Aged IRF3-KO Mice are Protected from Sepsis

References

• Sepsis Alliance Critical Fact Sheet. www.sepsis.org›sepsis–factsheet–v2–4. Accessed January, 2018.
   Google Scholar
• Rowe T, Araujo KL, Van Ness PH, Pisani MA, Juthani-Mehta M. Outcomes of older adults with sepsis at admission to an intensive care unit. Open Forum Infect Dis. 2016;3(1):ofw010.
   PubMed Web of Science ®Google Scholar
• Nacionales DC, Gentile LF, Vanzant E, et al. Aged mice are unable to mount an effective myeloid response to sepsis. J Immunol. 2014;192(2):612–622.
   PubMed Web of Science ®Google Scholar
• Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200–211.
   PubMed Web of Science ®Google Scholar
• Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304(16):1787–1794.
   PubMed Web of Science ®Google Scholar
• Mankowski RT, Anton SD, Ghita GL, et al. Older sepsis survivors suffer persistent disability burden and poor long-term survival. J Am Geriatr Soc. 2020;68(9):1962–1969.
   PubMed Web of Science ®Google Scholar
• Jones TK, Fuchs BD, Small DS, et al. Post-acute care use and hospital readmission after sepsis. Ann Am Thorac Soc. 2015;12(6):904–913.
   PubMed Web of Science ®Google Scholar
• Opal SM, Girard TD, Ely EW. The immunopathogenesis of sepsis in elderly patients. Clin Infect Dis. 2005;41(Suppl 7):S504–512.
   PubMed Web of Science ®Google Scholar
• Piccirillo JF, Vlahiotis A, Barrett LB, Flood KL, Spitznagel EL, Steyerberg EW. The changing prevalence of comorbidity across the age spectrum. Crit Rev Oncol Hematol. 2008;67(2):124–132.
   PubMed Web of Science ®Google Scholar
• Gentile LF, Nacionales DC, Lopez MC, et al. Protective immunity and defects in the neonatal and elderly immune response to sepsis. J Immunol. 2014;192(7):3156–3165. doi:10.4049/jimmunol.1301726
   PubMed Web of Science ®Google Scholar
• Stortz JA, Hollen MK, Nacionales DC, et al. Old mice demonstrate organ dysfunction as well as prolonged inflammation, immunosuppression, and weight loss in a modified surgical sepsis model. Crit Care Med. 2019;47(11):e919–e929.
   PubMed Web of Science ®Google Scholar
• Turnbull IR, Wlzorek JJ, Osborne D, Hotchkiss RS, Coopersmith CM, Buchman TG. Effects of age on mortality and antibiotic efficacy in cecal ligation and puncture. Shock. 2003;19(4):310–313.
   PubMed Web of Science ®Google Scholar
• Saito M, Inoue S, Yamashita K, Kakeji Y, Fukumoto T, Kotani J. IL-15 improves aging-induced persistent T cell exhaustion in mouse models of repeated sepsis. Shock. 2020;53(2):228–235.
   PubMed Web of Science ®Google Scholar
• Takeda K, Akira S. TLR signaling pathways. Semin Immunol. 2004;16(1):3–9.
   PubMed Web of Science ®Google Scholar
• Cai X, Chiu Y-H, Chen Zhijian J. The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Mol Cell. 2014;54(2):289–296.
   PubMed Web of Science ®Google Scholar
• Reikine S, Nguyen JB, Modis Y. Pattern recognition and signaling mechanisms of RIG-I and MDA5. Front Immunol. 2014;5:342.
   PubMed Web of Science ®Google Scholar
• Sabbah A, Chang TH, Harnack R, et al. Activation of innate immune antiviral responses by Nod2. Nat Immunol. 2009;10(10):1073–1080.
   PubMed Web of Science ®Google Scholar
• Hornung V, Ablasser A, Charrel-Dennis M, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458(7237):514–518.
   PubMed Web of Science ®Google Scholar
• Walker WE, Bozzi AT, Goldstein DR. IRF3 contributes to sepsis pathogenesis in the mouse cecal ligation and puncture model. J Leukoc Biol. 2012;92(6):1261–1268.
   PubMed Web of Science ®Google Scholar
• Heipertz EL, Harper J, Goswami DG, et al. IRF3 signaling within the mouse stroma influences sepsis pathogenesis. J Immunol. 2021;206(2):398–409.
   PubMed Web of Science ®Google Scholar
• Walker WE, Booth CJ, Goldstein DR. TLR9 and IRF3 cooperate to induce a systemic inflammatory response in mice injected with liposome:DNA. Mol Ther. 2010;18(4):775–784.
   PubMed Web of Science ®Google Scholar
• Petro TM. IFN regulatory factor 3 in health and disease. J Immunol. 2020;205(8):1981–1989.
   PubMed Web of Science ®Google Scholar
• Mogensen TH. IRF and STAT transcription factors - from basic biology to roles in infection, protective immunity, and primary immunodeficiencies. Front Immunol. 2019;9:3047.
