Role of adipose tissue inflammaging and metabolic dysfunction during sepsis

脓毒症期间脂肪组织炎症和代谢功能障碍的作用

• 批准号: 10563704
• 负责人: Christina Camell
• 金额: $ 54.82万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563704
• 关键词: Address; Adenosine; Adipocytes; Adipose tissue; Age; B-Lymphocytes; Bacterial Infections; Binding; Catecholamines; Cells; Chronic; Cyclic AMP-Dependent Protein Kinases; Data; Elderly; Endotoxemia; Environment; Event; Gram-Negative Bacteria; Homeostasis; Hospitalization; Hydrolysis; Immune; Immune system; Impaired cognition; Impairment; Individual; Infection; Inflammaging; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; K-Series Research Career Programs; Life; Lipase; Lipids; Lipolysis; Lipopolysaccharides; Macrophage; Mediating; Mediator; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolic syndrome; Modeling; Molecular; Morbidity - disease rate; Mus; Myeloid Cells; Nonesterified Fatty Acids; Operative Surgical Procedures; Organ; Organism; Pathway interactions; Pattern; Population; Predisposition; Production; Purinergic P1 Receptors; Risk; Role; Sepsis; Serum; Signal Pathway; Signal Transduction; Survivors; TLR4 gene; TNF gene; Testing; Tissue Expansion; Tissues; Triglycerides; Visceral; age related; aged; cytokine; ecto-nucleotidase; growth differentiation factor 3; immune activation; improved; inhibitor; innovation; insulin sensitivity; mortality; mouse model; new therapeutic target; older patient; pathogenic bacteria; pharmacologic; prevent; receptor; response; septic; single-cell RNA sequencing; sterol esterase; therapeutic target

SUMMARY Sepsis is a life-threatening, systemic response to infection and is 13-times more likely to occur in individuals over 65, leading to hospitalization, increased mortality, and chronic repercussions. Why older persons are more susceptible to sepsis is poorly defined, although hyperactivation of the immune system is an underlying feature. Visceral white adipose tissue (vWAT) is the organ that ages first; changes include tissue expansion and increased immune cell activation. We demonstrated that a hyperinflammatory state in old organisms contributes to increased mortality in response to infection, whereas young mice remain healthy. We also discovered that there is an accumulation of aged adipose B cells (AABs) and inflammatory macrophages in vWAT of old mice. We showed that these immune cells inhibit lipolysis, a metabolic pathway essential for maintaining energy homeostasis. Lipolysis is also necessary to keep inflammation in check in mice challenged with lipopolysaccharide (LPS), a bacterial pathogen-associated molecular pattern from gram-negative bacteria. Together these studies support the premise that age-related inflammation mediated by the vWAT contributes to risk of sepsis. This proposal seeks to identify how signaling events from vWAT immune cells, which regulate lipolysis in adipocytes, are altered with age and sepsis. We recently described a role for the NLRP3 inflammasome activation and the expansion of AABs that increase inflammation, and reduce tissue function, including lipolysis and insulin sensitivity. These findings have led to our hypothesis that vWAT lipolysis is impaired in old organisms due to exacerbated inflammasome activation and altered signaling by AABs, and this negatively impacts responses to endotoxemia and sepsis. We will test this hypothesis in three aims that focus on a mouse model of endotoxemia. Aim 1: Define the lipolytic response of adipocytes from old vs. young mice. Aim 2: Determine if inflammasome activation and GDF3 mediate reduced lipolysis and increased inflammation in vWAT upon LPS challenge of old mice. Aim 3: Determine the role of adenosine signaling on lipolysis in old vWAT during LPS challenge. This information will contribute to the identification of new signaling pathways that can be targeted to treat sepsis in the elderly.

总结 脓毒症是一种危及生命的全身性感染反应， 65，导致住院治疗，死亡率增加和慢性影响。为什么老年人 尽管免疫系统的过度激活是一个潜在的特征，但对脓毒症易感的定义很差。 内脏白色脂肪组织（vWAT）是最先老化的器官;变化包括组织扩张和 增强免疫细胞激活。我们证明了老年机体的高度炎症状态 感染导致死亡率增加，而年轻的小鼠保持健康。我们还发现 在老年小鼠的vWAT中存在老年脂肪B细胞（AAB）和炎性巨噬细胞的积累。 我们发现这些免疫细胞抑制脂肪分解，这是维持能量所必需的代谢途径 体内平衡脂肪分解也是必要的，以保持炎症在检查小鼠的挑战， 脂多糖（LPS），来自革兰氏阴性菌的细菌病原体相关分子模式。 这些研究共同支持了这样的前提，即由vWAT介导的年龄相关炎症有助于 败血症的风险。该提案旨在确定来自vWAT免疫细胞的信号事件如何调节 脂肪细胞中的脂肪分解，随着年龄和败血症而改变。我们最近描述了NLRP 3的作用 炎性小体激活和AAB的扩张增加炎症，并降低组织功能， 包括脂肪分解和胰岛素敏感性。这些发现导致我们假设vWAT脂解是 由于AAB的炎性小体活化加剧和信号传导改变， 对内毒素血症和脓毒症的反应有负面影响。我们将在三个目标中检验这一假设， 内毒素血症的小鼠模型。目的1：确定老年与年轻小鼠脂肪细胞的脂解反应。 目的2：确定炎性小体活化和GDF 3是否介导减少的脂解和增加的炎症 LPS攻击老年小鼠后vWAT中的细胞凋亡。目的3：确定腺苷信号在老年人脂肪分解中的作用 LPS激发期间的vWAT。这些信息将有助于识别新的信号通路， 可以靶向治疗老年脓毒症。