via Regulation of RAPGEF3-Rac1 Signaling, Am J Respir Crit Care Med. 195 (2017) 639-651

S. Liu, X. Cai, J. Wu, et al., Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation, Science. 347 (2015), aaa2630

D.B. Stetson, R. Medzhitov, Recognition of cytosolic DNA activates an IRF3-dependent innate immune response, Immunity. 24 (2006) 93-103

E.R. Sang, Y. Tian, L.C. Miller, et al., Epigenetic Evolution of ACE2 and IL-6 Genes: Non-Canonical Interferon-Stimulated Genes Correlate to COVID-19 Susceptibility in Vertebrates, Genes (Basel). 12 (2021) 154

F. Dos Anjos, J.L.B. Simoes, C.E. Assmann, et al., Potential Therapeutic Role of Purinergic Receptors in Cardiovascular Disease Mediated by SARS-CoV-2, J Immunol Res. 2020 (2020), 8632048

M. Lovaszi, Z.H. Nemeth, W.C. Gause, et al., Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis, FASEB J. 35 (2021), e21935

G.R. Milne, T.M. Palmer, Anti-inflammatory and immunosuppressive effects of the A2A adenosine receptor, The Scientific World Journal. 11 (2011) 320-339

Y. Qin, Q. Liu, S. Tian, et al., TRIM9 short isoform preferentially promotes DNA and RNA virus-induced production of type I interferon by recruiting GSK3β to TBK1, Cell Res. 26 (2016) 613-628

C. Zhang, G. Shang, X. Gui, et al., Structural basis of STING binding with and phosphorylation by TBK1, Nature. 567 (2019) 394-398

D.L. Burdette, K.M. Monroe, K. Sotelo-Troha, et al., STING is a direct innate immune sensor of cyclic di-GMP, Nature. 478 (2011) 515-518

D. Zhang, L. Liu, L. Pang, et al., Biological evaluation and energetic analyses of novel GSK-3β inhibitors, J Cell Biochem. 119 (2018) 3510-3518

Relative Articles

Supplements(0)

Cited By

Proportional views