   PubMed Web of Science ®Google Scholar
• Heipertz EL, Harper J, Walker WE. STING and TRIF contribute to mouse sepsis, depending on severity of the disease model. Shock. 2017;47(5):621–631.
   PubMed Web of Science ®Google Scholar
• Albus U. Guide for the Care and Use of Laboratory Animals. 8th ed. London, England: SAGE Publications Sage UK; 2012.
   Google Scholar
• Osuchowski MF, Ayala A, Bahrami S, et al. Minimum quality threshold in pre-clinical sepsis studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis. Intensive Care Med Exp. 2018;6(1):26.
   PubMedGoogle Scholar
• Walker WE. Methods to study the innate immune response to sepsis. Methods Mol Biol. 2018;1717:189–206.
   PubMedGoogle Scholar
• Heipertz EL, Harper J, Lopez CA, Fikrig E, Hughes ME, Walker WE. Circadian rhythms influence the severity of sepsis in mice via a TLR2-dependent, leukocyte-intrinsic mechanism. J Immunol. 2018;201(1):193–201.
   PubMed Web of Science ®Google Scholar
• Wardi G, Tainter CR, Ramnath VR, et al. Age-related incidence and outcomes of sepsis in California, 2008-2015. J Crit Care. 2021;62:212–217.
   PubMed Web of Science ®Google Scholar
• Kotfis K, Wittebole X, Jaschinski U, et al. A worldwide perspective of sepsis epidemiology and survival according to age: observational data from the ICON audit. J Crit Care. 2019;51:122–132.
   PubMed Web of Science ®Google Scholar
• Brakenridge SC, Efron PA, Stortz JA, et al. The impact of age on the innate immune response and outcomes after severe sepsis/septic shock in trauma and surgical intensive care unit patients. J Trauma Acute Care Surg. 2018;85(2):247–255.
   PubMed Web of Science ®Google Scholar
• Starr ME, Saito H. Sepsis in old age: review of human and animal studies. Aging Dis. 2014;5(2):126–136.
   PubMed Web of Science ®Google Scholar
• Yang Y, Yang KS, Hsann YM, Lim V, Ong BC. The effect of comorbidity and age on hospital mortality and length of stay in patients with sepsis. J Crit Care. 2010;25(3):398–405.
   PubMed Web of Science ®Google Scholar
• Martin GS, Mannino DM, Moss M. The effect of age on the development and outcome of adult sepsis. Crit Care Med. 2006;34(1):15–21.
   PubMed Web of Science ®Google Scholar
• Tran DD, Groeneveld AB, van der Meulen J, et al. Age, chronic disease, sepsis, organ system failure, and mortality in a medical intensive care unit. Crit Care Med. 1990;18(5):474–479.
   PubMed Web of Science ®Google Scholar
• Ren Z, Gay R, Thomas A, et al. Effect of age on susceptibility to Salmonella Typhimurium infection in C57BL/6 mice. J Med Microbiol. 2009;58(Pt 12):1559–1567.
   PubMed Web of Science ®Google Scholar
• Das P, Panda SK, Agarwal B, et al. Novel chitohexaose analog protects young and aged mice from CLP induced polymicrobial sepsis. Sci Rep. 2019;9(1):2904.
   PubMedGoogle Scholar
• Coletta C, Modis K, Olah G, et al. Endothelial dysfunction is a potential contributor to multiple organ failure and mortality in aged mice subjected to septic shock: preclinical studies in a murine model of cecal ligation and puncture. Crit Care. 2014;18(5):511.
   PubMed Web of Science ®Google Scholar
• Starr ME, Takahashi H, Okamura D, et al. Increased coagulation and suppressed generation of activated protein C in aged mice during intra-abdominal sepsis. Am J Physiol Heart Circ Physiol. 2015;308(2):H83–91.
   PubMed Web of Science ®Google Scholar
• Drechsler S, Weixelbaumer K, Raeven P, et al. Relationship between age/gender-induced survival changes and the magnitude of inflammatory activation and organ dysfunction in post-traumatic sepsis. PLoS One. 2012;7(12):e51457.
   PubMed Web of Science ®Google Scholar
• Turnbull IR, Clark AT, Stromberg PE, et al. Effects of aging on the immunopathologic response to sepsis. Crit Care Med. 2009;37(3):1018–1023.
   PubMed Web of Science ®Google Scholar
• Sato M, Tanaka N, Hata N, Oda E, Taniguchi T. Involvement of the IRF family transcription factor IRF-3 in virus-induced activation of the IFN-beta gene. FEBS Lett. 1998;425(1):112–116.
   PubMed Web of Science ®Google Scholar
• Yanai H, Chiba S, Hangai S, et al. Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice. Proc Natl Acad Sci USA. 2018;115(20):5253–5258.
