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Domino Effect of Interleukin-15 and CD8 T-Cell–Mediated Neuronal Apoptosis in Experimental Traumatic Brain Injury
- Source :
- Journal of Neurotrauma. 38:1450-1463
- Publication Year :
- 2021
- Publisher :
- Mary Ann Liebert Inc, 2021.
-
Abstract
- The 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.
- Subjects :
- Male
030506 rehabilitation
Traumatic brain injury
medicine.medical_treatment
Central nervous system
Apoptosis
CD8-Positive T-Lymphocytes
03 medical and health sciences
0302 clinical medicine
Immune system
Brain Injuries, Traumatic
medicine
Animals
Cytotoxic T cell
Rats, Wistar
Interleukin-15
Neurons
business.industry
Interleukin
medicine.disease
Rats
Disease Models, Animal
medicine.anatomical_structure
Cytokine
Interleukin 15
Cancer research
Neurology (clinical)
0305 other medical science
business
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15579042 and 08977151
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Journal of Neurotrauma
- Accession number :
- edsair.doi.dedup.....a4f3373784387e27a2179b90f1c61c50