Temporal changes in the microglial proteome of male and female mice after a diffuse brain injury using label‐free quantitative proteomics

• Published in: Glia 2023-04, Vol.71 (4), p.880-903
• Main Authors: Doust, Yasmine V., Bindoff, Aidan, Holloway, Olivia G., Wilson, Richard, King, Anna E., Ziebell, Jenna M.
• Format: Article
• Language: English
• Subjects: Animals; biological sex; Brain; Brain Injuries - metabolism; Brain Injuries, Diffuse - metabolism; Brain Injuries, Traumatic - metabolism; Clearances; Debris; Estrogens; Female; Females; Gender differences; Head injuries; Inflammation; Insulin; Male; Males; Mice; Mice, Inbred C57BL; Microglia; Microglia - metabolism; Percussion; Phagocytosis; Proteins; Proteome - metabolism; Proteomes; Proteomics; Reduction; Sex differences; TBI; Traumatic brain injury
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.24313

Traumatic brain injury (TBI) triggers neuroinflammatory cascades mediated by microglia, which promotes tissue repair in the short‐term. These cascades may exacerbate TBI‐induced tissue damage and symptoms in the months to years post‐injury. However, the progression of the microglial function across time post‐injury and whether this differs between biological sexes is not well understood. In this study, we examined the microglial proteome at 3‐, 7‐, or 28‐days after a midline fluid percussion injury (mFPI) in male and female mice using label‐free quantitative proteomics. Data are available via ProteomeXchange with identifier PXD033628. We identified a reduction in microglial proteins involved with clearance of neuronal debris via phagocytosis at 3‐ and 7‐days post‐injury. At 28 days post‐injury, pro‐inflammatory proteins were decreased and anti‐inflammatory proteins were increased in microglia. These results indicate a reduction in microglial clearance of neuronal debris in the days post‐injury with a shift to anti‐inflammatory function by 28 days following TBI. The changes in the microglial proteome that occurred across time post‐injury did not differ between biological sexes. However, we did identify an increase in microglial proteins related to pro‐inflammation and phagocytosis as well as insulin and estrogen signaling in males compared with female mice that occurred with or without a brain injury. Although the microglial response was similar between males and females up to 28 days following TBI, biological sex differences in the microglial proteome, regardless of TBI, has implications for the efficacy of treatment strategies targeting the microglial response post‐injury. Main Points Microglia undergo temporal changes in phagocytic and inflammatory proteins following diffuse TBI regardless of sex. Pro‐inflammatory, phagocytic, insulin, and estrogen signaling proteins were increased in male mice with or without TBI.