Old age increases microglial senescence, exacerbates secondary neuroinflammation, and worsens neurological outcomes after acute traumatic brain injury in mice

Abstract

Following traumatic brain injury (TBI), individuals over 65 years of age show increased mortality and worse functional outcomes compared to younger persons. As neuroinflammation is a key pathobiological mechanism of secondary injury after TBI, we examined how aging affects posttraumatic microglial responses and functional outcomes. Young (12-week-old) and aged (18month-old) male C57Bl/6 mice were subjected to moderate-level controlled cortical impact (CCI) or sham surgery and neurological function was evaluated. At 72 hours post-injury, brain, blood, and spleen leukocyte counts were assessed ex vivo using flow cytometry. Aged mice demonstrated more severe deficits in forelimb grip strength, balance and motor coordination, spontaneous locomotor activity, and anxiety-like behavior. These animals also exhibited more robust microglial proliferation and significantly higher numbers of brain-infiltrating leukocytes. Microglia in aged mice showed impairments in phagocytic activity and higher production of interleukin-1β (IL-1β). Infiltrating myeloid cells in aged TBI mice also had deficits in phagocytosis, but showed diminished pro-inflammatory cytokine production and greater reactive oxygen species production. Expression of several senescence markers (Bcl-2, p16 ink4a , p21 cip1a , lipofuscin, and H2AX (pS139)) was increased with age and/or TBI in both microglia and injured cortex. Although there was no difference in the number of circulating blood neutrophils as a function of age, young mice exhibited more pronounced TBI-induced splenomegaly and splenic myeloid cell expansion. Thus,

Systemic treatment with human amnion epithelial cells after experimental traumatic brain injury

“…As expected, our results indicated that the ipsilateral hemisphere of TBI mice contained significantly increased total leukocytes, myeloid cells, T cells, neutrophils and monocytes when compared to sham-operated mice at 48 h post-injury. These findings add to the growing literature suggesting a significant infiltration of immune cells during the acute stages of TBI [30,[34][35][36][37]. However, treatment with hAECs was not sufficient to prevent such infiltration.…”

“…The finding that CCI increased splenic mass at 48 h post-injury adds to the growing pre-clinical literature that this model of TBI results in acute splenomegaly [34,39]. Notably, this finding is in contrast to that seen in ischemic stroke, where splenic atrophy and loss of splenocytes is commonly reported [40].…”

Microglial Depletion with CSF1R Inhibitor During Chronic Phase of Experimental Traumatic Brain Injury Reduces Neurodegeneration and Neurological Deficits

“…The entirety of each sample was acquired on medium flow rate until zero events were obtained, providing absolute cell counts for each hemisphere. Resident microglia were identified as the CD11b ϩ Ly6C Ϫ CD45 int population (Ritzel et al, 2019), whereas peripherally derived immune cells were identified as CD45 hi as described previously (Ritzel et al, 2018). Tissue and cell type matched fluorescence minus one (FMO) controls were used to determine the gating for each antibody.…”

Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

“…TBI is an especially serious condition in the elderly and in individuals sustaining repetitive brain injuries [37][38][39][40][41][42][43][44][45]. For instance, similar injuries result in more severe pathology and neurological impairment in the elderly than in other age groups [37,46].…”