Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes
Rajendra Karki, Bhesh Raj Sharma, Shraddha Tuladhar, Evan Peter Williams, Lillian Zalduondo, Parimal Samir, Min Zheng, Balamurugan Sundaram, Balaji Banoth, R K Subbarao Malireddi, Patrick Schreiner, Geoffrey Neale, Peter Vogel, Richard Webby, Colleen Beth Jonsson, Thirumala-Devi Kanneganti, Rajendra Karki, Bhesh Raj Sharma, Shraddha Tuladhar, Evan Peter Williams, Lillian Zalduondo, Parimal Samir, Min Zheng, Balamurugan Sundaram, Balaji Banoth, R K Subbarao Malireddi, Patrick Schreiner, Geoffrey Neale, Peter Vogel, Richard Webby, Colleen Beth Jonsson, Thirumala-Devi Kanneganti
Abstract
COVID-19 is characterized by excessive production of pro-inflammatory cytokines and acute lung damage associated with patient mortality. While multiple inflammatory cytokines are produced by innate immune cells during SARS-CoV-2 infection, we found that only the combination of TNF-α and IFN-γ induced inflammatory cell death characterized by inflammatory cell death, PANoptosis. Mechanistically, TNF-α and IFN-γ co-treatment activated the JAK/STAT1/IRF1 axis, inducing nitric oxide production and driving caspase-8/FADD-mediated PANoptosis. TNF-α and IFN-γ caused a lethal cytokine shock in mice that mirrors the tissue damage and inflammation of COVID-19, and inhibiting PANoptosis protected mice from this pathology and death. Furthermore, treating with neutralizing antibodies against TNF-α and IFN-γ protected mice from mortality during SARS-CoV-2 infection, sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock. Collectively, our findings suggest that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other infectious and autoinflammatory diseases by limiting tissue damage/inflammation.
Keywords: COVID-19; IFN-γ; PANoptosis; SARS-CoV-2; TNF-α; apoptosis; cytokine storm; inflammation; necroptosis; pyroptosis.
Conflict of interest statement
Declaration of Interests St. Jude Children’s Research hospital filed a provisional patent application on TNF-α and IFN-γ signaling described in this study, listing R.K. and T.-D.K. as inventors (serial no. 63/106,012).
Copyright © 2020 Elsevier Inc. All rights reserved.
Figures
References
- Albina J.E., Reichner J.S. Role of nitric oxide in mediation of macrophage cytotoxicity and apoptosis. Cancer Metastasis Rev. 1998;17:39–53.
- Aouba A., Baldolli A., Geffray L., Verdon R., Bergot E., Martin-Silva N., Justet A. Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series. Ann. Rheum. Dis. 2020;79:1381–1382.
- Atal S., Fatima Z. IL-6 Inhibitors in the Treatment of Serious COVID-19: A Promising Therapy? Pharmaceut. Med. 2020;34:223–231.
- Bailey A., Pope T.W., Moore S.A., Campbell C.L. The tragedy of TRIUMPH for nitric oxide synthesis inhibition in cardiogenic shock: where do we go from here? Am. J. Cardiovasc. Drugs. 2007;7:337–345.
- Belkhelfa M., Rafa H., Medjeber O., Arroul-Lammali A., Behairi N., Abada-Bendib M., Makrelouf M., Belarbi S., Masmoudi A.N., Tazir M., Touil-Boukoffa C. IFN-γ and TNF-α are involved during Alzheimer disease progression and correlate with nitric oxide production: a study in Algerian patients. J. Interferon Cytokine Res. 2014;34:839–847.
- Benaoudia S., Martin A., Puig Gamez M., Gay G., Lagrange B., Cornut M., Krasnykov K., Claude J.B., Bourgeois C.F., Hughes S., et al. A genome-wide screen identifies IRF2 as a key regulator of caspase-4 in human cells. EMBO Rep. 2019;20:e48235.
- Blanco-Melo D., Nilsson-Payant B.E., Liu W.C., Uhl S., Hoagland D., Moller R., Jordan T.X., Oishi K., Panis M., Sachs D., et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020;181:1036–1045.e9.
