Sexual dimorphism in the inflammatory response to traumatic brain injury

• Published in: Glia Vol. 65; no. 9; pp. 1423 - 1438
• Main Authors: Villapol, Sonia, Loane, David J., Burns, Mark P.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2017
• Subjects: Activation analysis; Animals; Arginase - metabolism; Astrocytes - immunology; Astrocytes - pathology; Brain; Brain Injuries, Traumatic - immunology; Brain Injuries, Traumatic - pathology; Cell activation; Cell Death; Cortex; cytokine; Cytokines; Disease Models, Animal; Female; Females; Glial cells; Gliosis; Gliosis - immunology; Gliosis - pathology; Head injuries; Hybridization analysis; Immunofluorescence; Infiltration; Inflammation; Inflammation - pathology; Inflammation - physiopathology; Inflammatory response; Interleukin 1; Macrophage Activation - immunology; Macrophage Activation - physiology; Macrophages; Male; Mice; Mice, Inbred C57BL; Microglia; Microglia - immunology; Microglia - pathology; Microglial cells; Mortality; mRNA; Neuroimmunomodulation - physiology; Rodents; Sex; Sex Characteristics; Sexual dimorphism; sex‐differences; Transforming Growth Factor beta - metabolism; trauma; Traumatic brain injury; Tumor necrosis factor; cytokine; trauma; inflammation; microglia; sex-differences
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23171

The activation of resident microglial cells, alongside the infiltration of peripheral macrophages, are key neuroinflammatory responses to traumatic brain injury (TBI) that are directly associated with neuronal death. Sexual disparities in response to TBI have been previously reported; however it is unclear whether a sex difference exists in neuroinflammatory progression after TBI. We exposed male and female mice to moderate‐to‐severe controlled cortical impact injury and studied glial cell activation in the acute and chronic stages of TBI using immunofluorescence and in situ hybridization analysis. We found that the sex response was completely divergent up to 7 days postinjury. TBI caused a rapid and pronounced cortical microglia/macrophage activation in male mice with a prominent activated phenotype that produced both pro‐ (IL‐1β and TNFα) and anti‐inflammatory (Arg1 and TGFβ) cytokines with a single‐phase, sustained peak from 1 to 7 days. In contrast, TBI caused a less robust microglia/macrophage phenotype in females with biphasic pro‐inflammatory response peaks at 4 h and 7 days, and a delayed anti‐inflammatory mRNA peak at 30 days. We further report that female mice were protected against acute cell loss after TBI, with male mice demonstrating enhanced astrogliosis, neuronal death, and increased lesion volume through 7 days post‐TBI. Collectively, these findings indicate that TBI leads to a more aggressive neuroinflammatory profile in male compared with female mice during the acute and subacute phases postinjury. Understanding how sex affects the course of neuroinflammation following brain injury is a vital step toward developing personalized and effective treatments for TBI. Main Points After brain damage, male mice show increased microglial activation, macrophage infiltration, astrogliosis and cell death compared to female mice. Traumatic brain injury induces sex and timing‐dependent cytokine production in microglia/macrophages cells.