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Journal of neurotrauma · May 2021
Domino Effect of Interleukin-15 and CD8 T-Cell-Mediated Neuronal Apoptosis in Experimental Traumatic Brain Injury.
- Liang Wu, Ning-Ning Ji, Hang Wang, Jing-Yu Hua, Guo-Lin Sun, Pan-Pan Chen, Rong Hua, and Yong-Mei Zhang.
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China.
- J. Neurotrauma. 2021 May 15; 38 (10): 1450-1463.
AbstractThe effects of local factors on activation of immune cells infiltrating the central nervous system (CNS) in a rat model of traumatic brain injury (TBI) remain elusive. The cytokine, interleukin (IL)-15, is crucial for development and activation of CD8 T lymphocytes, a prominent lymphocytic population present in TBI lesions. We investigated whether IL-15 originates from astrocytes and whether IL-15 can evoke the CD8 T-lymphocyte response in TBI. We observed that astrocytes were activated in a rat model of TBI and that IL-15 was overexpressed on the surface of astrocytes. Further, CD8 T lymphocytes infiltrating TBI lesions colocalized with IL-15-expressing astrocytes. Activated CD8 T lymphocytes released granzyme B (Gra-b), which, in turn, activated caspase-3-induced poly(ADP-ribose) polymerase cleavage and, ultimately, neuronal apoptosis. Conversely, inhibition of astrocyte activation by pre-treatment with the specific inhibitor, fluorocitrate (FC), that reduces carbon flux through the Krebs cycle in astrocytes resulted in improved neurological function and memory. FC pre-treatment was also associated with downregulated IL-15 expression and CD8 T-cell activation as well as decreased levels of neuronal apoptosis, suggesting that IL-15 initiated a domino effect toward apoptosis. In contrast, rats pre-treated with recombinant rat IL-15 showed upregulated CD8 T-cell numbers and Gra-b levels, in addition to induction of neuronal apoptosis. Together, our results indicated that IL-15 could induce neuronal apoptosis by enhancing CD8 T-cell function in a rat model of TBI.
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