GDF-15 as a mediator of immune-regulated sickness response during infection

GDF-15 作为感染期间免疫调节疾病反应的介质

• 批准号: 10598705
• 负责人: George S. Yap
• 金额: $ 22.8万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-07 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598705
• 关键词: Affect; Animals; Biochemical; Biological Availability; Biological Response Modifiers; Body Weight decreased; Cells; Clinical; Communicable Diseases; Data; Desire for food; Disease; Disease Management; Eating; Exhibits; GDF15 gene; Genetic; Health Promotion; Hematopoietic; Hormones; Immune; Immune response; Immunologics; Infection; Inflammatory; Interferon Type II; Interleukin-10; Lymphocyte; Macrophage; Malignant Neoplasms; Mediating; Mediator; Modality; Mus; Outcome; Pathogenicity; Regulation; Regulatory Pathway; Reporting; Role; Stress; Testing; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; cell type; cytokine; cytokine release syndrome; hindbrain; human disease; immunoregulation; insight; novel; pathogen; protective effect; receptor; resistance mechanism; response; stressor

Abstract: The cytokine IFN-γ controls both protective and pathogenic host responses during Toxoplasma gondii infection. By activating hemopoietic and non-hemopoietic cell autonomous resistance mechanisms, this cytokine mediates toxoplasmastatic and toxoplasmacidal activities that control pathogen replication. Much less is known about how the same cytokine regulates host sickness responses. We have recently obtained data indicating that IFN-γ regulates the systemic levels of the stress hormone GDF-15, without affecting tissue levels of the hormone. GDF-15 is produced by a variety of immune and tissue cell types in response to a broad range of stressors and acts through the GFRAL-receptor expressed in the hindbrain to suppress appetite and induce weight loss. Circulating GDF15 levels are elevated in a wide range of human diseases states including infections and cancer and is often associated with poor clinical outcomes. GDF-15 has been reported to have immunomodulatory effects on macrophages and lymphocytes. Consistent with its systemic regulation by IFN-γ, IL-10 deficient animals infected with T. gondii exhibit higher levels of circulating GDF-15. Thus we hypothesize that GDF-15 may be a principal mediator of the pathogenic effects of IFN-γ that promote sickness responses during T. gondii infection. Our experimental aims utilize a combination of genetic and immunological approaches to rigorously evaluate our hypothesis that GDF- 15 mediates the effects of IFN-γ to promote sickness responses during Toxoplasma infection. Our discovery that an immune cytokine controls of the systemic availability of the stress hormone GDF-15 is an novel finding and may have implications for the management of disease conditions associated with “cytokine storms”. Specific Aim 1 will interrogate the role of specific proinflammatory cytokines in inducing elevations in tissue GDF-15 levels during infection. Specific Aim 2 will test the hypothesis that IFNγ triggers the release of GDF-15 from tissue stores by promoting its maturation and release, putatively through a TRANS-cellular mechanism. Specific Aim 3 will interrogate the role and function of endogenous GDF-15 in regulating the immune and sickness responses in wildtype and IL-10-deficient mice during T. gondii infection. Completion of this project will provide fundamental insights into how immune cytokines control the host sickness response during infection. These insights may provide avenues to promote health by decreasing disease sequelae that result from hyperactivation of immune response.

摘要： 细胞因子IFN-γ在免疫过程中控制保护性和致病性宿主应答。 弓形虫感染。通过激活造血和非造血细胞 自主抗性机制，这种细胞因子介导弓形虫抑制和 控制病原体复制的杀弓形虫活性。我们所知的更少 相同的细胞因子如何调节宿主的疾病反应。我们最近获得了 数据表明IFN-γ调节应激激素GDF-15的全身水平， 而不影响组织中的激素水平。GDF-15是由多种免疫细胞产生的。 和组织细胞类型，以应对广泛的压力，并通过 GFRAL-受体在后脑中表达，以抑制食欲并诱导体重减轻。 循环GDF 15水平在广泛的人类疾病状态中升高，包括 感染和癌症，并且通常与不良临床结果相关。GDF-15具有 据报道对巨噬细胞和淋巴细胞具有免疫调节作用。 与IFN-γ的系统调节一致，IL-10缺陷动物感染T. 弓形虫表现出更高水平的循环GDF-15。因此，我们假设GDF-15可能 是促进疾病的IFN-γ致病作用的主要介质 在T.弓形虫感染我们的实验目标是利用以下组合： 遗传学和免疫学的方法来严格评估我们的假设，GDF- 15介导IFN-γ促进弓形虫感染期间疾病反应的作用 感染我们发现，免疫细胞因子控制着免疫系统的可用性， 应激激素GDF-15是一项新发现，可能对 管理与“细胞因子风暴”相关的疾病状况。具体目标1将 研究特异性促炎细胞因子在诱导组织炎症反应中的作用， 感染期间的GDF-15水平。具体目标2将检验IFNγ触发 通过促进GDF-15的成熟和释放， 通过跨细胞机制进行纯化。具体目标3将询问角色 内源性GDF-15在调节免疫和疾病反应中的功能 在野生型和IL-10缺陷小鼠中，弓形虫感染完成本项目 将提供免疫细胞因子如何控制宿主疾病的基本见解 感染时的反应。这些见解可以提供促进健康的途径， 减少由免疫反应过度激活引起的疾病后遗症。