- Brubaker S.W., Brewer S.M., Massis L.M., Napier B.A., Monack D.M. A Rapid Caspase-11 Response Induced by IFNg Priming Is Independent of Guanylate Binding Proteins. iScience. 2020;23:101612.
- Chan A.S., Rout A. Use of Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios in COVID-19. J. Clin. Med. Res. 2020;12:448–453.
- Channappanavar R., Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin. Immunopathol. 2017;39:529–539.
- Chen K.W., Demarco B., Heilig R., Shkarina K., Boettcher A., Farady C.J., Pelczar P., Broz P. Extrinsic and intrinsic apoptosis activate pannexin-1 to drive NLRP3 inflammasome assembly. EMBO J. 2019;38:e101638.
- Cheung E.W., Zachariah P., Gorelik M., Boneparth A., Kernie S.G., Orange J.S., Milner J.D. Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City. JAMA. 2020;324:294–296.
- Chousterman B.G., Swirski F.K., Weber G.F. Cytokine storm and sepsis disease pathogenesis. Semin. Immunopathol. 2017;39:517–528.
- Christgen S., Zheng M., Kesavardhana S., Karki R., Malireddi R.K.S., Banoth B., Place D.E., Briard B., Sharma B.R., Tuladhar S., et al. Identification of the PANoptosome: A Molecular Platform Triggering Pyroptosis, Apoptosis, and Necroptosis (PANoptosis) Front. Cell. Infect. Microbiol. 2020;10:237.
- Croker B.A., Lawson B.R., Rutschmann S., Berger M., Eidenschenk C., Blasius A.L., Moresco E.M., Sovath S., Cengia L., Shultz L.D., et al. Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger. Proc. Natl. Acad. Sci. USA. 2008;105:15028–15033.
- Crowe J.E. In: Fetal and Neonata Physiology. Fifth Edition. Polin R., Abman S., Rowitch D., Benitz W., editors. 2017. Host Defense Mechanisms Against Viruses; pp. 1175–1197.
- Damsky W., King B.A. JAK inhibitors in dermatology: The promise of a new drug class. J. Am. Acad. Dermatol. 2017;76:736–744.
- De Boer W.I. Cytokines and therapy in COPD: a promising combination? Chest. 2002;121(5, Suppl):209S–218S.
- de Jong M.D., Simmons C.P., Thanh T.T., Hien V.M., Smith G.J., Chau T.N., Hoang D.M., Chau N.V., Khanh T.H., Dong V.C., et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat. Med. 2006;12:1203–1207.
- Degrandi D., Kravets E., Konermann C., Beuter-Gunia C., Klümpers V., Lahme S., Wischmann E., Mausberg A.K., Beer-Hammer S., Pfeffer K. Murine guanylate binding protein 2 (mGBP2) controls Toxoplasma gondii replication. Proc. Natl. Acad. Sci. USA. 2013;110:294–299.
- Del Valle D.M., Kim-Schulze S., Huang H.H., Beckmann N.D., Nirenberg S., Wang B., Lavin Y., Swartz T.H., Madduri D., Stock A., et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat. Med. 2020;26:1636–1643.
- Dhuriya Y.K., Sharma D. Necroptosis: a regulated inflammatory mode of cell death. J. Neuroinflammation. 2018;15:199.
- Dillon C.P., Oberst A., Weinlich R., Janke L.J., Kang T.B., Ben-Moshe T., Mak T.W., Wallach D., Green D.R. Survival function of the FADD-CASPASE-8-cFLIP(L) complex. Cell Rep. 2012;1:401–407.
- Du C., Guan Q., Diao H., Yin Z., Jevnikar A.M. Nitric oxide induces apoptosis in renal tubular epithelial cells through activation of caspase-8. Am. J. Physiol. Renal Physiol. 2006;290:F1044–F1054.
- Dubey M., Nagarkoti S., Awasthi D., Singh A.K., Chandra T., Kumaravelu J., Barthwal M.K., Dikshit M. Nitric oxide-mediated apoptosis of neutrophils through caspase-8 and caspase-3-dependent mechanism. Cell Death Dis. 2016;7:e2348.
