Aging is associated to maladaptive immune response and worse outcome after traumatic brain injury

Abstract

Traumatic brain injury is increasingly common in older individuals. Older age is one of the strongest predictors for poor prognosis after brain trauma, a phenomenon driven by the presence of extra-cranial comorbidities as well as pre-existent pathologies associated with cognitive impairment and brain volume loss (such as cerebrovascular disease or age-related neurodegeneration). Furthermore, ageing is associated with a dysregulated immune response, which includes attenuated responses to infection and vaccination, and a failure to resolve inflammation leading to chronic inflammatory states. In traumatic brain injury, where the immune response is imperative for the clearance of cellular debris and survey of the injured milieu, an appropriate self-limiting response is vital to promote recovery. Currently, our understanding of age-related factors that contribute to the outcome is limited; but a more complete understanding is essential for the development of tailored therapeutic strategies to mitigate the consequences of traumatic brain injury. Here we show greater functional deficits, white matter abnormalities and worse long-term outcomes in aged compared with young C57BL/6J mice after either moderate or severe traumatic brain injury. These effects are associated with altered systemic, meningeal and brain tissue immune response. Importantly, the impaired acute systemic immune response in the mice was similar to the findings observed in our clinical cohort. Traumatic brain-injured patient cohort over 70 years of age showed lower monocyte and lymphocyte counts compared with those under 45 years. In mice, traumatic brain injury was associated with alterations in peripheral immune subsets, which differed in aged compared with adult mice. There was a significant increase in transcription of immune and inflammatory genes in the meninges post-traumatic brain injury, including monocyte/leucocyte-recruiting chemokines. Immune cells were recruited to the region of the dural injury, with a significantly higher number of CD11b+ myeloid cells in aged compared with the adult mice. In brain tissue, when compared with the young adult mice, we observed a more pronounced and widespread reactive astrogliosis 1 month after trauma in aged mice, sustained by an early and persistent induction of proinflammatory astrocytic state. These findings provide important insights regarding age-related exacerbation of neurological damage after brain trauma.

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ORCID for Emma J. Norton: orcid.org/0000-0003-1877-2474

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