Contribution of STAT3 to the pathogenesis of COVID-19

Abdollah Jafarzadeh, Maryam Nemati, Sara Jafarzadeh, Abdollah Jafarzadeh, Maryam Nemati, Sara Jafarzadeh

Abstract

Hyper-inflammatory responses, lymphopenia, unbalanced immune responses, cytokine storm, large viral replication and massive cell death play fundamental roles in the pathogenesis of COVID-19. Extreme production of many kinds of pro-inflammatory cytokines and chemokines occur in severe COVID-19 that called cytokine storm. Signal transducer and activator of transcription-3 (STAT-3) present in the cytoplasm in an inactive form and can be stimulated by a vast range of cytokines, chemokines and growth factors. Thus, STAT-3 can participate in the induction of inflammatory responses during coronavirus infections. STAT-3 can also suppress anti-virus interferon response and induce unbalanced anti-virus adaptive immune response, through influencing Th17-, Th1-, Treg-, and B cell-mediated functions. Furthermore, STAT-3 can contribute to the M2 macrophage polarization, lung fibrosis and thrombosis. Moreover, STAT-3 may be directly targeted by some virus-derived protein and operate as a pro-viral or anti-viral element in a virus-specific process. Here, the possible contribution of STAT-3 to the pathogenesis of COVID-19 was explained, while providing potential approaches to target this transcription factor in an attempt for COVID-19 treatment.

Keywords: COVID-19; Immune response; Inflammation; Pathogenesis; SARS-CoV-2; STAT3; Treatment.

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Fig. 1
Fig. 1
Activation of STAT-3: Binding of numerous cytokines or growth factors to their specific receptors induces phosphorylation of the receptor-associated JAK1 and then STAT3 is phosphorylated by JAK1. Phosphorylated STAT3 is dimerized and translocated to the nucleus, which causes the expression of target genes contributing to the immunosuppression, inflammation, angiogenesis, proliferation and survival.
Fig. 2
Fig. 2
Contribution of STAT-3-mediated pathways to COVID-19 pathogenesis. Activated STAT-3 can down-regulate lymphopoiesis, E-cadherin expression by vascular endothelial cells, Treg cell activity and anti-viral immune responses (including type I IFN-mediated signaling, NK cells activity, Th1 cell responses and CD8+ CTLs) supporting the lymphopenia, the vascular leak, hyper-inflammation and virus persistence, respectively. Activated STAT-3 can up-regulate the formation of the extracellular matrix, the expression of plasminogen activator inhibitor-1, the polarization and activation of Th17 cells and the polarization of M2 macrophages promoting lung fibrosis, thrombosis, hyper-inflammation/cytokine storm, and virus persistence/lung fibrosis, respectively.

References

    1. Eaaswarkhanth M., Al Madhoun A., Al-Mulla F. Could the D614G substitution in the SARS-CoV-2 spike (S) protein be associated with higher COVID-19 mortality? Int. J. Infect. Dis. 2020;96:459–460.
    1. Tahaghoghi-Hajghorbani S., Zafari P., Masoumi E., Rajabinejad M., Jafari-Shakib R., Hasani B., et al. The role of dysregulated immune responses in COVID-19 pathogenesis. Virus Res. 2020;290:198197.
    1. Yao X.H., Li T.Y., He Z.C., Ping Y.F., Liu H.W., Yu S.C., et al. [A pathological report of three COVID-19 cases by minimally invasive autopsies] Chin. J. Pathol. 2020;49:E009.
    1. Wu J.H., Li X., Huang B., Su H., Li Y., Luo D.J., et al. [Pathological changes of fatal coronavirus disease 2019 (COVID-19) in the lungs: report of 10 cases by postmortem needle autopsy] Chin. J. Pathol. 2020;49:568–575.
    1. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.
    1. Jafarzadeh A., Chauhan P., Saha B., Jafarzadeh S., Nemati M. Contribution of monocytes and macrophages to the local tissue inflammation and cytokine storm in COVID-19: lessons from SARS and MERS, and potential therapeutic interventions. Life Sci. 2020;257:118102.
