title: NOX2 drives M1-like microglial/macrophage activation and neurodegeneration following experimental traumatic brain injury.
abstract: Following traumatic brain injury (TBI), activation of microglia and peripherally derived inflammatory macrophages occurs in association with tissue damage. This neuroinflammatory response may have beneficial or detrimental effects on neuronal survival, depending on the functional polarization of these cells along a continuum from M1-like to M2-like activation states. The mechanisms that regulate M1-like and M2-like activation after TBI are not well understood, but appear in part to reflect the redox state of the lesion microenvironment. NADPH oxidase (NOX2) is a critical enzyme system that generates reactive oxygen species in microglia/macrophages. After TBI, NOX2 is strongly up-regulated in M1-like, but not in M2-like polarized cells. Therefore, we hypothesized that NOX2 drives M1-like neuroinflammation and contributes to neurodegeneration and loss of neurological function after TBI. In the present studies we inhibited NOX2 activity using NOX2-knockout mice or the selective peptide inhibitor gp91ds-tat. We show that NOX2 is highly up-regulated in infiltrating macrophages after injury, and that NOX2 deficiency reduces markers of M1-like activation, limits tissue loss and neurodegeneration, and improves motor recovery after moderate-level control cortical injury (CCI). NOX2 deficiency also promotes M2-like activation after CCI, through increased IL-4Rα signaling in infiltrating macrophages, suggesting that NOX2 acts as a critical switch between M1- and M2-like activation states after TBI. Administration of gp91ds-tat to wild-type CCI mice starting at 24h post-injury reduces deficits in cognitive function and increased M2-like activation in the hippocampus. Collectively, our data indicate that increased NOX2 activity after TBI drives M1-like activation that contributes to inflammatory-mediated neurodegeneration, and that inhibiting this pathway provides neuroprotection, in part by altering M1-/M2-like balance towards the M2-like neuroinflammatory response.
authors.affiliation: Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Alok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Barrett
authors.affiliation: Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA; Posgrado en Neuroetologia, Universidad Veracruzana, Xalapa, Mexico; Centro de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa, Mexico.
authors.forename: Dulce-Mariely
authors.initials: DM
authors.lastname: Alvarez-Croda
authors.affiliation: Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Stoica
authors.affiliation: Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Alan I
authors.initials: AI
authors.lastname: Faden
authors.affiliation: Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: dloane@anes.umm.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Loane
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000378:metabolism* / Q000473:pathology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004660:Encephalitis / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D000074662:NADPH Oxidase 2 / Q000235:genetics / Q000378:metabolism*; D065852:Spatial Memory
chemical_list: C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2
keywords: M1-/M2-like; Macrophage; Microglia; NADPH oxidase; NOX2; Neurodegeneration; Neuroinflammation; Traumatic brain injury