Immunometabolic regulation after CNS injury

PROJECT SUMMARY_______________. _________________________________ _ Progressive neurodegeneration is a long-term sequela of traumatic brain injury (TBI), with ~2% of the population living with neurological disabilities caused by a prior head injury. The brain is considered an immune privileged organ, yet a coordinated series of spatially- and temporally-regulated cerebral immune responses develop after TBI to increase cognitive dysfunction. Our objective is to test the overarching hypothesis that cerebral metabolic dysregulation activates meningeal innate lymphoid cells (ILCs), which are critical for the initiation, modulation, and resolution of inflammation, to perpetuate a chronic, pro-inflammatory cascade that culminates in poor TBI outcomes. Specifically, we propose that reduced activation of the master energetic sensor, 5’-AMP-activated protein kinase (AMPK), induces a senescence-associated secretory phenotype (SASP) within astrocytes after TBI. In turn, senescent astrocytes expand pro-inflammatory ILCs, which recruit peripheral immune cells into the CNS to drive chronic neurological injury. To test this possibility, three Specific Aims are proposed. Aim 1 will test the hypothesis that astrocyte-specific AMPK activation limits neurodegeneration after TBI. Aim 2 will test the hypothesis that astrocyte-specific AMPK activation restrains pro-inflammatory ILC expansion after TBI. Aim 3 will test the hypothesis that regulatory ILC2 reduce chronic neurological injury after TBI. Expected outcomes: We will utilize state-of-the-art, in vivo targeting approaches to demonstrate that acute metabolic derangements within the CNS initiate a deleterious cascade that culminates in progressive neurodegeneration. Our conceptually innovative, mechanistic studies will identify astrocyte senescence as a cellular convergence point to integrate cerebral metabolism with inflammatory changes. We also will elucidate a novel route of cell-cell communication whereby astrocytes coordinate peripheral immune responses via regulation of meningeal ILCs, providing a mechanism whereby pathological changes within the CNS microenvironment are translated into context-specific peripheral immunity. Taken together, we will identify a heretofore unexplored association between cerebral metabolic changes, astrocyte senescence, chronic neuroinflammation, and cognitive decline after CNS injury. Clinical significance: Progressive neurological injury is a clinically significant issue that worsens quality of life after TBI. Currently, no FDA-approved therapies effectively prevent, delay, or reverse chronic neurological injury after TBI, emphasizing a dire need for novel therapeutic approaches. From a translational perspective, our studies will demonstrate the feasibility and efficacy of a novel, cell-based therapeutic approach whereby ILC2 reduce chronic neuroinflammation and progressive neurodegeneration after TBI. Beyond neurotrauma, our studies may provide therapeutic approaches to limit neurological injury after stroke, spinal cord injury, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and other dementias.