Project Grant R01EY035307

ARGINASE POSITIVE MONOCYTE MEDIATED RGC NEUROPROTECTION AFTER TRAUMATIC OPTIC NEUROPATHY - PROJECT SUMMARY: ACUTE RETINAL GANGLION CELL (RGC) AND OPTIC NERVE INJURY DUE TO TRAUMA, AUTOIMMUNE INFLAMMATION, AND ISCHEMIA REPERFUSION RESULTS IN PERMANENT DISABILITY DUE TO EVENTUAL NEURONAL DEATH. TRADITIONALLY, INFLAMMATION AFTER ACUTE NEURONAL INJURY HAS BEEN CONSIDERED A MAJOR DRIVER OF SECONDARY DAMAGE, LEADING TO NEURONAL LOSS. THE INNATE IMMUNE RESPONSE OF INFILTRATING NEUTROPHILS AND MONOCYTES (MYELOID CELLS) AFTER NEURONAL INJURY RESULTS IN PRODUCTION OF MATRIX METALLOPROTEASES, PROINFLAMMATORY CYTOKINES, AND REACTIVE OXYGEN SPECIES THAT ARE DIRECTLY NEUROTOXIC, AND CONTRIBUTE GLIAL CELL MODULATION THAT PREVENT NEUROLOGICAL RECOVERY. HOWEVER, ANIMAL MODEL STUDIES HAVE DEMONSTRATED THAT CERTAIN IMMUNE CELL SUBSETS CAN HAVE NEUROPROTECTIVE AND REPARATIVE EFFECTS INCLUDING IN THE EYE. WE HAVE IDENTIFIED THAT THIS IMMUNE MEDIATED REGENERATION AFTER OPTIC NERVE CRUSH IS INITIATED BY A NOVEL IMMATURE ALTERNATIVELY ACTIVATED NEUTROPHIL CHARACTERIZED AS LY6GLOW CD14+ CD101-. THESE ALTERNATIVELY ACTIVATED NEUTROPHILS RECRUIT ARGINASE+ (ARG+) MONOCYTES THAT STAY AT THE SITE OF INJURY AND CONTINUE TO STIMULATE AXON REGENERATION. ADDITIONALLY, ALTERNATIVELY ACTIVATED NEUTROPHILS MODULATE MICROGLIA THAT LIKELY CONTRIBUTE TO THE NEURO-REPARATIVE ENVIRONMENT AFTER RGC INJURY. THE PRESENCE OF ARG+ MONOCYTES IN THE CENTRAL NERVOUS SYSTEM AFTER INJURY HAS BEEN ASSOCIATED WITH INFLAMMATION RESOLUTION AND NEUROREPAIR, HOWEVER THE MECHANISM IN WHICH ARG+ MONOCYTES DO THIS IS NOT KNOWN. IN ADDITION TO UNDERSTANDING THE BENEFICIAL EFFECTS OF ALTERNATIVELY ACTIVATED NEUTROPHILS ON RECRUITED MONOCYTES AND MICROGLIA, WE HAVE ALSO IDENTIFIED A HUMAN MONOCYTE POPULATION THAT SHOWS NEUROPROTECTIVE EFFECTS AND STIMULATES AXON REGENERATION AFTER ONC. THE OVERALL GOALS OF THIS WORK ARE BASED ON THE HYPOTHESIS THAT MONOCYTES CAN BE POLARIZED IN SITU TOWARDS THE UNIQUE NEUROREGENERATIVE PHENOTYPE TO IMPROVE NEURONAL RECOVERY AFTER ONC. THIS HYPOTHESIS WILL BE INTERROGATED IN THREE AIMS. IN AIM 1 WE WILL DETERMINE THE INTERACTIONS BETWEEN NEUTROPHILS AND MONOCYTES THAT RESULT IN MONOCYTE POLARIZATION TOWARDS AN ARG+ REPARATIVE PHENOTYPE. IN AIM 2, WE WILL FOCUS ON THE ROLE OF RETINAL MICROGLIA IN CONTRIBUTING TO MODULATION OF THE OCULAR INFLAMMATORY ENVIRONMENT AND POLARIZATION OF IMMUNE CELLS TOWARDS A NEURO-REPARATIVE PHENOTYPE. AIM 3 WILL DETERMINE THE TRANSLATIONAL CAPACITY OF THESE MECHANISTIC MOUSE EXPERIMENTS BY EXPLORING THE NEUROREGENERATIVE CAPACITY OF POLARIZING HUMAN MONOCYTES TO STIMULATE AXON REGENERATION AFTER ONC. THE OUTCOMES OF THESE STUDIES WILL BE TO UNDERSTAND THE UNDERLYING CYTOKINE, GROWTH FACTOR AND METABOLIC SIGNALS THAT INFLUENCE MONOCYTES TO TAKE ON A NEURO-REPARATIVE ROLE AFTER OPTIC NERVE INJURY. TO DATE, THE ROLE OF ARG+ MYELOID CELLS ON NEUROPROTECTION HAS BEEN CORRELATIVE. THIS WORK WILL HELP US GAIN A MECHANISTIC UNDERSTANDING OF THE FACTORS RESPONSIBLE FOR DRIVING MYELOID CELLS TOWARDS THE NEURO-REGENERATIVE PHENOTYPE AND COULD LEAD TO IMMUNE BASED THERAPIES TO DRIVE NEURON RECOVERY AFTER ACUTE INJURY.