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.

项目摘要 败血症是一个巨大的公共卫生问题，有必要更好地了解基本机制 败血症和免疫调节。我们的研究将定义抗炎机制和功能 N-烯酰胺多巴胺（Olda）和N-芳基多烯酰二胺（NADA）的败血症的作用，它们是内源性的 在周围和中枢神经系统（PNS，CNS）中产生的酰基丙巴胺。奥尔达和纳达展览 在瞬态受体电势香草素1（TRPV1）和大麻素受体1（CB1R）上的活性。在老鼠中 金黄色葡萄球菌肺炎，腹腔内多细胞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的早期实质性上调，2）降低促炎性 细胞因子和趋化因子以及3）在24小时时降低急性肺损伤和败血症评分。纳达也是 减少了CGRP并增加了经LPS处理小鼠的血浆中的物质P。我们在骨髓的研究 TRPV1 - / - 和野生型小鼠的嵌合体表明，NADA通过非 - 表达的TRPV1诱导IL-10 髓样细胞。我们进一步的初步数据表明，神经元TRPV1介导了抗炎和 Olda在LPS处理的小鼠中的保护作用，更具体地说，这些作用是由 中枢神经系统中的TRPV1神经元而不是PN。最后，我们观察到血浆和大脑水平升高 LPS处理的小鼠中的Olda和Nada，这表明这些新型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。总的来说，我们的数据导致了我们的中心假设 有一个基于CNS的神经免疫调节链接，涉及神经元TRPV1的激活 内源性脂质（例如Olda和Nada），并调节急性的炎症反应和结果 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在急性炎症和败血症中的作用，并确定CB1R在TRPV1依赖性中的作用 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，通过循环单核细胞上调IL-10的产生 败血症的重点是物质P，CGRP和交感神经系统的作用。 AIM＃3将定义 Olda和Nada对败血症结果的影响以及败血症对内生产生的影响 Olda和Nada，以及TRPV1和CB1R的表达。这些研究将提高对 Nada，Olda和Trpv1在败血症中的神经免疫调节作用和内源性作用， 确定新型治疗靶标的最终目标。