Robert Dantzer, D.V.M., Ph.D. - US grants

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.

Project Summary ? Cancer-related fatigue is one of the most common and disruptive symptoms experienced by patients. It is often present at the time of diagnosis, worsens throughout treatment, and persists well after the cessation of treatment in a significant proportion of patients. The specific mechanisms responsible for fatigue remain largely unknown. Consequently, there are no mechanism-guided therapies for fatigue and the primary approach to patients reporting severe fatigue is education and counseling in the self-management of fatigue. Although conservation of energy is an important strategy in the management of fatigue, the possibility that cancer-related fatigue originates from alterations in energy metabolism has not been examined. The present project fills this void. Our working hypothesis is that cancer-related fatigue is the behavioral consequence of the excess metabolic demand imposed on the organism by the tumor and the inflammation it is possibly associated with. The relative metabolic inefficiency that results from this condition is worsened by the mitochondrial impairment that develops in peripheral tissues and the brain in response to chemotherapy and radiotherapy. To test our hypothesis, we will use two syngeneic murine models of cancer that both respond to a combination of cisplatin and local irradiation, a non-inflammatory model mimicking human papilloma virus-related head and neck cancer, and an inflammatory model represented by Lewis lung carcinoma. We will measure behavioral fatigue in both conditions by decreased voluntary wheel running and alterations in motivated behavior to account for the motivational component of fatigue. In Aim 1, we will determine whether inflammation associated with the tumor and its treatment needs to propagate to the brain for fatigue to develop. This will be done by comparing the time course of inflammation at the periphery and in the brain to that of fatigue before intervening to either block immune signaling molecules by passive immunization or deplete the innate immune cells that mediate the inflammatory process at the periphery and in the brain. In Aim 2, we will test the hypothesis that metabolic reprogramming by cancer and inflammation leads to a condition of relative energy metabolism deficiency that is exacerbated by cancer therapy-induced mitochondrial dysfunction. This will be done by determining the association between metabolic reprogramming and behavioral fatigue before assessing whether intensifying mitochondrial damage exacerbates the behavioral and metabolic phenotypes of fatigue while preventing mitochondrial damage has the reverse effect. In Aim 3, we will test the hypothesis that activation of cytosol DNA sensors by self DNA leaking from mitochondria and cell nuclei triggers this whole process. This research should help understand and treat cancer-related fatigue.