TRPV1-dependent neuro-immune modulation and regulation of endogenous acyl-dopamines in sepsis and acute inflammation

脓毒症和急性炎症中内源性酰基多巴胺的 TRPV1 依赖性神经免疫调节和调节

• 批准号: 10634744
• 负责人: Judith Hellman
• 金额: $ 52.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-03 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634744
• 关键词: Abdomen; Ablation; Acute; Acute Lung Injury; Adult; Anti-Inflammatory Agents; Antiinflammatory Effect; Area; Autonomic nervous system; Bacteremia; Blood; Bone Marrow; Brain; Brain region; CNR1 gene; Cells; Central Nervous System; Cessation of life; Chemical Sympathectomy; Chimera organism; Data; Dopamine; Endotoxemia; Exhibits; Goals; Hippocampus; Homeostasis; Hour; Hypothalamic structure; Immune; Immune response; Immune system; Immunomodulators; Infection; Inflammation; Inflammatory; Inflammatory Response; Injections; Injury; Interleukin-10; Intra-abdominal; Knockout Mice; Life; Link; Lipids; Location; Lumbar spinal cord structure; Mediating; Midbrain structure; Mus; N-arachidonoyl dopamine; Nervous System; Neurocognitive; Neuroimmune; Neuroimmunomodulation; Neurons; Neuropeptides; Organ failure; Outcome; Peptides; Peripheral Nervous System; Plasma; Play; Pneumonia; Population; Process; Production; Propranolol; Public Health; Pulmonary Edema; Regulation; Reporting; Resolution; Role; Sepsis; Shock; Staphylococcus aureus; Substance P; Sympathetic Nervous System; TACR1 gene; TRPV1 gene; Up-Regulation; Vanilloid; Wild Type Mouse; antagonist; beta-2 Adrenergic Receptors; cecal ligation puncture; chemokine; cytokine; functional outcomes; immunoregulation; improved; inflammatory pain; knock-down; lung injury; monocyte; mouse model; neuroinflammation; new therapeutic target; novel; organ injury; polymicrobial sepsis; protective effect; public health relevance; receptor; septic; therapeutic target; therapy development

PROJECT SUMMARY Sepsis is a formidable public health problem, and there is a need to better understand the basic mechanisms of sepsis and immunomodulation. Our studies will define the anti-inflammatory mechanisms and functional effects in sepsis of N-oleoyl dopamine (OLDA) and N-arachidonoyl dopamine (NADA), which are endogenous acyl-dopamines produced in the peripheral and central nervous systems (PNS, CNS). OLDA and NADA exhibit activity at the transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptor 1 (CB1R). In mice with S. aureus pneumonia, intraabdominal polymicrobial sepsis, or endotoxemia, we found that OLDA or NADA administration 1) induces an early substantial upregulation of systemic IL-10, 2) decreases pro-inflammatory cytokines and chemokines, and 3) reduces acute lung injury and sepsis scores at 24 hours. NADA also reduces CGRP and increases Substance P in the plasmas of LPS-treated mice. Our studies in bone marrow chimeras of Trpv1-/- and wild-type mice indicated that NADA induces IL-10 via TRPV1 expressed by non- myeloid cells. Our further preliminary data suggest that neuronal TRPV1 mediates the anti-inflammatory and protective actions of OLDA in LPS-treated mice, and more specifically, that these effects are mediated by TRPV1 neurons in the CNS rather than the PNS. Finally, we observed increased plasma and brain levels of OLDA and NADA in LPS-treated mice, which suggest that these novel endogenous lipids may be dynamically regulated during acute inflammation and sepsis. Collectively, our data have led to our central hypothesis that there is a CNS based neuro-immunomodulatory link that involves the activation of neuronal TRPV1 by endogenous lipids, such as OLDA and NADA, and regulates inflammatory responses and outcomes of acute inflammation and sepsis. Aim #1 will localize the TRPV1 neurons responsible for the anti-inflammatory actions of OLDA and NADA in acute inflammation and sepsis and determine the role of CB1R in the TRPV1-dependent anti-inflammatory actions of OLDA and NADA. Aim #2 will identify the downstream mechanisms by which the activation of neuronal TRPV1 by OLDA or NADA upregulates IL-10 production by circulating monocytes in sepsis, focusing on the roles of Substance P, CGRP, and the sympathetic nervous system. Aim #3 will define the effects of OLDA and NADA on sepsis outcomes, and the effects of sepsis on endogenous production of OLDA and NADA, and expression of TRPV1 and CB1R. These studies will advance the understanding of the neuro-immunomodulatory effects and endogenous roles of NADA, OLDA and TRPV1 in sepsis, with the ultimate goal to identify novel therapeutic targets.

项目总结 败血症是一个可怕的公共卫生问题，有必要更好地了解其基本机制。 脓毒症和免疫调节。我们的研究将确定抗炎机制和功能 内源性N-油酰基多巴胺(Olda)和N-花生四烯酰基多巴胺(NADA)在脓毒症中的作用 外周和中枢神经系统(PNS，CNS)产生的酰基多巴胺。奥尔达和NADA展览 瞬时受体电位香草素1(TRPV1)和大麻素受体1(CB1R)的活性。在小鼠中 金黄色葡萄球菌肺炎，腹内多菌败血症，或内毒素血症，我们发现Olda或NADA 给药1)诱导早期系统IL-10的显著上调，2)减少促炎作用 细胞因子和趋化因子，以及3)减少24小时的急性肺损伤和脓毒症评分。没有也没有 降低内毒素处理小鼠血浆中CGRP含量，升高P物质含量。我们对骨髓的研究 TRPV1-/-和野生型小鼠的嵌合体表明，NADA通过非T细胞表达的TRPV1诱导IL-10 髓系细胞。我们进一步的初步数据表明，神经元TRPV1介导了抗炎和 Olda对内毒素处理小鼠的保护作用，更具体地说，这些作用是通过 TRPV1神经元在中枢神经系统而不是三叉神经节。最后，我们观察到血浆和大脑中 OLDA和NADA，提示这些新的内源性脂质可能是动态的 在急性炎症和败血症期间受到调节。总而言之，我们的数据导致了我们的核心假设 有一种以中枢神经系统为基础的神经免疫调节联系，涉及通过以下方式激活神经元TRPV1 内源性脂质，如Olda和NADA，并调节炎症反应和急性 炎症和败血症。Aim#1将定位负责抗炎作用的TRPV1神经元 OLDA和NADA在急性炎症和脓毒症中的表达及确定CB1R在TRPV1依赖中的作用 Olda和NADA的抗炎作用。目标2将确定下游机制，通过这些机制 OLDA或NADA激活神经元TRPV1上调循环单核细胞产生IL-10 脓毒症，侧重于P物质、CGRP和交感神经系统的作用。目标#3将定义 OLDA和NADA对脓毒症结局的影响，以及脓毒症对内源性生产的影响 Olda和NADA，以及TRPV1和CB1R的表达。这些研究将促进对 NADA、OLDA和TRPV1在脓毒症中的神经免疫调节作用和内源性作用 最终目标是确定新的治疗靶点。