Glucocorticoid and Adrenergic Receptor Signaling at the Neuroimmune Interface

神经免疫界面的糖皮质激素和肾上腺素能受体信号传导

• 批准号: RGPIN-2019-04706
• 负责人: Haeryfar, SMMansour
• 金额: $ 3.06万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761028
• 关键词: Glucocorticoid; Adrenergic; Receptor; Signaling; Neuroimmune

The nervous and the immune system work together to preserve our balance at molecular, cellular and organismal levels. To quickly deal with threats and stressors, a "fight-or-flight" response is mounted. This automatic and powerful response is characterized by the activation of the sympathetic nervous system (SNS) and by the release of hormones known as glucocorticoids (GCs) from the adrenal glands. SNS mediators and GCs are known to alter certain aspects of host defense, including conventional T (Tconv) cell responses. However, how stress, which activates the SNS and triggers GC release, affects unconventional immune cell types is ill-defined. These include natural killer T (NKT) cells and myeloid-derived suppressor cells (MDSCs). NKT cells are a unique subset of innate-like T lymphocytes. Unlike Tconv cells, NKT cells respond to glycolipids, molecules that are composed of sugar and fat, by rapidly secreting large quantities of soluble molecules called cytokines that mediate cell-to-cell communication in the immune system. This dictates the functions of numerous other cell types that participate in host defense. Therefore, it is pertinent to understand how NKT cell responses are initiated, perpetuated and regulated during stress. MDSCs are a diverse population of cells belonging to the myeloid lineage. They potently inhibit host responses to microbes, transformed cells and inflammatory cues. Therefore, their activities can be beneficial or detrimental to our homeostasis. Whether MDSC functions are controlled by mediators of the fight-or-flight response remains unexplored. In preliminary studies, we have found that stress due to physical confinement hinders the ability of mouse NKT cells to produce cytokines. In addition, restraint stress led to swift and robust accumulation of a cell population with similarities to MDSCs in the liver. The proposed program will address how the release of SNS mediators and GCs during stress influences NKT cell and MDSC functions. We have defined three project "clusters" within this interdisciplinary program. We will decipher the role(s) of SNS mediators and GCs on NKT cell survival and reactivity to glycolipids. We will reveal neurohormonal and immunological mechanisms underlying MDSC accumulation in the liver of stressed animals. Finally, we will extend our studies to other unconventional immune cell types and other models of stress with or without adaptation to GCs. The proposed program will improve our understanding of cellular and molecular cross-talk at the neuroimmune interface, and will elucidate how NKT cells and MDSCs are impacted by a fight-or-flight response. Our studies may generate novel and potentially marketable products, models or strategies for studying and/or manipulating unconventional immune responses. Equally important, this program will enable the training of a future generation of highly sought-after experts in the important, yet somewhat neglected, area of neuroimmune biology.

神经系统和免疫系统共同努力，以保持我们在分子，细胞和有机体水平上的平衡。为了快速应对威胁和压力源，人们会做出“战或逃”的反应。这种自动和强大的反应的特点是激活交感神经系统（SNS）和释放激素称为糖皮质激素（GC）从肾上腺。已知SNS介质和GC改变宿主防御的某些方面，包括常规T（Tconv）细胞应答。然而，激活SNS并触发GC释放的压力如何影响非常规免疫细胞类型尚不清楚。这些细胞包括自然杀伤T（NKT）细胞和髓源性抑制细胞（MDSC）。 NKT细胞是一种独特的先天性T淋巴细胞亚群。与Tconv细胞不同，NKT细胞对糖脂（由糖和脂肪组成的分子）做出反应，迅速分泌大量称为细胞因子的可溶性分子，介导免疫系统中的细胞间通讯。这决定了参与宿主防御的许多其他细胞类型的功能。因此，了解NKT细胞反应如何在应激过程中启动，持续和调节是相关的。 MDSC是属于骨髓谱系的细胞的多样化群体。它们有效地抑制宿主对微生物、转化细胞和炎症信号的反应。因此，它们的活动可能对我们的体内平衡有益或有害。MDSC的功能是否由战或逃反应的介体控制仍有待研究。 在初步研究中，我们发现由于物理限制导致的压力阻碍了小鼠NKT细胞产生细胞因子的能力。此外，束缚应激导致肝脏中与MDSC相似的细胞群迅速而稳健地积累。该计划将解决如何释放SNS介质和GC在压力影响NKT细胞和MDSC的功能。我们在这个跨学科的计划中定义了三个项目“集群”。我们将解读SNS介质和GC对NKT细胞存活和糖脂反应性的作用。我们将揭示应激动物肝脏中MDSC积累的神经激素和免疫机制。最后，我们将把我们的研究扩展到其他非传统的免疫细胞类型和其他有或没有适应GC的应激模型。 该计划将提高我们对神经免疫界面细胞和分子串扰的理解，并将阐明NKT细胞和MDSC如何受到战斗或逃跑反应的影响。我们的研究可能会产生新的和潜在的适销产品，模型或研究和/或操纵非常规免疫反应的策略。同样重要的是，该计划将能够培养未来一代在重要但有点被忽视的神经免疫生物学领域备受追捧的专家。