Goswami Dinesh G, Walker Wendy E
Center 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.
Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA.
J Inflamm Res. 2021 Nov 3;14:5757-5767. doi: 10.2147/JIR.S335203. eCollection 2021.
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.
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.
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.
These results demonstrate that IRF3 plays a detrimental role in sepsis in aged mice and highlight the impact of biological sex.
脓毒症是住院和死亡的主要原因。老年人（>65岁）尤其易患脓毒症，且发病率和死亡率高于年轻人。我们之前表明，干扰素调节因子3（IRF3）在接受盲肠结扎和穿刺（CLP）的年轻小鼠脓毒症发病机制中起作用。在本研究中，我们调查了IRF3在衰老背景下是否对脓毒症有影响。
使用包括补液和抗生素的临床相关CLP脓毒症模型，在老年野生型（WT）和IRF3基因敲除（KO）小鼠中诱导脓毒症。评估动物存活率、疾病评分和体温过低作为脓毒症发病机制的指标。还测量了指示器官损伤的血清细胞因子和血清酶。
老年WT小鼠对脓毒症高度易感（死亡率90%）。相比之下，老年IRF3-KO小鼠受到显著保护（死亡率20%）。与WT小鼠相比，老年IRF3-KO小鼠在CLP后疾病评分更低，体温过低减轻。与WT脓毒症小鼠相比，老年IRF3-KO脓毒症小鼠血清细胞因子白细胞介素（IL）-6、IL-12/23p40和巨噬细胞趋化蛋白（MCP）-1以及肌酸激酶（CK）更低。发现老年雄性小鼠比雌性小鼠更易患脓毒症。然而，雌性小鼠产生的血清细胞因子和CK水平更高。
这些结果表明，IRF3在老年小鼠脓毒症中起有害作用，并突出了生物性别的影响。