    1. Ragab D., Salah Eldin H., Taeimah M., Khattab R., Salem R. The COVID-19 cytokine storm; what we know so far. Front. Immunol. 2020;11:1446.
    1. Lingeswaran M., Goyal T., Ghosh R., Suri S., Mitra P., Misra S., et al. Inflammation, immunity and immunogenetics in COVID-19: a narrative review. Indian J. Clin. Biochem. 2020;35:260–273.
    1. Gharibi T., Babaloo Z., Hosseini A., Abdollahpour-Alitappeh M., Hashemi V., Marofi F., et al. Targeting STAT3 in cancer and autoimmune diseases. Eur. J. Pharmacol. 2020;878:173107.
    1. Chang Z., Wang Y., Zhou X., Long J.E. STAT3 roles in viral infection: antiviral or proviral? Future Virol. 2018;13:557–574.
    1. Li X., Xu S., Yu M., Wang K., Tao Y., Zhou Y., et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J. Allergy Clin. Immunol. 2020;146:110–118.
    1. Luo W., Li Y.X., Jiang L.J., Chen Q., Wang T., Ye D.W. Targeting JAK-STAT signaling to control cytokine release syndrome in COVID-19. Trends Pharmacol. Sci. 2020;41:531–543.
    1. Schwartz D.M., Kanno Y., Villarino A., Ward M., Gadina M., O'Shea J.J. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug Discov. 2017;17:78.
    1. Day C.W., Baric R., Cai S.X., Frieman M., Kumaki Y., Morrey J.D., et al. A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo. Virology. 2009;395:210–222.
    1. Magro G. SARS-CoV-2 and COVID-19: is interleukin-6 (IL-6) the 'culprit lesion' of ARDS onset? What is there besides Tocilizumab? SGP130Fc. Cytokine X. 2020
    1. Chen X., Zhao B., Qu Y., Chen Y., Xiong J., Feng Y., et al. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. Clin. Infect. Dis. 2020;71(8):1937–1942.
    1. Gubernatorova E.O., Gorshkova E.A., Polinova A.I., Drutskaya M.S. IL-6: relevance for immunopathology of SARS-CoV-2. Cytokine Growth Factor Rev. 2020;53:13–24.
    1. Herold T., Jurinovic V., Arnreich C., Hellmuth J.C., von Bergwelt-Baildon M., Klein M., Weinberger T., et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J. Allergy Clin. Immunol. 2020;146(1):128–136.
    1. Strope J.D., Chau C.H., Figg W.D. Are sex discordant outcomes in COVID-19 related to sex hormones? Semin. Oncol. 2020;47:335–340.
    1. Wang J., Xu Y., Zhang X., Wang S., Peng Z., Guo J., et al. Leptin correlates with monocytes activation and severe condition in COVID-19 patients. J. Leukoc. Biol. 2021 doi: 10.1002/JLB.5HI1020-704R.
    1. Barrett D. In: Cytokine Storm Syndrome. Cron R., Behrens E., editors. Springer; Cham: 2019. IL-6 blockade in cytokine storm syndromes.
    1. Narazaki M., Kishimoto T. The two-faced cytokine IL-6 in host defense and diseases. Int. J. Mol. Sci. 2018;19
    1. Patra T., Meyer K., Geerling L., Isbell T.S., Hoft D.F., Brien J., et al. SARS-CoV-2 spike protein promotes IL-6 trans-signaling by activation of angiotensin II receptor signaling in epithelial cells. PLoS Pathog. 2020;16
    1. Jafarzadeh A., Larussa T., Nemati M., Jalapour S. T cell subsets play an important role in the determination of the clinical outcome of Helicobacter pylori infection. Microb. Pathog. 2018;116:227–236.
    1. Jafarzadeh A., Nemati M. Therapeutic potentials of ginger for treatment of Multiple sclerosis: a review with emphasis on its immunomodulatory, anti-inflammatory and anti-oxidative properties. J. Neuroimmunol. 2018;324:54–75.