- Durbin J.E., Hackenmiller R., Simon M.C., Levy D.E. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell. 1996;84:443–450.
- Elmore S. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 2007;35:495–516.
- Fan E., Beitler J.R., Brochard L., Calfee C.S., Ferguson N.D., Slutsky A.S., Brodie D. COVID-19-associated acute respiratory distress syndrome: is a different approach to management warranted? Lancet Respir. Med. 2020;8:816–821.
- Fenner J.E., Starr R., Cornish A.L., Zhang J.G., Metcalf D., Schreiber R.D., Sheehan K., Hilton D.J., Alexander W.S., Hertzog P.J. Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity. Nat. Immunol. 2006;7:33–39.
- Fritsch M., Günther S.D., Schwarzer R., Albert M.C., Schorn F., Werthenbach J.P., Schiffmann L.M., Stair N., Stocks H., Seeger J.M., et al. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature. 2019;575:683–687.
- George M.R. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J. Blood Med. 2014;5:69–86.
- Ghahramani S., Tabrizi R., Lankarani K.B., Kashani S.M.A., Rezaei S., Zeidi N., Akbari M., Heydari S.T., Akbari H., Nowrouzi-Sohrabi P., Ahmadizar F. Laboratory features of severe vs. non-severe COVID-19 patients in Asian populations: a systematic review and meta-analysis. Eur. J. Med. Res. 2020;25:30.
- Giampietri C., Starace D., Petrungaro S., Filippini A., Ziparo E. Necroptosis: molecular signalling and translational implications. Int. J. Cell Biol. 2014;2014:490275.
- Gurung P., Anand P.K., Malireddi R.K., Vande Walle L., Van Opdenbosch N., Dillon C.P., Weinlich R., Green D.R., Lamkanfi M., Kanneganti T.D. FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes. J. Immunol. 2014;192:1835–1846.
- Gurung P., Burton A., Kanneganti T.D. NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β-mediated osteomyelitis. Proc. Natl. Acad. Sci. USA. 2016;113:4452–4457.
- Hadjadj J., Yatim N., Barnabei L., Corneau A., Boussier J., Smith N., Péré H., Charbit B., Bondet V., Chenevier-Gobeaux C., et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science. 2020;369:718–724.
- He W.T., Wan H., Hu L., Chen P., Wang X., Huang Z., Yang Z.H., Zhong C.Q., Han J. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res. 2015;25:1285–1298.
- Hernandez-Cuellar E., Tsuchiya K., Hara H., Fang R., Sakai S., Kawamura I., Akira S., Mitsuyama M. Cutting edge: nitric oxide inhibits the NLRP3 inflammasome. J. Immunol. 2012;189:5113–5117.
- Honarpour N., Du C., Richardson J.A., Hammer R.E., Wang X., Herz J. Adult Apaf-1-deficient mice exhibit male infertility. Dev. Biol. 2000;218:248–258.
- Honda K., Yanai H., Negishi H., Asagiri M., Sato M., Mizutani T., Shimada N., Ohba Y., Takaoka A., Yoshida N., Taniguchi T. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature. 2005;434:772–777.
- Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., Zhang L., Fan G., Xu J., Gu X., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.
- Huet T., Beaussier H., Voisin O., Jouveshomme S., Dauriat G., Lazareth I., Sacco E., Naccache J.M., Bézie Y., Laplanche S., et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatol. 2020;2:e393–e400.
- Jiang L., Tang K., Levin M., Irfan O., Morris S.K., Wilson K., Klein J.D., Bhutta Z.A. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect. Dis. 2020;20:e276–e288.
- Jose R.J., Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir. Med. 2020;8:e46–e47.
- Kam K.Q., Yung C.F., Cui L., Tzer Pin Lin R., Mak T.M., Maiwald M., Li J., Chong C.Y., Nadua K., Tan N.W.H., Thoon K.C. A Well Infant With Coronavirus Disease 2019 With High Viral Load. Clin. Infect. Dis. 2020;71:847–849.
