Neuroimmune Mechanisms of Recovery from Comorbid Depression and Chronic Pain

摘要 抑郁症和慢性疼痛经常同时发生，很难治疗。在第一个获奖期内，我们 确定了抑郁症和疼痛的共同机制以及抑郁症特有的机制。我们 表明脊髓中的炎症活动是小鼠疼痛和抑郁的根源 慢性神经病理性疼痛模型对神经损伤的反应。然而，抑郁症还需要- 燃烧诱导色氨酸代谢酶吲哚-2，3-双加氧酶(IDO1)的激活。 在这份续订申请中，我们建议将重点从开发的基础机制转移到 抑郁和慢性疼痛对内源性解决机制的影响，这种内源性解决机制通常防止 过渡到这些不适应的、长期的炎症后果。我们得到了令人振奋的新消息 研究发现CD8 T细胞在解决抑郁和疼痛方面起着关键作用。 我们的初步数据表明，T细胞和内源性外周血单核细胞产生细胞- IL-10是解决炎症引起的疼痛和抑郁所必需的。老鼠 在两种不同的外周炎症模型中，遗传缺乏T细胞会导致持续的疼痛和抑郁。 提顿。将T细胞过继转移到这些小鼠可以正常缓解疼痛和抑郁，而不会改变 外周炎症的过程。与对照组相比，T细胞缺陷小鼠持续的抑郁 与IDO1持续升高和大脑中缺乏IL-10产生有关。 我们的总体假设是CD8 T细胞通过诱导IL-10促进抑郁和疼痛的缓解 由单核/巨噬细胞产生。这导致了中枢神经胶质细胞激活的下调。 OU系统。此外，我们认为，在体内培养的CD8 T细胞，无论是在抗原特定的情况下- 特异性或非抗原特异性的方法将比来自幼稚小鼠的T细胞更有效地促进RES- 消退炎症引起的疼痛和抑郁。 我们将追求3个具体目标来检验这组假说：目标1：检查T细胞在 抑郁样行为和疼痛的解决；目标2：调查其贡献、来源和目标 内源性IL-10细胞在促进抑郁和疼痛缓解中的作用；目的3：评估T细胞是否 在体内进行教育，以促进抑郁和疼痛的解决。 我们的建议是创新的，因为神经免疫T细胞依赖机制的概念是 从抑郁中恢复疼痛开启了治疗并存疼痛的全新视角 和抑郁症。这个项目意义重大，因为抑郁症和慢性抑郁症并存的发病率很高。 疼痛和缺乏有效的治疗。如果成功，我们的项目将揭开未探索的内生路径- 管理抑郁和疼痛的解决方法，从而允许开发新的治疗策略 治疗，包括体外T细胞教育或疫苗接种策略。

SUMMARY Depression and chronic pain frequently co-occur and are difficult to treat. In the first award period, we identified mechanisms common to both depression and pain as well as mechanisms specific to depression. We showed that inflammatory activity in the spinal cord is at the origin of both pain and depression in a mouse model of chronic neuropathic pain in response to nerve injury. However, depression additionally requires in- flammation-induced activation of the tryptophan metabolizing enzyme indoleamine 2,3 dioxygenase (IDO1). In this renewal application, we propose to change our focus from the mechanisms underlying devel- opment of depression and chronic pain to the endogenous resolution mechanism that normally prevents transition to these maladaptive, long-lasting consequences of inflammation. We have obtained exciting new findings identifying a key role for CD8 T cells in the resolution of depression and pain. Our preliminary data indicate that T cells and endogenous peripheral monocytes that produce the cyto- kine interleukin (IL)-10 are required for resolution of inflammation-induced pain and depression. Mice that genetically lack T cells develop prolonged pain and depression in two different models of peripheral inflamma- tion. Adoptive transfer of T cells to these mice normalizes resolution of pain and depression without altering the course of peripheral inflammation. The prolonged depression in T cell-deficient mice versus control mice is associated with persistent elevation of IDO1 and lack of IL-10 production in the brain. Our overall hypothesis is that CD8 T cells promote resolution of depression and pain by inducing IL-10 production by monocytes/macrophages. This leads to the downregulation of glial activation in the central nerv- ous system. In addition, we propose that CD8 T cells that have been educated in vivo in either an antigen-spe- cific or a non–antigen-specific way will be more efficient than T cells from naïve mice will be in promoting res- olution of inflammation-induced pain and depression. We will pursue 3 specific aims to test this set of hypotheses: Aim 1: Examine the role of T cells in the resolution of depression-like behavior and pain; Aim 2: Investigate the contribution, source, and target cell of endogenous IL-10 in promoting resolution of depression and pain; Aim 3: Assess whether T cells are educated in vivo to promote resolution of depression and pain. Our proposal is innovative because the concept that neuroimmune T cell-dependent mechanisms are re- quired for recovery from depression pain opens a totally novel perspective on the treatment of comorbid pain and depression. This project is significant because of the high prevalence of comorbid depression and chronic pain and the lack of effective treatment. If successful, our project will unravel unexplored endogenous path- ways governing resolution of depression and pain, and thereby allow the development of novel strategies for treatment, including ex vivo T cell education or vaccination strategies.