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

摘要： 细胞因子干扰素-γ控制保护性和致病性宿主反应 弓形虫感染。通过激活造血细胞和非造血细胞 自主耐药机制，这种细胞因子介导弓形虫抑制和 控制病原体复制的弓形体杀灭活性。我们对此知之甚少 同样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，干扰素-γ调节全身应激激素GDF-15的水平， 而不影响荷尔蒙的组织水平。GDF-15是由多种免疫细胞产生的 和组织细胞类型对广泛的应激源做出反应，并通过 在后脑表达的GFFR-受体抑制食欲和诱导体重减轻。 循环中的GDF15水平在多种人类疾病状态中升高，包括 感染和癌症，往往与不良的临床结果有关。GDF-15具有 据报道，它对巨噬细胞和淋巴细胞具有免疫调节作用。 与干扰素-γ对其系统调节一致，IL-10缺陷动物感染T. 弓形虫循环中的GDF-15水平较高。因此，我们假设GDF-15可能 是干扰素-γ致病作用的主要介体 弓形虫感染期间的反应。我们的实验目标结合了 遗传学和免疫学方法严格评估我们的假设，即GDF- 15介导干扰素-γ促进弓形虫致病反应的作用 感染。我们的发现是一种免疫细胞因子控制着全身的可利用度 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 特异炎性细胞因子在诱导组织内升高中的作用 感染期间GDF-15水平。《特殊目的2》将测试干扰素γ触发的假设 通过促进GDF-15的成熟和释放，从组织存储中释放GDF-15， 推测是通过一种跨细胞机制。《特定目标3》将审问这个角色 以及内源性GDF-15在调节免疫和疾病反应中的作用 在弓形虫感染期间野生型和IL-10缺陷的小鼠。本项目竣工 将为免疫细胞因子如何控制寄主疾病提供基本的见解 在感染过程中的反应。这些见解可能通过以下方式提供促进健康的途径 减少免疫反应过度激活引起的疾病后遗症。

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.