- Kaneko N., Kuo H.-H., Boucau J., Farmer J.R., Allard-Chamard H., Mahajan V.S., Piechocka-Trocha A., Lefteri K., Osborn M., Bals J., et al. The Loss of Bcl-6 Expressing T Follicular Helper Cells and Germinal Centers in COVID-19. Cell. 2020;183:13–15.
- Karki R., Lee E., Place D., Samir P., Mavuluri J., Sharma B.R., Balakrishnan A., Malireddi R.K.S., Geiger R., Zhu Q., et al. IRF8 Regulates Transcription of Naips for NLRC4 Inflammasome Activation. Cell. 2018;173:920–933.e13.
- Karki R., Sharma B.R., Lee E., Banoth B., Malireddi R.K.S., Samir P., Tuladhar S., Mummareddy H., Burton A.R., Vogel P., Kanneganti T.D. Interferon regulatory factor 1 regulates PANoptosis to prevent colorectal cancer. JCI Insight. 2020;5:e136720.
- Kato H., Takeuchi O., Sato S., Yoneyama M., Yamamoto M., Matsui K., Uematsu S., Jung A., Kawai T., Ishii K.J., et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006;441:101–105.
- Kayagaki N., Warming S., Lamkanfi M., Vande Walle L., Louie S., Dong J., Newton K., Qu Y., Liu J., Heldens S., et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011;479:117–121.
- Kayagaki N., Stowe I.B., Lee B.L., O’Rourke K., Anderson K., Warming S., Cuellar T., Haley B., Roose-Girma M., Phung Q.T., et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015;526:666–671.
- Kayagaki N., Lee B.L., Stowe I.B., Kornfeld O.S., O’Rourke K., Mirrashidi K.M., Haley B., Watanabe C., Roose-Girma M., Modrusan Z., et al. IRF2 transcriptionally induces GSDMD expression for pyroptosis. Sci. Signal. 2019;12:eaax4917.
- Kesavardhana S., Malireddi R.K.S., Burton A.R., Porter S.N., Vogel P., Pruett-Miller S.M., Kanneganti T.D. The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development. J. Biol. Chem. 2020;295:8325–8330.
- Kimura T., Kadokawa Y., Harada H., Matsumoto M., Sato M., Kashiwazaki Y., Tarutani M., Tan R.S., Takasugi T., Matsuyama T., et al. Essential and non-redundant roles of p48 (ISGF3 gamma) and IRF-1 in both type I and type II interferon responses, as revealed by gene targeting studies. Genes Cells. 1996;1:115–124.
- Kox M., Waalders N.J.B., Kooistra E.J., Gerretsen J., Pickkers P. Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions. JAMA. 2020;324:1565–1567.
- Kuriakose T., Man S.M., Malireddi R.K., Karki R., Kesavardhana S., Place D.E., Neale G., Vogel P., Kanneganti T.D. ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways. Sci. Immunol. 2016;1:aag2045.
- Kuriakose T., Zheng M., Neale G., Kanneganti T.D. IRF1 Is a Transcriptional Regulator of ZBP1 Promoting NLRP3 Inflammasome Activation and Cell Death during Influenza Virus Infection. J. Immunol. 2018;200:1489–1495.
- Laing A.G., Lorenc A., Del Molino Del Barrio I., Das A., Fish M., Monin L., Muñoz-Ruiz M., McKenzie D.R., Hayday T.S., Francos-Quijorna I., et al. A dynamic COVID-19 immune signature includes associations with poor prognosis. Nat. Med. 2020;26:1623–1635.
- Lakhani S.A., Masud A., Kuida K., Porter G.A., Jr., Booth C.J., Mehal W.Z., Inayat I., Flavell R.A. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science. 2006;311:847–851.
- Laubach V.E., Shesely E.G., Smithies O., Sherman P.A. Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc. Natl. Acad. Sci. USA. 1995;92:10688–10692.
- Lee J., Parvathareddy J., Yang D., Bansal S., O’Connell K., Golden J.E., Jonsson C.B. Emergence and Magnitude of ML336 Resistance in Venezuelan Equine Encephalitis Virus Depends on the Microenvironment. J Virol. 2020 doi: 10.1128/JVI.00317-20.