    1. Faure E., Poissy J., Goffard A., Fournier C., Kipnis E., Titecat M., et al. Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside? PloS One. 2014;9
    1. Josset L., Menachery V.D., Gralinski L.E., Agnihothram S., Sova P., Carter V.S., et al. Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus. mBio. 2013;4:e00165–13.
    1. Xu Z., Shi L., Wang Y., Zhang J., Huang L., Zhang C., et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 2020;8:420–422.
    1. Tahmasebi S., El-Esawi M.A., Mahmoud Z.H., Timoshin A., Valizadeh H., Roshangar L., et al. Immunomodulatory effects of nanocurcumin on Th17 cell responses in mild and severe COVID-19 patients. J. Cell. Physiol. 2020 doi: 10.1002/jcp.30233.
    1. Orlov M., Wander P.L., Morrell E.D., Mikacenic C., Wurfel M.M. A case for targeting Th17 Cells and IL-17A in SARS-CoV-2 infections. J. Immunol. 2020;205:892–898.
    1. Mikacenic C., Hansen E.E., Radella F., Gharib S.A., Stapleton R.D., Wurfel M.M. Interleukin-17A is associated with alveolar inflammation and poor outcomes in acute respiratory distress syndrome. Crit. Care Med. 2016;44:496–502.
    1. Wu D., Yang X.O. TH17 responses in cytokine storm of COVID-19: an emerging target of JAK2 inhibitor Fedratinib. J. Microbiol. Immunol. Infect. 2020;53:368–370.
    1. Min H.K., Choi J., Lee S.Y., Seo H.B., Jung K., Na H.S., et al. Protein inhibitor of activated STAT3 reduces peripheral arthritis and gut inflammation and regulates the Th17/Treg cell imbalance via STAT3 signaling in a mouse model of spondyloarthritis. J. Transl. Med. 2019;17:18.
    1. Sun P., Qie S., Liu Z., Ren J., Li K., Xi J. Clinical characteristics of hospitalized patients with SARS-CoV-2 infection: a single arm meta-analysis. J. Med. Virol. 2020;92:612–617.
    1. Li S.W., Wang C.Y., Jou Y.J., Yang T.C., Huang S.H., Wan L., et al. SARS coronavirus papain-like protease induces Egr-1-dependent up-regulation of TGF-beta1 via ROS/p38 MAPK/STAT3 pathway. Sci. Rep. 2016;6:25754.
    1. Chen W. A potential treatment of COVID-19 with TGF-beta blockade. Int. J. Biol. Sci. 2020;16:1954–1955.
    1. Lodyga M., Hinz B. TGF-beta1 - a truly transforming growth factor in fibrosis and immunity. Semin. Cell Dev. Biol. 2020;101:123–139.
    1. Matsuyama T., Kubli S.P., Yoshinaga S.K., Pfeffer K., Mak T.W. An aberrant STAT pathway is central to COVID-19. Cell Death Differ. 2020;27:3209–3225.
    1. Pechkovsky D.V., Prêle C.M., Wong J., Hogaboam C.M., McAnulty R.J., Laurent G.J., et al. STAT3-mediated signaling dysregulates lung fibroblast-myofibroblast activation and differentiation in UIP/IPF. Am. J. Pathol. 2012;180:1398–1412.
    1. Pedroza M., Le T.T., Lewis K., Karmouty-Quintana H., To S., George A.T., et al. STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation. Faseb. J. : official publication of the Federation of American Societies for Experimental Biology. 2016;30:129–140.
