Octopaminergic Signaling Mediates Neural Regulation of Innate Immunity in Caenorhabditis elegans.
Octopaminergic Signaling Mediates Neural Regulation of Innate Immunity in Caenorhabditis elegans.
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作者：
Sellegounder D;Yuan CH;Wibisono P;Liu Y;Sun J
对病原体感染的免疫反应不足或过度是疾病的主要原因。越来越多的证据表明，神经系统调节免疫系统，以帮助维持免疫稳态。然而，这种调节的确切机制在很大程度上是未知的。在这里，我们表明存在的章鱼胺能免疫抑制途径秀丽隐杆线虫。我们的研究结果表明，该途径在正常条件下具有张力活性，以维持免疫稳态或抑制不需要的先天免疫应答，但在病原体感染后下调，以增强先天免疫。由于过度的先天免疫应答与人类健康状况如克罗恩病、类风湿性关节炎、动脉粥样硬化、糖尿病和阿尔茨海默病有关，因此阐明先天免疫的章鱼胺能神经调节可能有助于开发先天免疫疾病的新治疗方法。在病原体感染后，神经系统调节先天免疫以赋予宿主协调的保护。然而，这种监管的确切机制仍不清楚。先前的研究表明，OCTR-1，一个假定的G蛋白偶联受体的儿茶酚胺，功能的感觉神经元命名为“灰”，以抑制先天性免疫反应在秀丽隐杆线虫。目前尚不清楚什么分子在神经免疫调节回路中充当OCTR-1配体。在这里，我们确定神经递质章鱼胺（OA）作为OCTR-1的内源性配体在免疫调节和显示，OA产生RIC神经元的功能在OCTR-1神经回路，以抑制先天免疫。RIC神经元在病原体存在下失活，但被非病原性细菌短暂激活。我们的数据支持一种模型，其中章鱼胺能免疫抑制途径在正常条件下具有张力活性，以维持免疫稳态或抑制不需要的先天免疫应答，但在病原体感染后下调，以增强先天免疫。由于过度的先天免疫反应与无数的人类健康问题有关，我们的研究可能有助于开发更有效的先天免疫疾病治疗方法。
Insufficient or excessive immune responses to pathogen infection are major causes of disease. Increasing evidence indicates that the nervous system regulates the immune system to help maintain immunological homeostasis. However, the precise mechanisms of this regulation are largely unknown. Here we show the existence of an octopaminergic immunoinhibitory pathway in Caenorhabditis elegans. Our study results indicate that this pathway is tonically active under normal conditions to maintain immunological homeostasis or suppress unwanted innate immune responses but downregulated upon pathogen infection to allow enhanced innate immunity. As excessive innate immune responses have been linked to human health conditions such as Crohn's disease, rheumatoid arthritis, atherosclerosis, diabetes, and Alzheimer's disease, elucidating octopaminergic neural regulation of innate immunity could be helpful in the development of new treatments for innate immune diseases. Upon pathogen infection, the nervous system regulates innate immunity to confer coordinated protection to the host. However, the precise mechanisms of such regulation remain unclear. Previous studies have demonstrated that OCTR-1, a putative G protein-coupled receptor for catecholamine, functions in the sensory neurons designated “ASH” to suppress innate immune responses in Caenorhabditis elegans. It is unknown what molecules act as OCTR-1 ligands in the neural immune regulatory circuit. Here we identify neurotransmitter octopamine (OA) as an endogenous ligand for OCTR-1 in immune regulation and show that the OA-producing RIC neurons function in the OCTR-1 neural circuit to suppress innate immunity. RIC neurons are deactivated in the presence of pathogens but transiently activated by nonpathogenic bacteria. Our data support a model whereby an octopaminergic immunoinhibitory pathway is tonically active under normal conditions to maintain immunological homeostasis or suppress unwanted innate immune responses but downregulated upon pathogen infection to allow enhanced innate immunity. As excessive innate immune responses have been linked to a myriad of human health concerns, our study could potentially benefit the development of more-effective treatments for innate immune disorders.