- Lee J.S., Park S., Jeong H.W., Ahn J.Y., Choi S.J., Lee H., Choi B., Nam S.K., Sa M., Kwon J.S., et al. Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19. Sci. Immunol. 2020;5:eabd1554.
- Lei C., Su B., Dong H., Fakhr B.S., Grassi L.G., Di Fenza R., Gianni S., Pinciroli R., Vassena E., Morais C.C.A., et al. Protocol for a randomized controlled trial testing inhaled nitric oxide therapy in spontaneously breathing patients with COVID-19. medRxiv. 2020 doi: 10.1101/2020.03.10.20033522.
- Leisman D.E., Ronner L., Pinotti R., Taylor M.D., Sinha P., Calfee C.S., Hirayama A.V., Mastroiani F., Turtle C.J., Harhay M.O., et al. Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir Med. 2020 doi: 10.1016/S2213-2600(20)30404-5.
- Lin Y., Devin A., Rodriguez Y., Liu Z.G. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 1999;13:2514–2526.
- Lin C.F., Lin C.M., Lee K.Y., Wu S.Y., Feng P.H., Chen K.Y., Chuang H.C., Chen C.L., Wang Y.C., Tseng P.C., Tsai T.T. Escape from IFN-γ-dependent immunosurveillance in tumorigenesis. J. Biomed. Sci. 2017;24:10.
- Lippi G., Plebani M., Henry B.M. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin. Chim. Acta. 2020;506:145–148.
- Liu Q., Zhou Y.H., Yang Z.Q. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell. Mol. Immunol. 2016;13:3–10.
- Liu T., Zhang L., Joo D., Sun S.C. NF-κB signaling in inflammation. Signal Transduct. Target. Ther. 2017;2:17023.
- Locatelli F., Jordan M.B., Allen C., Cesaro S., Rizzari C., Rao A., Degar B., Garrington T.P., Sevilla J., Putti M.C., et al. Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis. N. Engl. J. Med. 2020;382:1811–1822.
- Lucas C., Wong P., Klein J., Castro T.B.R., Silva J., Sundaram M., Ellingson M.K., Mao T., Oh J.E., Israelow B., et al. Yale IMPACT Team Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature. 2020;584:463–469.
- Lukens J.R., Gurung P., Vogel P., Johnson G.R., Carter R.A., McGoldrick D.J., Bandi S.R., Calabrese C.R., Vande Walle L., Lamkanfi M., Kanneganti T.D. Dietary modulation of the microbiome affects autoinflammatory disease. Nature. 2014;516:246–249.
- Lythgoe M.P., Middleton P. Ongoing Clinical Trials for the Management of the COVID-19 Pandemic. Trends Pharmacol. Sci. 2020;41:363–382.
- Malireddi R.K.S., Gurung P., Mavuluri J., Dasari T.K., Klco J.M., Chi H., Kanneganti T.D. TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation. J. Exp. Med. 2018;215:1023–1034.
- Malireddi R.K.S., Kesavardhana S., Kanneganti T.D. ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis) Front. Cell. Infect. Microbiol. 2019;9:406.
- Malireddi R.K.S., Gurung P., Kesavardhana S., Samir P., Burton A., Mummareddy H., Vogel P., Pelletier S., Burgula S., Kanneganti T.D. Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity-independent pyroptosis, apoptosis, necroptosis, and inflammatory disease. J. Exp. Med. 2020;217 jem.20191644.
- Man S.M., Karki R., Malireddi R.K., Neale G., Vogel P., Yamamoto M., Lamkanfi M., Kanneganti T.D. The transcription factor IRF1 and guanylate-binding proteins target activation of the AIM2 inflammasome by Francisella infection. Nat. Immunol. 2015;16:467–475.
- Man S.M., Karki R., Sasai M., Place D.E., Kesavardhana S., Temirov J., Frase S., Zhu Q., Malireddi R.K.S., Kuriakose T., et al. IRGB10 Liberates Bacterial Ligands for Sensing by the AIM2 and Caspase-11-NLRP3 Inflammasomes. Cell. 2016;167:382–396.e17.
