Pyruvate affects inflammatory responses of macrophages during influenza A virus infection
Hazar Abusalamah, Jessica M Reel, Christopher R Lupfer, Hazar Abusalamah, Jessica M Reel, Christopher R Lupfer
Abstract
Pyruvate is the end product of glycolysis and transported into the mitochondria for use in the tricarboxylic acid (TCA) cycle. It is also a common additive in cell culture media. We discovered that inclusion of sodium pyruvate in culture media during infection of mouse bone marrow derived macrophages with influenza A virus impaired cytokine production (IL-6, IL-1β, and TNF-α). Sodium pyruvate did not inhibit viral RNA replication. Instead, the addition of sodium pyruvate alters cellular metabolism and diminished mitochondrial reactive oxygen species (ROS) production and lowered immune signaling. Overall, sodium pyruvate affects the immune response produced by macrophages but does not inhibit virus replication.
Keywords: Antioxidant; Inflammasome; Inflammation; Influenza A virus; Pyruvate.
Copyright © 2020 Elsevier B.V. All rights reserved.
Figures
References
- Agostini L. Nalp3 forms an Il-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity. 2004;20(March 3):319–325. doi: 10.1016/s1074-7613(04)00046-9.
- Akira S., Uematsu S., Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(February 4):783–801. doi: 10.1016/j.cell.2006.02.015.
- Allen I.C. The Nlrp3 inflammasome mediates in vivo innate immunity to influenza a virus through recognition of viral rna. Immunity. 2009;30(April 4):556–565. doi: 10.1016/j.immuni.2009.02.005.
- Barnett J.A. A history of research on yeasts 5: the fermentation pathway. Yeast. 2003;20(April 6):509–543. doi: 10.1002/yea.986.
- Brand M.D., Nicholls D.G. Assessing mitochondrial dysfunction in cells. Biochem. J. 2011;435(April 2):297–312. doi: 10.1042/BJ20110162.
- Chandler J.D. Metabolic pathways of lung inflammation revealed by High-Resolution metabolomics (hrm) of H1n1 influenza virus infection in mice. Am J Physiol Regul Integr Comp Physiol. 2016;311(November 5):R906–R916. doi: 10.1152/ajpregu.00298.2016.
- Cline T.D., Beck D., Bianchini E. Influenza virus replication in macrophages: balancing protection and pathogenesis. J. Gen. Virol. 2017;98(October10):2401–2412. doi: 10.1099/jgv.0.000922.
- Crozat K., Beutler B. Tlr7: a New sensor of viral infection. Proc Natl Acad Sci U S A. 2004;101(May 18):6835–6836. doi: 10.1073/pnas.0401347101.
- Das U.N. Pyruvate Is an endogenous anti-inflammatory and anti-oxidant molecule. Med Sci Monit. 2006;12(May 5):RA79–84.
- Diers A.R. Pyruvate fuels mitochondrial respiration and proliferation of breast cancer cells: effect of monocarboxylate transporter inhibition. Biochem. J. 2012;444(June 3):561–571. doi: 10.1042/BJ20120294.
- Halestrap A.P., Price N.T. The proton-linked monocarboxylate transporter (mct) family: structure, function and regulation. Biochem. J. 1999;343(October Pt 2):281–299.
- Han H. Profiling serum cytokines in covid-19 patients reveals Il-6 and Il-10 are disease severity predictors. Emerg Microbes Infect. 2020;9(December 1):1123–1130. doi: 10.1080/22221751.2020.1770129.
- Heid M.E. Mitochondrial reactive oxygen species induces Nlrp3-dependent lysosomal damage and inflammasome activation. J. Immunol. 2013;191(November 10):5230–5238. doi: 10.4049/jimmunol.1301490.
- Horby Peter. Effect of dexamethasone in hospitalized patients with covid-19: preliminary report. MedRxiv. 2020 doi: 10.1101/2020.06.22.20137273. 2020-06-22.
- Huo C. Lethal influenza a virus preferentially activates Tlr3 and triggers a severe inflammatory response. Virus Res. 2018;257(09):102–112. doi: 10.1016/j.virusres.2018.09.012.
- Karmen A., Wroblewski F., Ladue J.S. Transaminase activity in human blood. J. Clin. Invest. 1955;34(January 1):126–131. doi: 10.1172/JCI103055.
- Kato H. Differential roles of Mda5 and rig-I helicases in the recognition of rna viruses. Nature. 2006;441(May 7089):101–105. doi: 10.1038/nature04734.
- Kido H. Energy metabolic disorder Is a Major risk factor in severe influenza virus infection: proposals for New therapeutic options based on animal model experiments. Respir Investig. 2016;54(September 5):312–319. doi: 10.1016/j.resinv.2016.02.007.