    1. Shieh J.M., Tseng H.Y., Jung F., Yang S.H., Lin J.C. Elevation of IL-6 and IL-33 levels in serum associated with lung fibrosis and skeletal muscle wasting in a bleomycin-induced lung injury mouse model. Mediat. Inflamm. 2019;2019
    1. Zuo S., Zhu Z., Liu Y., Li H., Song S., Yin S. CXCL16 induces the progression of pulmonary fibrosis through promoting the phosphorylation of STAT3. Can. Respir. J. J. Can. Thorac. Soc. 2019;2019
    1. Ayaub E.A., Dubey A., Imani J., Botelho F., Kolb M.R.J., Richards C.D., et al. Overexpression of OSM and IL-6 impacts the polarization of pro-fibrotic macrophages and the development of bleomycin-induced lung fibrosis. Sci. Rep. 2017;7:13281.
    1. Kobayashi T., Tanaka K., Fujita T., Umezawa H., Amano H., Yoshioka K., et al. Bidirectional role of IL-6 signal in pathogenesis of lung fibrosis. Respir. Res. 2015;16:99.
    1. Yang M.L., Wang C.T., Yang S.J., Leu C.H., Chen S.H., Wu C.L., et al. IL-6 ameliorates acute lung injury in influenza virus infection. Sci. Rep. 2017;7:43829.
    1. Lauder S.N., Jones E., Smart K., Bloom A., Williams A.S., Hindley J.P., et al. Interleukin-6 limits influenza-induced inflammation and protects against fatal lung pathology. Eur. J. Immunol. 2013;43:2613–2625.
    1. Liu B., Li M., Zhou Z., Guan X., Xiang Y. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J. Autoimmun. 2020;111:102452.
    1. Zhang C., Wu Z., Li J.W., Zhao H., Wang G.Q. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int. J. Antimicrob. Agents. 2020;55:105954.
    1. Zuo Y., Warnock M., Harbaugh A., Yalavarthi S., Gockman K., Zuo M., et al. Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients. medRxiv. 2020 doi: 10.1101/2020.08.29.20184358.
    1. Bester J., Matshailwe C., Pretorius E. Simultaneous presence of hypercoagulation and increased clot lysis time due to IL-1β, IL-6 and IL-8. Cytokine. 2018;110:237–242.
    1. Nosaka M., Ishida Y., Kimura A., Kuninaka Y., Taruya A., Ozaki M., et al. Crucial involvement of IL-6 in thrombus resolution in mice via macrophage recruitment and the induction of proteolytic enzymes. Front. Immunol. 2019;10:3150.
    1. Cimmino G., Cirillo P. Tissue factor: newer concepts in thrombosis and its role beyond thrombosis and hemostasis. Cardiovasc. Diagn. Ther. 2018;8:581–593.
    1. Jafarzadeh A., Jafarzadeh S., Nozari P., Mokhtari P., Nemati M. Lymphopenia an important immunological abnormality in patients with COVID-19: possible mechanisms. Scand. J. Immunol. 2020
    1. Zeng Q., Li Y-z, Huang G., Wu W., Dong S-y, Xu Y. Mortality of COVID-19 is associated with cellular immune function compared to immune function in Chinese han population. medRxiv. 2020 doi: 10.1101/2020.03.08.20031229.
    1. Zheng M., Gao Y., Wang G., Song G., Liu S., Sun D., et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell. Mol. Immunol. 2020;17:533–535.
    1. Maeda K., Malykhin A., Teague-Weber B.N., Sun X.H., Farris A.D., Coggeshall K.M. Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus-prone B6.Sle1.Yaa animals. Blood. 2009;113:4534–4540.
    1. Maeda K., Baba Y., Nagai Y., Miyazaki K., Malykhin A., Nakamura K., et al. IL-6 blocks a discrete early step in lymphopoiesis. Blood. 2005;106:879–885.
    1. Giamarellos-Bourboulis E.J., Netea M.G., Rovina N., Akinosoglou K., Antoniadou A., Antonakos N., et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020;27:992–1000. e3.
    1. Zhang C., Wu Z., Li J.W., Zhao H., Wang G.Q. The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality. Int. J. Antimicrob. Agents. 2020
    1. Jenkins B.J., Roberts A.W., Greenhill C.J., Najdovska M., Lundgren-May T., Robb L., et al. Pathologic consequences of STAT3 hyperactivation by IL-6 and IL-11 during hematopoiesis and lymphopoiesis. Blood. 2007;109:2380–2388.