- Matsuyama T., Kimura T., Kitagawa M., Pfeffer K., Kawakami T., Watanabe N., Kündig T.M., Amakawa R., Kishihara K., Wakeham A., et al. Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development. Cell. 1993;75:83–97.
- Mehta P., McAuley D.F., Brown M., Sanchez E., Tattersall R.S., Manson J.J., HLH Across Speciality Collaboration, UK COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033–1034.
- Miklossy G., Hilliard T.S., Turkson J. Therapeutic modulators of STAT signalling for human diseases. Nat. Rev. Drug Discov. 2013;12:611–629.
- Moulian N., Truffault F., Gaudry-Talarmain Y.M., Serraf A., Berrih-Aknin S. In vivo and in vitro apoptosis of human thymocytes are associated with nitrotyrosine formation. Blood. 2001;97:3521–3530.
- Müller U., Steinhoff U., Reis L.F., Hemmi S., Pavlovic J., Zinkernagel R.M., Aguet M. Functional role of type I and type II interferons in antiviral defense. Science. 1994;264:1918–1921.
- Murphy J.M., Czabotar P.E., Hildebrand J.M., Lucet I.S., Zhang J.G., Alvarez-Diaz S., Lewis R., Lalaoui N., Metcalf D., Webb A.I., et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity. 2013;39:443–453.
- Newton K., Sun X., Dixit V.M. Kinase RIP3 is dispensable for normal NF-kappa Bs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4. Mol. Cell. Biol. 2004;24:1464–1469.
- Newton K., Wickliffe K.E., Dugger D.L., Maltzman A., Roose-Girma M., Dohse M., Kőműves L., Webster J.D., Dixit V.M. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature. 2019;574:428–431.
- Oberst A., Dillon C.P., Weinlich R., McCormick L.L., Fitzgerald P., Pop C., Hakem R., Salvesen G.S., Green D.R. Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature. 2011;471:363–367.
- Orning P., Weng D., Starheim K., Ratner D., Best Z., Lee B., Brooks A., Xia S., Wu H., Kelliher M.A., et al. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science. 2018;362:1064–1069.
- Papa S., Zazzeroni F., Pham C.G., Bubici C., Franzoso G. Linking JNK signaling to NF-kappaB: a key to survival. J. Cell Sci. 2004;117:5197–5208.
- Peiris J.S., Chu C.M., Cheng V.C., Chan K.S., Hung I.F., Poon L.L., Law K.I., Tang B.S., Hon T.Y., Chan C.S., et al. HKU/UCH SARS Study Group Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003;361:1767–1772.
- Perrone L.A., Szretter K.J., Katz J.M., Mizgerd J.P., Tumpey T.M. Mice lacking both TNF and IL-1 receptors exhibit reduced lung inflammation and delay in onset of death following infection with a highly virulent H5N1 virus. J. Infect. Dis. 2010;202:1161–1170.
- Pervin S., Singh R., Chaudhuri G. Nitric oxide-induced cytostasis and cell cycle arrest of a human breast cancer cell line (MDA-MB-231): potential role of cyclin D1. Proc. Natl. Acad. Sci. USA. 2001;98:3583–3588.
- Petersen E., Koopmans M., Go U., Hamer D.H., Petrosillo N., Castelli F., Storgaard M., Al Khalili S., Simonsen L. Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics. Lancet Infect. Dis. 2020;20:e238–e244.
- Petros A., Bennett D., Vallance P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet. 1991;338:1557–1558.
- Qiu P., Cui X., Sun J., Welsh J., Natanson C., Eichacker P.Q. Antitumor necrosis factor therapy is associated with improved survival in clinical sepsis trials: a meta-analysis. Crit. Care Med. 2013;41:2419–2429.
- Qureshy Z. Targeting the JAK/STAT pathway in solid tumors. J. Cancer Metastasis Treat. 2020;6:27.
- 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.
- Refaeli Y., Van Parijs L., Alexander S.I., Abbas A.K. Interferon gamma is required for activation-induced death of T lymphocytes. J. Exp. Med. 2002;196:999–1005.
