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.

项目概要 脓毒症是一个可怕的公共卫生问题，需要更好地了解其基本机制 败血症和免疫调节。我们的研究将确定抗炎机制和功能 N-油酰多巴胺 (OLDA) 和 N-花生四烯酰多巴胺 (NADA) 对败血症的影响，这是内源性的 外周和中枢神经系统（PNS、CNS）产生酰基多巴胺。 OLDA 和 NADA 展览 瞬时受体电位香草酸 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、腹内多种微生物败血症或内毒素血症，我们发现 OLDA 或 NADA 给药 1) 诱导全身 IL-10 早期显着上调，2) 减少促炎作用 细胞因子和趋化因子，3) 减少 24 小时急性肺损伤和脓毒症评分。纳达也 降低 CGRP 并增加 LPS 处理小鼠血浆中的 P 物质。我们的骨髓研究 Trpv1-/- 和野生型小鼠的嵌合体表明 NADA 通过非小鼠表达的 TRPV1 诱导 IL-10 骨髓细胞。我们进一步的初步数据表明神经元 TRPV1 介导抗炎和 OLDA 对 LPS 处理小鼠的保护作用，更具体地说，这些作用是由 TRPV1 神经元位于 CNS 而不是 PNS。最后，我们观察到血浆和大脑水平增加 LPS 处理小鼠中的 OLDA 和 NADA，这表明这些新的内源性脂质可能会动态变化 在急性炎症和败血症期间受到调节。总的来说，我们的数据得出了我们的中心假设： 存在一个基于中枢神经系统的神经免疫调节链接，涉及通过以下方式激活神经元 TRPV1 内源性脂质，如 OLDA 和 NADA，调节炎症反应和急性炎症的结果 炎症和败血症。目标 #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作用，并确定 CB1R 在 TRPV1 依赖性 OLDA 和 NADA 的抗炎作用。目标 #2 将确定下游机制 OLDA 或 NADA 激活神经元 TRPV1 上调循环单核细胞产生 IL-10 脓毒症，重点关注 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产生的影响 OLDA 和 NADA，以及 TRPV1 和 CB1R 的表达。这些研究将增进对 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。