    1. Jafarzadeh A., Nemati M., Saha B., Bansode Y., S J. Protective potentials of type III interferons (IFN-λ) in COVID-19 patients: lessons from different basically and clinically properties attributed to the type I- and III interferons. Viral Immunol. 2020 doi: 10.1089/vim.2020.0076.
    1. Tsai M.H., Pai L.M., Lee C.K. Fine-tuning of type I interferon response by STAT3. Front. Immunol. 2019;10:1448.
    1. Finigan J.H., Downey G.P., Kern J.A. Human epidermal growth factor receptor signaling in acute lung injury. Am. J. Respir. Cell Mol. Biol. 2012;47:395–404.
    1. Venkataraman T., Coleman C.M., Frieman M.B. Overactive epidermal growth factor receptor signaling leads to increased fibrosis after severe acute respiratory syndrome coronavirus infection. J. Virol. 2017;91
    1. Miyauchi K. Helper T cell responses to respiratory viruses in the lung: development, virus suppression, and pathogenesis. Viral Immunol. 2017;30:421–430.
    1. Frank K., Paust S. Dynamic natural killer cell and T cell responses to influenza infection. Frontiers in cellular and infection microbiology. 2020;10:425.
    1. Jafarzadeh A., Shokri F. The antibody response to HBs antigen is regulated by coordinated Th1 and Th2 cytokine production in healthy neonates. Clin. Exp. Immunol. 2003;131:451–456.
    1. Ju B., Zhang Q., Ge J., Wang R., Sun J., Ge X., et al. Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature. 2020;584:115–119.
    1. Janice Oh H.L., Ken-En Gan S., Bertoletti A., Tan Y.J. Understanding the T cell immune response in SARS coronavirus infection. Emerg. Microb. Infect. 2012;1:e23.
    1. Neidleman J., Luo X., Frouard J., Xie G., Gill G., Stein E.S., et al. SARS-CoV-2-specific T cells exhibit unique features characterized by robust helper function, lack of terminal differentiation, and high proliferative potential. bioRxiv : the preprint server for biology. 2020 doi: 10.1101/2020.06.08.138826.
    1. Sattler A., Angermair S., Stockmann H., Heim K.M., Khadzhynov D., Treskatsch S., et al. SARS-CoV-2 specific T-cell responses and correlations with COVID-19 patient predisposition. J. Clin. Invest. 2020;130:6477–6489.
    1. Velazquez-Salinas L., Verdugo-Rodriguez A., Rodriguez L.L., Borca M.V. The role of interleukin 6 during viral infections. Front. Microbiol. 2019;10:1057.
    1. Kortylewski M., Xin H., Kujawski M., Lee H., Liu Y., Harris T., et al. Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Canc. Cell. 2009;15:114–123.
    1. Eddahri F., Denanglaire S., Bureau F., Spolski R., Leonard W.J., Leo O., et al. Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities. Blood. 2009;113:2426–2433.
    1. Nurieva R.I., Chung Y., Hwang D., Yang X.O., Kang H.S., Ma L., et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008;29:138–149.
    1. Yang X.O., Panopoulos A.D., Nurieva R., Chang S.H., Wang D., Watowich S.S., et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J. Biol. Chem. 2007;282:9358–9363.
    1. Zhang Y., Zhang Y., Gu W., Sun B. TH1/TH2 cell differentiation and molecular signals. Adv. Exp. Med. Biol. 2014;841:15–44.
    1. Schmitt N., Ueno H. Regulation of human helper T cell subset differentiation by cytokines. Curr. Opin. Immunol. 2015;34:130–136.
