Age increases reactive oxygen species production in macrophages and potentiates oxidative damage after spinal cord injury

Abstract

Age potentiates neurodegeneration and impairs recovery from spinal cord injury (SCI). Previously, we observed that age alters the balance of destructive (M1) and protective (M2) macrophages, however, the age-related pathophysiology in SCI is poorly understood. NADPH oxidase (NOX) contributes to reactive oxygen species (ROS)-mediated damage and macrophage activation in neurotrauma. Further, NOX/ROS increase with CNS age. Here, we found significantly higher ROS generation in 14 vs. 4-month-old (MO) mice after contusion SCI. Notably, NOX2 increased in 14 MO ROS-producing macrophages suggesting that macrophages and NOX contribute to SCI oxidative stress. Indicators of lipid peroxidation, a downstream cytotoxic effect of ROS accumulation, were significantly higher in 14 vs. 4 MO SCI mice. We also detected a higher percentage of ROS-producing M2 (Arginase-1-positive) macrophages in 14 vs. 4 MO mice, a previously unreported SCI phenotype, and increased M1 (CD16/32-positive) macrophages with age. Thus, NOX and ROS are age-related mediators of SCI pathophysiology and normally protective M2 macrophages may potentiate secondary injury through ROS generation in the aged injured spinal cord.

Aging alters Hv1‐mediated microglial polarization and enhances neuroinflammation after peripheral surgery

“…It is also suggested that the level of microglial NADPH oxidase activity is a major regulator of the shift between M1/proinflammatory and M2/immunoregulatory microglial phenotypes . Zhang et al reported that aging significantly increased NADPH oxidase activation and reactive oxygen species production in Arg1‐positive M2 microglia/macrophages, thereby further increasing age‐related, macrophage‐mediated spinal cord injury secondary tissue damage . Another study by Kumar et al demonstrated that aged mice had increased microglia/macrophage expression of major histocompatibility complex II and NADPH oxidase, and reduced antioxidant enzyme expression which was associated with worse outcome in traumatic brain injury …”

“…Emerging evidence now supports M1/M2 microglia/macrophage polarization alters in several types of acute CNS injuries, including traumatic brain injury, spinal cord injury, and stroke . Aging is suggested to alter the balance between destructive M1 and protective M2 phenotypes, thus contributed to enhanced neuroinflammation and tissue damage following CNS injuries . However, the effect of age on brain microglial polarization in response to peripheral surgical intervention is unclear.…”

“…[11][12][13][14] Aging is suggested to alter the balance between destructive M1 and protective M2 phenotypes, thus contributed to enhanced neuroinflammation and tissue damage following CNS injuries. 15,16 However, the effect of age on brain microglial polarization in response to peripheral surgical intervention is unclear.…”

Predictive screening of M1 and M2 macrophages reveals the immunomodulatory effectiveness of post spinal cord injury azithromycin treatment

“…For surface receptors (CD86, CD206, Marco) the total threshold area was determined for the entire lesion epicenter then normalized to the threshold area for TomL. Previously we established that TomL specifically labels macrophages within the spinal cord lesion epicenter46 and there was no effect of AZM treatment on TomL density at either time point (p > 0.05).…”

Lycium Barbarum Polysaccharides Alleviates Oxidative Damage Induced by H2O2 Through Down-Regulating MicroRNA-194 in PC-12 and SH-SY5Y Cells

“…Considering the irreversible property of the primary injury, scientists focus on exploring strategies to reduce secondary injury to adjacent tissues, in order to improve outcome of SCI treatments [4]. Oxidative stress is critical for pathophysiology of secondary damage [5]. In the cell membranes of the CNS, there are a great amount of lipids which are easily vulnerable to free radical.…”