Novel Interactions Between the Immune and Neuroendocrine Systems

免疫系统和神经内分泌系统之间的新相互作用

• 批准号: 7964048
• 负责人: DENNIS D. TAUB
• 金额: $ 52.8万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964048
• 关键词: Age; Aging; Anorexia; Anti-Inflammatory Agents; Anti-inflammatory; Architecture; Biology; Blood Circulation; Bone Marrow; Brain; CD8B1 gene; Cell Differentiation process; Cell Survival; Cells; Cytokine Signaling; Data; Disease; Eating; Elderly; Emigrant; Energy Metabolism; Equilibrium; Goals; Hematopoiesis; Hematopoietic stem cells; Hormonal; Hormones; Immune; Immune Cell Activation; Immunity; Immunocompromised Host; Inflammation; Inflammatory; Infusion procedures; Injury; Intervention; Knockout Mice; Leptin; Leukocytes; Ligands; Lymphoid; Mediating; Mediator of activation protein; Mus; Nature; Neurosecretory Systems; Obesity; Output; Pathway interactions; Peripheral; Play; Proto-Oncogene Protein c-kit; Research; Role; Sensory; Signal Pathway; Signal Transduction; Somatotropin; Stomach; Symptoms; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Thymus Gland; Thymus Hormones; Work; aged; cell growth regulation; cytokine; ghrelin; ghrelin receptor; growth hormone secretagogue receptor; improved; novel; peptide hormone; progenitor; receptor; receptor expression; reconstitution; thymocyte

The decline in adaptive immunity, T lymphocyte output and the contraction of the T cell receptor (TCR) repertoire with age is largely attributable to thymic involution. The loss of thymic function with age may be due to diminished numbers of thymic progenitors and the loss of critical cytokines and hormones from the thymic microenvironment. We have previously demonstrated that the orexigenic peptide hormone, ghrelin, and the anorexigenic hormone, leptin, are expressed by immune cells and regulate T-cell activation and inflammation. Our current work has demonstrated that both ghrelin and ghrelin receptor expression within the thymus diminishes with progressive aging. Infusion of ghrelin into old mice significantly improves the age-associated changes in thymic architecture and thymocyte counts with an increase in recent thymic emigrants (RTEs) and improvement of TCR diversity of peripheral CD4+ and CD8+ T cells. The ghrelin-induced thymopoiesis during aging was associated with enhancement of early thymocyte progenitors (ETP) and bone marrow-derived lineage negative sca-1, c-kit high (LSK) cell. Furthermore, the ghrelin and GHS-R deficient mice displayed enhanced age-associated thymic involution with reduced thymopoiesis and contraction of LSK hematopoietic stem cell compartment. The accelerated thymic involution observed in GHS-R knock out mice was reflected in major perturbations in the TCR repertoire of peripheral T lymphocyte subsets. Similarly, leptin infusion into old mice demonstrated similar effects on thymic progenitors and thymic involution as was observed with ghrelin and the pituitary hormone, growth hormone (GH). It appears that hormone-induced changes appear to be mediated via distinct signaling pathways. Our findings demonstrate a novel role for these hormones and their receptors in thymic biology and suggest a possible therapeutic benefit of harnessing these hormonal pathways in reconstitution of thymic function in elderly and in immunocompromised subjects. Moreover, we have found that these hormones modulate a variety of leukocyte functions and support the existence of a functional immunoregulatory network involving orexigenic and anorexigenic hormones in controlling immune cellular activation and differentiation, hematopoiesis and cell survival. Recent work has focused on the effects of these hormones on T-cell signaling and differentiation and the role of these hormones in the control of inflammatory cytokine signaling and activation.

随着年龄的增长，获得性免疫、T淋巴细胞输出和T细胞受体（TCR）库的收缩的下降在很大程度上归因于胸腺退化。 胸腺功能随年龄的丧失可能是由于胸腺祖细胞数量减少以及胸腺微环境中关键细胞因子和激素的丧失。 我们以前已经证明，食欲肽激素，生长激素释放肽，和食欲激素，瘦素，是由免疫细胞表达和调节T细胞活化和炎症。我们目前的工作表明，生长激素释放肽和生长激素释放肽受体的表达在胸腺内减少进行性衰老。 向老年小鼠输注生长激素释放肽显著改善了胸腺结构和胸腺细胞计数的年龄相关变化，增加了近期胸腺移行细胞（RTEs），并改善了外周CD 4+和CD 8 + T细胞的TCR多样性。 衰老过程中Ghrelin诱导的胸腺生成与早期胸腺祖细胞（ETP）和骨髓来源的sca-1、c-kit高表达（LSK）细胞的增加有关。此外，ghrelin和GHS-R缺陷小鼠表现出增强的与年龄相关的胸腺退化，胸腺生成减少和LSK造血干细胞区室收缩。在GHS-R基因敲除小鼠中观察到的加速胸腺退化反映在外周T淋巴细胞亚群TCR库的主要扰动中。同样，向老年小鼠输注瘦素对胸腺祖细胞和胸腺退化也表现出与胃饥饿素和垂体激素、生长激素（GH）类似的影响。 它似乎是通过不同的信号转导途径介导的酶诱导的变化。我们的研究结果表明，这些激素及其受体在胸腺生物学中的新作用，并建议利用这些激素途径在老年人和免疫功能低下的受试者中重建胸腺功能可能具有治疗益处。此外，我们已经发现，这些激素调节各种白细胞功能，并支持存在一个功能性免疫调节网络，涉及食欲和食欲激素控制免疫细胞活化和分化，造血和细胞存活。 最近的工作集中在这些激素对T细胞信号传导和分化的影响，以及这些激素在控制炎症细胞因子信号传导和激活中的作用。