   PubMed Web of Science ®Google Scholar
• Dang O, Navarro L, David M. Inhibition of lipopolysaccharide-induced interferon regulatory factor 3 activation and protection from septic shock by hydroxystilbenes. Shock. 2004;21(5):470–475.
   PubMed Web of Science ®Google Scholar
• Sakaguchi S, Negishi H, Asagiri M, et al. Essential role of IRF-3 in lipopolysaccharide-induced interferon-beta gene expression and endotoxin shock. Biochem Biophys Res Commun. 2003;306(4):860–866.
   PubMed Web of Science ®Google Scholar
• Nasir N, Jamil B, Siddiqui S, Talat N, Khan FA, Hussain R. Mortality in sepsis and its relationship with gender. Pak J Med Sci. 2015;31(5):1201–1206.
   PubMed Web of Science ®Google Scholar
• Zhang MQ, Macala KF, Fox-Robichaud A, Mendelson AA, Lalu MM. Sex- and gender-dependent differences in clinical and preclinical sepsis. Shock. 2021;56(2):178–187.
   PubMed Web of Science ®Google Scholar
• Cerceo E, Rachoin JS, Gaughan J, Weisberg L. Association of gender, age, and race on renal outcomes and mortality in patients with severe sepsis and septic shock. J Crit Care. 2021;61:52–56.
   PubMed Web of Science ®Google Scholar
• Adrie C, Azoulay E, Francais A, et al. Influence of gender on the outcome of severe sepsis: a reappraisal. Chest. 2007;132(6):1786–1793.
   PubMed Web of Science ®Google Scholar
• Schroder J, Kahlke V, Staubach KH, Zabel P, Stuber F. Gender differences in human sepsis. Arch Surg. 1998;133(11):1200–1205.
   PubMed Web of Science ®Google Scholar
• Bosch F, Angele MK, Chaudry IH. Gender differences in trauma, shock and sepsis. Mil Med Res. 2018;5(1):35.
   PubMedGoogle Scholar
• Angele MK, Frantz MC, Chaudry IH. Gender and sex hormones influence the response to trauma and sepsis: potential therapeutic approaches. Clinics (Sao Paulo, Brazil). 2006;61(5):479–488.
   PubMedGoogle Scholar
• Erikoğlu M, Sahin M, Ozer S, Avunduk MC. Effects of gender on the severity of sepsis. Surg Today. 2005;35(6):467–472.
   PubMed Web of Science ®Google Scholar
• Eachempati SR, Hydo L, Barie PS. Gender-based differences in outcome in patients with sepsis. Arch Surg. 1999;134(12):1342–1347.
   PubMed Web of Science ®Google Scholar
• Al Abbasi B, Torres P, Ramos-Tuarez F, et al. Implementation of the surviving sepsis campaign in patients with heart failure: gender-specific outcomes. Cureus. 2020;12(7):e9140.
   PubMed Web of Science ®Google Scholar
• Pietropaoli AP, Glance LG, Oakes D, Fisher SG. Gender differences in mortality in patients with severe sepsis or septic shock. Gend Med. 2010;7(5):422–437.
   PubMedGoogle Scholar
• van Vught LA, Scicluna BP, Wiewel MA, et al. Association of gender with outcome and host response in critically ill sepsis patients. Crit Care Med. 2017;45(11):1854–1862.
   PubMed Web of Science ®Google Scholar
• Madsen TE, Simmons J, Choo EK, Portelli D, McGregor AJ, Napoli AM. The DISPARITY study: do gender differences exist in Surviving Sepsis Campaign resuscitation bundle completion, completion of individual bundle elements, or sepsis mortality? J Crit Care. 2014;29(3):473.e477–411.
   PubMed Web of Science ®Google Scholar
• Nachtigall I, Tafelski S, Rothbart A, et al. Gender-related outcome difference is related to course of sepsis on mixed ICUs: a prospective, observational clinical study. Crit Care. 2011;15(3):R151.
   PubMed Web of Science ®Google Scholar
• Zhang M, Montroy J, Sharma R, et al. The effects of biological sex on sepsis treatments in animal models: a systematic review and a narrative elaboration on sex- and gender-dependent differences in sepsis. Crit Care Explorat. 2021;3(6):e0433.
   PubMedGoogle Scholar
• Remick DG, Bolgos GR, Siddiqui J, Shin J, Nemzek JA. Six at six: interleukin-6 measured 6 h after the initiation of sepsis predicts mortality over 3 days. Shock. 2002;17(6):463–467.
   PubMed Web of Science ®Google Scholar
• Chiswick EL, Mella JR, Bernardo J, Remick DG. Acute-phase deaths from murine polymicrobial sepsis are characterized by innate immune suppression rather than exhaustion. J Immunol. 2015;195(8):3793–3802.
   PubMed Web of Science ®Google Scholar
• Klein SL. The effects of hormones on sex differences in infection: from genes to behavior. Neurosci Biobehav Rev. 2000;24(6):627–638.
   PubMed Web of Science ®Google Scholar