Journal of Inflammation Research (Nov 2021)
Aged IRF3-KO Mice are Protected from Sepsis
Abstract
Dinesh G Goswami,1 Wendy E Walker1,2 1Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA; 2Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USACorrespondence: Wendy E WalkerTexas Tech University Health Sciences Center El Paso, 5001 El Paso Drive, El Paso, TX, 79905, USATel +1-915-215-4268Fax +1-915- 783-1253Email [email protected]: Sepsis is a leading cause of hospital admissions and deaths. Older adults (> 65 years) are particularly susceptible to sepsis and experience higher morbidity and mortality rates than younger people. We previously showed that interferon regulatory factor 3 (IRF3) contributes to sepsis pathogenesis in young mice subject to cecal ligation and puncture (CLP). In this study, we investigated if IRF3 contributes to sepsis in the context of aging.Methods: Sepsis was induced in aged wild-type (WT) and IRF3-knock-out (KO) mice, using a clinically-relevant CLP-sepsis model including fluids and antibiotics. Animal survival, disease score and hypothermia were evaluated as indicators of sepsis pathogenesis. Serum cytokines and serum enzymes indicative of organ damage were also measured.Results: Aged WT mice were highly susceptible to sepsis (90% mortality). In comparison, aged IRF3-KO mice were significantly protected (20% mortality). Aged IRF3-KO mice showed a lower disease score and reduced hypothermia following CLP, compared to WT mice. Serum cytokines interleukin (IL)-6, IL-12/23p40 and macrophage chemoattractant protein (MCP)-1, and creatinine kinase (CK) were lower in aged IRF3-KO septic mice compared to WT counterparts. Aged male mice were found to be more susceptible to sepsis compared to females. Female mice, however, produced higher levels of serum cytokines and CK.Conclusion: These results demonstrate that IRF3 plays a detrimental role in sepsis in aged mice and highlight the impact of biological sex.Keywords: septicemia, CLP, interferon regulatory factor 3, aging, mice, sex