- Rodríguez-Lago I., Ramírez de la Piscina P., Elorza A., Merino O., Ortiz de Zárate J., Cabriada J.L. Characteristics and Prognosis of Patients With Inflammatory Bowel Disease During the SARS-CoV-2 Pandemic in the Basque Country (Spain) Gastroenterology. 2020;159:781–783.
- Rudd K.E., Johnson S.C., Agesa K.M., Shackelford K.A., Tsoi D., Kievlan D.R., Colombara D.V., Ikuta K.S., Kissoon N., Finfer S., et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395:200–211.
- Salim T., Sershen C.L., May E.E. Investigating the Role of TNF-α and IFN-γ Activation on the Dynamics of iNOS Gene Expression in LPS Stimulated Macrophages. PLoS ONE. 2016;11:e0153289.
- Samir P., Malireddi R.K.S., Kanneganti T.D. The PANoptosome: A Deadly Protein Complex Driving Pyroptosis, Apoptosis, and Necroptosis (PANoptosis) Front. Cell. Infect. Microbiol. 2020;10:238.
- Sarhan J., Liu B.C., Muendlein H.I., Li P., Nilson R., Tang A.Y., Rongvaux A., Bunnell S.C., Shao F., Green D.R., Poltorak A. Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. Proc. Natl. Acad. Sci. USA. 2018;115:E10888–E10897.
- Sass G., Koerber K., Bang R., Guehring H., Tiegs G. Inducible nitric oxide synthase is critical for immune-mediated liver injury in mice. J. Clin. Invest. 2001;107:439–447.
- Satija R., Farrell J.A., Gennert D., Schier A.F., Regev A. Spatial reconstruction of single-cell gene expression data. Nat. Biotechnol. 2015;33:495–502.
- Sato M., Suemori H., Hata N., Asagiri M., Ogasawara K., Nakao K., Nakaya T., Katsuki M., Noguchi S., Tanaka N., Taniguchi T. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Immunity. 2000;13:539–548.
- Sauer J.D., Sotelo-Troha K., von Moltke J., Monroe K.M., Rae C.S., Brubaker S.W., Hyodo M., Hayakawa Y., Woodward J.J., Portnoy D.A., Vance R.E. The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides. Infect. Immun. 2011;79:688–694.
- Schoggins J.W., MacDuff D.A., Imanaka N., Gainey M.D., Shrestha B., Eitson J.L., Mar K.B., Richardson R.B., Ratushny A.V., Litvak V., et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature. 2014;505:691–695.
- Schroder K., Hertzog P.J., Ravasi T., Hume D.A. Interferon-gamma: an overview of signals, mechanisms and functions. J. Leukoc. Biol. 2004;75:163–189.
- Selleri C., Sato T., Anderson S., Young N.S., Maciejewski J.P. Interferon-gamma and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J. Cell. Physiol. 1995;165:538–546.
- Shi J., Zhao Y., Wang K., Shi X., Wang Y., Huang H., Zhuang Y., Cai T., Wang F., Shao F. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526:660–665.
- Silvin A., Chapuis N., Dunsmore G., Goubet A.G., Dubuisson A., Derosa L., Almire C., Henon C., Kosmider O., Droin N., et al. Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19. Cell. 2020;182:1401–1418.e18.
- Skarnes W.C., Rosen B., West A.P., Koutsourakis M., Bushell W., Iyer V., Mujica A.O., Thomas M., Harrow J., Cox T., et al. A conditional knockout resource for the genome-wide study of mouse gene function. Nature. 2011;474:337–342.
- Suthar M.S., Ma D.Y., Thomas S., Lund J.M., Zhang N., Daffis S., Rudensky A.Y., Bevan M.J., Clark E.A., Kaja M.K., et al. IPS-1 is essential for the control of West Nile virus infection and immunity. PLoS Pathog. 2010;6:e1000757.
- Taabazuing C.Y., Okondo M.C., Bachovchin D.A. Pyroptosis and Apoptosis Pathways Engage in Bidirectional Crosstalk in Monocytes and Macrophages. Cell Chem Biol. 2017;24:507–514.e4.