    1. Weiskopf D., Schmitz K.S., Raadsen M.P., Grifoni A., Okba N.M.A., Endeman H., et al. Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome. Science immunology. 2020;5
    1. Kaneko N., Kuo H.H., Boucau J., Farmer J.R., Allard-Chamard H., Mahajan V.S., et al. Loss of Bcl-6-expressing t follicular helper cells and germinal centers in COVID-19. Cell. 2020;183:143–157.
    1. Yinda C.K., Port J.R., Bushmaker T., Owusu I.O., Avanzato V.A., Fischer R.J., et al. K18-hACE2 mice develop respiratory disease resembling severe COVID-19. PLoS Pathog. 2020;17:e1009195.
    1. Yang Y., Shen C., Li J., Yuan J., Wei J., Huang F., et al. Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19. J. Allergy Clin. Immunol. 2020;146:119–127. e4.
    1. Roncati L., Nasillo V., Lusenti B., Riva G. Signals of T(h)2 immune response from COVID-19 patients requiring intensive care. Ann. Hematol. 2020;99:1419–1420.
    1. Li C.K., Wu H., Yan H., Ma S., Wang L., Zhang M., et al. T cell responses to whole SARS coronavirus in humans. J. Immunol. 2008;181:5490–5500. Baltimore, Md : 1950.
    1. Stritesky G.L., Muthukrishnan R., Sehra S., Goswami R., Pham D., Travers J., et al. The transcription factor STAT3 is required for T helper 2 cell development. Immunity. 2011;34:39–49.
    1. Deenick E.K., Pelham S.J., Kane A., Ma C.S. Signal transducer and activator of transcription 3 control of human T and B cell responses. Front. Immunol. 2018;9:168.
    1. Karnowski A., Chevrier S., Belz G.T., Mount A., Emslie D., D'Costa K., et al. B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1. J. Exp. Med. 2012;209:2049–2064.
    1. Yu Z.X., Ji M.S., Yan J., Cai Y., Liu J., Yang H.F., et al. The ratio of Th17/Treg cells as a risk indicator in early acute respiratory distress syndrome. Crit. Care. 2015;19:82.
    1. Chen G., Wu D., Guo W., Cao Y., Huang D., Wang H., et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Invest. 2020;130:2620–2629.
    1. Qin C., Zhou L., Hu Z., Zhang S., Yang S., Tao Y., et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in wuhan, China. Clin. Infect. Dis. 2020;71:762–768.
    1. Wang F., Hou H., Luo Y., Tang G., Wu S., Huang M., et al. The laboratory tests and host immunity of COVID-19 patients with different severity of illness. JCI insight. 2020;5
    1. Engin A.B., Engin E.D., Engin A. The effect of environmental pollution on immune evasion checkpoints of SARS-CoV-2. Environ. Toxicol. Pharmacol. 2021;81
    1. Li G., Cao Y., Sun Y., Xu R., Zheng Z., Song H. Ultrafine particles in the airway aggravated experimental lung injury through impairment in Treg function. Biochem. Biophys. Res. Commun. 2016;478:494–500.
    1. Lin S., Wu H., Wang C., Xiao Z., Xu F. Regulatory T cells and acute lung injury: cytokines, uncontrolled inflammation, and therapeutic implications. Front. Immunol. 2018;9:1545.
    1. Wei L.-L., Wang W.-J., Chen D.-X., Xu B. Dysregulation of the immune response affects the outcome of critical COVID-19 patients. J. Med. Virol. 2020 doi: 10.1002/jmv.26181.
    1. Pyle C.J., Uwadiae F.I., Swieboda D.P., Harker J.A. Early IL-6 signalling promotes IL-27 dependent maturation of regulatory T cells in the lungs and resolution of viral immunopathology. PLoS Pathog. 2017;13
    1. Chen X., Tang J., Shuai W., Meng J., Feng J., Han Z. Macrophage polarization and its role in the pathogenesis of acute lung injury/acute respiratory distress syndrome. Inflamm. Res. : official journal of the European Histamine Research Society [et al] 2020;69:883–895.
