Neuroimmune Mechanisms of Recovery from Comorbid Depression and Chronic Pain

总结 抑郁症和慢性疼痛经常同时发生，并且难以治疗。在第一个奖项期间，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起源 对神经损伤作出反应的慢性神经病理性疼痛模型。然而，抑郁症还需要- 色氨酸代谢酶吲哚胺2，3双加氧酶（IDO1）的火焰诱导活化。 在这个更新的应用程序中，我们建议改变我们的重点，从发展的机制， 抑郁症和慢性疼痛的内源性解决机制，通常防止 过渡到这些适应不良的，长期的炎症后果。我们获得了令人振奋的消息 研究结果确定了CD8 T细胞在解决抑郁症和疼痛中的关键作用。 我们的初步数据表明，T细胞和内源性外周单核细胞产生的细胞， 活化白细胞介素（IL）-10是缓解炎症诱导疼痛和抑郁症所必需的。的小鼠 在两种不同的外周炎症模型中，遗传缺乏的T细胞会产生长期的疼痛和抑郁， 是的。将T细胞连续转移到这些小鼠中，可以使疼痛和抑郁的缓解正常化，而不会改变 外周炎症的过程。T细胞缺陷小鼠与对照小鼠相比， 与IDO 1的持续升高和脑中IL-10产生的缺乏相关。 我们的总体假设是，CD8 T细胞通过诱导IL-10来促进抑郁和疼痛的消退。 由单核细胞/巨噬细胞产生。这导致中枢神经系统中胶质细胞活化的下调， 我们的系统此外，我们提出，已经在体内接受抗原特异性或免疫刺激的CD8 T细胞， 特异性或非抗原特异性的方式将比来自幼稚小鼠的T细胞在促进免疫应答方面更有效。 缓解炎症引起的疼痛和抑郁。 我们将追求3个具体的目标来测试这组假设：目标1：检查T细胞在免疫中的作用。 抑郁样行为和疼痛的解决;目的2：调查贡献，来源和目标 内源性IL-10细胞在促进抑郁和疼痛消退中的作用;目的3：评估T细胞是否 在体内接受教育，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重新定义的。 从抑郁症疼痛中恢复的需求为治疗共病疼痛开辟了一个全新的视角 和抑郁症这个项目是重要的，因为共病抑郁症和慢性 疼痛和缺乏有效的治疗。如果成功的话，我们的项目将揭开未知的内在路径- 解决抑郁和疼痛的方法，从而允许开发新的策略， 治疗，包括离体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.