- Tan L., Wang Q., Zhang D., Ding J., Huang Q., Tang Y.Q., Wang Q., Miao H. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct. Target. Ther. 2020;5:33.
- Tisoncik J.R., Korth M.J., Simmons C.P., Farrar J., Martin T.R., Katze M.G. Into the eye of the cytokine storm. Microbiol. Mol. Biol. Rev. 2012;76:16–32.
- Vercammen D., Beyaert R., Denecker G., Goossens V., Van Loo G., Declercq W., Grooten J., Fiers W., Vandenabeele P. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J. Exp. Med. 1998;187:1477–1485.
- Vig M., Srivastava S., Kandpal U., Sade H., Lewis V., Sarin A., George A., Bal V., Durdik J.M., Rath S. Inducible nitric oxide synthase in T cells regulates T cell death and immune memory. J. Clin. Invest. 2004;113:1734–1742.
- Waggershauser C.H., Tillack-Schreiber C., Berchtold-Benchieb C., Szokodi D., Howaldt S., Ochsenkühn T. Letter: immunotherapy in IBD patients in a SARS-CoV-2 endemic area. Aliment. Pharmacol. Ther. 2020;52:898–899.
- Wang Y., Gao W., Shi X., Ding J., Liu W., He H., Wang K., Shao F. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017;547:99–103.
- Wang A., Pope S.D., Weinstein J.S., Yu S., Zhang C., Booth C.J., Medzhitov R. Specific sequences of infectious challenge lead to secondary hemophagocytic lymphohistiocytosis-like disease in mice. Proc. Natl. Acad. Sci. USA. 2019;116:2200–2209.
- Winkler E.S., Bailey A.L., Kafai N.M., Nair S., McCune B.T., Yu J., Fox J.M., Chen R.E., Earnest J.T., Keeler S.P., et al. SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nat Immunol. 2020;21:1327–1335.
- Wong V.W., Lerner E. Nitric oxide inhibition strategies. Future Sci. OA. 2015;1:FSO35.
- Xu W., Liu L.Z., Loizidou M., Ahmed M., Charles I.G. The role of nitric oxide in cancer. Cell Res. 2002;12:311–320.
- Yamamoto M., Sato S., Hemmi H., Hoshino K., Kaisho T., Sanjo H., Takeuchi O., Sugiyama M., Okabe M., Takeda K., Akira S. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science. 2003;301:640–643.
- Yang D., Liang Y., Zhao S., Ding Y., Zhuang Q., Shi Q., Ai T., Wu S.Q., Han J. ZBP1 mediates interferon-induced necroptosis. Cell. Mol. Immunol. 2020;17:356–368.
- Zhao Q., Meng M., Kumar R., Wu Y., Huang J., Deng Y., Weng Z., Yang L. Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A systemic review and meta-analysis. Int. J. Infect. Dis. 2020;96:131–135.
- Zheng T.S., Hunot S., Kuida K., Momoi T., Srinivasan A., Nicholson D.W., Lazebnik Y., Flavell R.A. Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation. Nat. Med. 2000;6:1241–1247.
- Zheng C., Zhou X.W., Wang J.Z. The dual roles of cytokines in Alzheimer’s disease: update on interleukins, TNF-α, TGF-β and IFN-γ. Transl. Neurodegener. 2016;5:7.
- Zheng M., Karki R., Vogel P., Kanneganti T.D. Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense. Cell. 2020;181:674–687.e13.
- Zheng M., Williams E.P., Malireddi R.K.S., Karki R., Banoth B., Burton A., Webby R., Channappanavar R., Jonsson C.B., Kanneganti T.D. Impaired NLRP3 inflammasome activation/pyroptosis leads to robust inflammatory cell death via caspase-8/RIPK3 during coronavirus infection. J. Biol. Chem. 2020;295:14040–14052.
- Zhou Z., He H., Wang K., Shi X., Wang Y., Su Y., Wang Y., Li D., Liu W., Zhang Y., et al. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science. 2020;368:eaaz7548.
Source: PubMed