    1. Zhao J., Yu H., Liu Y., Gibson S.A., Yan Z., Xu X., et al. Protective effect of suppressing STAT3 activity in LPS-induced acute lung injury. Am. J. Physiol. Lung Cell Mol. Physiol. 2016;311 L868-l80.
    1. Sang Y., Miller L.C., Blecha F. Macrophage polarization in virus-host interactions. J. Clin. Cell. Immunol. 2015;6
    1. Shirey K.A., Lai W., Pletneva L.M., Karp C.L., Divanovic S., Blanco J.C., et al. Role of the lipoxygenase pathway in RSV-induced alternatively activated macrophages leading to resolution of lung pathology. Mucosal Immunol. 2014;7:549–557.
    1. Liao M., Liu Y., Yuan J., Wen Y., Xu G., Zhao J., et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat. Med. 2020;26:842–844.
    1. Drareni K., Gautier J.F., Venteclef N., Alzaid F. Transcriptional control of macrophage polarisation in type 2 diabetes. Semin. Immunopathol. 2019;41:515–529.
    1. Yin Z., Ma T., Lin Y., Lu X., Zhang C., Chen S., et al. IL-6/STAT3 pathway intermediates M1/M2 macrophage polarization during the development of hepatocellular carcinoma. J. Cell. Biochem. 2018;119:9419–9432.
    1. Fu X.L., Duan W., Su C.Y., Mao F.Y., Lv Y.P., Teng Y.S., et al. Interleukin 6 induces M2 macrophage differentiation by STAT3 activation that correlates with gastric cancer progression. Canc. Immunol. Immunother. : CII. 2017;66:1597–1608.
    1. Mizutani T., Fukushi S., Murakami M., Hirano T., Saijo M., Kurane I., et al. Tyrosine dephosphorylation of STAT3 in SARS coronavirus-infected Vero E6 cells. FEBS Lett. 2004;577:187–192.
    1. Park B.K., Kim D., Park S., Maharjan S., Kim J., Choi J.K., et al. Differential signaling and virus production in Calu-3 cells and vero cells upon SARS-CoV-2 infection. Biomol. Ther. 2021 doi: 10.4062/biomolther.2020.226.
    1. Hojyo S., Uchida M., Tanaka K., Hasebe R., Tanaka Y., Murakami M., et al. How COVID-19 induces cytokine storm with high mortality. Inflamm. Regen. 2020;40:37.
    1. Zou S., Tong Q., Liu B., Huang W., Tian Y., Fu X. Targeting STAT3 in cancer immunotherapy. Mol. Canc. 2020;19:145.
    1. Siveen K.S., Sikka S., Surana R., Dai X., Zhang J., Kumar A.P., et al. Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim. Biophys. Acta. 2014;1845:136–154.
    1. Shamir I., Abutbul-Amitai M., Abbas-Egbariya H., Pasmanik-Chor M., Paret G., Nevo-Caspi Y. STAT3 isoforms differentially affect ACE2 expression: a potential target for COVID-19 therapy. J. Cell Mol. Med. 2020;24:12864–12868.
    1. Thilakasiri P.S., Dmello R.S., Nero T.L., Parker M.W., Ernst M., Chand A.L. Repurposing of drugs as STAT3 inhibitors for cancer therapy. Semin. Canc. Biol. 2021;68:31–46.
    1. Yue P., Turkson J. Targeting STAT3 in cancer: how successful are we? Expet Opin. Invest. Drugs. 2009;18:45–56.
    1. Wong A.L.A., Hirpara J.L., Pervaiz S., Eu J.Q., Sethi G., Goh B.C. Do STAT3 inhibitors have potential in the future for cancer therapy? Expet Opin. Invest. Drugs. 2017;26:883–887.
    1. Sen M., Grandis J.R. Nucleic acid-based approaches to STAT inhibition. JAK-STAT. 2012;1:285–291.
    1. Yang L., Lin S., Xu L., Lin J., Zhao C., Huang X. Novel activators and small-molecule inhibitors of STAT3 in cancer. Cytokine Growth Factor Rev. 2019;49:10–22.

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