Glucocorticoid and Adrenergic Receptor Signaling at the Neuroimmune Interface

神经和免疫系统共同努力，在分子、细胞和机体水平上保持我们的平衡。为了快速应对威胁和压力源，人们采取了“要么战斗，要么逃跑”的应对方式。这种自动而强大的反应的特征是交感神经系统(SNS)的激活和肾上腺释放被称为糖皮质激素(GCs)的激素。SNS介体和GC已知可以改变宿主防御的某些方面，包括传统的T(Tconv)细胞反应。然而，激活SNS并触发GC释放的压力如何影响非传统免疫细胞类型尚不清楚。这些细胞包括自然杀伤T细胞(NKT)和髓系来源的抑制细胞(MDSCs)。NKT细胞是先天T淋巴细胞的一个独特亚群。与Tconv细胞不同，NKT细胞对糖脂做出反应，糖脂是由糖和脂肪组成的分子，NKT细胞通过迅速分泌大量被称为细胞因子的可溶性分子来调节免疫系统中的细胞间通讯。这决定了许多其他类型的细胞参与宿主防御的功能。因此，了解NKT细胞在应激过程中如何启动、维持和调节反应是很有意义的。MDSCs是一组不同的细胞，属于髓系细胞系。它们能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，它们的活动对我们的动态平衡可能是有益的，也可能是有害的。MDSC的功能是否由战斗或逃跑反应的调解人控制仍不清楚。在初步研究中，我们发现由于物理限制造成的压力阻碍了小鼠NKT细胞产生细胞因子的能力。此外，束缚应激导致肝脏中与MDSCs相似的细胞群迅速而强劲地积累。拟议的计划将解决应激过程中SNS介体和GC的释放如何影响NKT细胞和MDSC的功能。在这个跨学科项目中，我们定义了三个项目“集群”。我们将破译SNS介体和GC在NKT细胞存活和糖脂反应性中的作用(S)。我们将揭示应激动物肝脏中MDSC聚集的神经激素和免疫学机制。最后，我们将把我们的研究扩展到其他非常规免疫细胞类型和其他应激模型，无论是否适应GCs。拟议的计划将提高我们对神经免疫界面上的细胞和分子串扰的理解，并将阐明NKT细胞和MDSCs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市场产品、模型或策略，用于研究和/或操纵非常规免疫反应。同样重要的是，该项目将能够培训未来一代非常受欢迎的神经免疫生物学领域的专家，这一领域虽然重要，但在某种程度上被忽视了。

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.