- Lupfer C. Inhibition of influenza a H3n8 virus infections in mice by morpholino oligomers. Arch. Virol. 2008;153(5):929–937. doi: 10.1007/s00705-008-0067-0.
- Lupfer C. Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection. Nat. Immunol. 2013;14(May 5):480–488. doi: 10.1038/ni.2563.
- Lupfer C.R. Reactive oxygen species regulate caspase-11 expression and activation of the Non-canonical Nlrp3 inflammasome during enteric pathogen infection. PLoS Pathog. 2014;10(September 9):e1004410. doi: 10.1371/journal.ppat.1004410.
- Mariathasan S. Cryopyrin activates the inflammasome in response to toxins and atp. Nature. 2006;440(March 7081):228–232. doi: 10.1038/nature04515.
- Matarese G., Procaccini C., De Rosa V. The intricate interface between immune and metabolic regulation: a role for leptin in the pathogenesis of multiple sclerosis? J. Leukoc. Biol. 2008;84(October 4):893–899. doi: 10.1189/jlb.0108022.
- Moon J.S. Mtorc1-induced Hk1-dependent glycolysis regulates Nlrp3 inflammasome activation. Cell Rep. 2015;12(July 1):102–115. doi: 10.1016/j.celrep.2015.05.046.
- Morgan M.J., Liu Z.G. Crosstalk of reactive oxygen species and Nf-kappab signaling. Cell Res. 2011;21(January 1):103–115. doi: 10.1038/cr.2010.178.
- Petrilli V. Activation of the Nalp3 inflammasome Is triggered by Low intracellular potassium concentration. Cell Death Differ. 2007;14(September 9):1583–1589. doi: 10.1038/sj.cdd.4402195.
- Ramos-Ibeas P. Pyruvate antioxidant roles in human fibroblasts and embryonic stem cells. Mol. Cell. Biochem. 2017;429(May 1-2):137–150. doi: 10.1007/s11010-017-2942-z.
- Roiniotis J. Hypoxia prolongs Monocyte/Macrophage survival and enhanced glycolysis Is associated with their maturation under aerobic conditions. J. Immunol. 2009;182(June 12):7974–7981. doi: 10.4049/jimmunol.0804216.
- Schell J.C., Rutter J. The Long and Winding Road to the mitochondrial pyruvate carrier. Cancer Metab. 2013;1(January 1):6. doi: 10.1186/2049-3002-1-6.
- Selvaraj V. Short-term dexamethasone in sars-cov-2 patients. R I Med J (2013) 2020;103(June 6):39–43.
- Seth R.B. Identification and characterization of mavs, a mitochondrial antiviral signaling protein that activates Nf-Kappab and Irf 3. Cell. 2005;122(September 5):669–682. doi: 10.1016/j.cell.2005.08.012.
- Shi L.Z. Hif1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of Th17 and treg cells. J. Exp. Med. 2011;208(July 7):1367–1376. doi: 10.1084/jem.20110278.
- Smallwood H.S. Targeting metabolic reprogramming by influenza infection for therapeutic intervention. Cell Rep. 2017;19(May 8):1640–1653. doi: 10.1016/j.celrep.2017.04.039.
- Sutterwala F.S. Critical role for Nalp3/Cias1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity. 2006;24(March 3):317–327. doi: 10.1016/j.immuni.2006.02.004.
- Theoharides T.C., Conti P. Dexamethasone for covid-19? Not so fast. J. Biol. Regul. Homeost. Agents. 2020;34(June 3) doi: 10.23812/20-EDITORIAL_1-5.
- Trompette A. Dietary fiber confers protection against flu by shaping Ly6c(-) patrolling monocyte hematopoiesis and Cd8(+) T cell metabolism. Immunity. 2018;48(May 5):992–1005. doi: 10.1016/j.immuni.2018.04.022.
- Vander Heiden M.G., Cantley L.C., Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(May 5930):1029–1033. doi: 10.1126/science.1160809.
- Votto J.J. Inhaled sodium pyruvate improved Fev1 and decreased expired breath levels of nitric oxide in patients with chronic obstructive pulmonary disease. J Aerosol Med Pulm Drug Deliv. 2008;21(December 4):329–334. doi: 10.1089/jamp.2007.0678.
- Xia S. Addition of sodium pyruvate to stored Red blood cells attenuates liver injury in a murine transfusion model. Mediators Inflamm. 2016;2016 doi: 10.1155/2016/3549207.
- Xie M. Pkm2-dependent glycolysis promotes Nlrp3 and Aim2 inflammasome activation. Nat. Commun. 2016;7(October):13280. doi: 10.1038/ncomms13280.
- Zhang W. Lactate Is a natural suppressor of rlr signaling by targeting mavs. Cell. 2019;178(June 1):176–189. doi: 10.1016/j.cell.2019.05.003. e15.
Source: PubMed