Biochemical and Biophysical Research Communications
CD8 T cell-derived perforin aggravates secondary spinal cord injury through destroying the blood-spinal cord barrier
Graphical abstract
Introduction
Spinal cord injury (SCI) causes primary vascular damage and initiates a cascade of events that alters blood-spinal cord barrier (BSCB) permeability [1]. However, little attention has been directed at how BSCB integrity affects post-SCI regeneration processes. Interestingly, after disrupting tight junction (TJ) proteins, perforin can increase BSCB permeability [2], promote inflammatory cytokine entry from peripheral blood to the injury site, as well as aggravate secondary inflammation at and around the injury site in viral infections and autoimmune diseases [3,4]. As previously reported, perforin is primarily secreted by CD8 cytotoxic T cell [5]. In peripheral blood and the central nervous system (CNS), CD8 T cell-derived perforin participates in a series of inflammatory and immune responses [6]. Overly strong action from CD8 T cells can cause lethal inflammation, and removing them specifically reduces the chances of mice dying from an immune response [7,8]. Nevertheless, it is unknown whether perforin functions similarly during acute trauma to the spinal cord.
This study firstly reveals that CD8 T cell-derived perforin destroys BSCB post-SCI, thus recruiting inflammatory cytokines to the injury site and aggravating secondary SCI. The data presented here expand on the well known functions of CD8T cells and the current realization that these lymphocytes contribute to injuries thought to only trigger an innate immune response.
Section snippets
Animals
C57BL/6J, CD8 T knockout(CD8T−/−), and Prf−/− mice were purchased from Jackson Laboratory and propagated by the experimental animal center of Jinan University Medical College. All mice aged 7–8 weeks weighed 17–22 g during surgery. The center was not pathogen-controlled. All procedures were approved and implemented by the Commission for Animal Protection and Use of Jinan University.
Contusive SCI model
An experimental model of acute SCI was established using the New York University spinal cord hitter [9]. Mice were
CD8-derived perforin harms recovery of spinal cord function
More CD8 T cells and perforin appeared in the injured sites after SCI than in the sham operation group (Fig. S1). At 3 d post-SCI, BMS continued to rise before peaking in Week 6 post-SCI (Fig. 1 A), while we did not find differences in BMS of WT and Prf1−/− mice without SCI (Fig. S2). Furthermore, compared with WT mice, regularity index, stride length, and cadence in Prf1−/− mice increased significantly in CatWalk-assisted gait analysis at 6 wk post-SCI (Fig. 1B–D). Meanwhile, Electromyography
Discussion
Inflammatory disruptions are more pronounced in CNS than other tissues, because neurons and gliocytes have limited regenerative capacity, leading to irreversible dysfunction after injury [29]. Therefore, controlling targeted inflammation is a valuable method to promote post-SCI functional recovery [30].
Perforin is a good candidate for targeted therapy because the protein is involved in numerous inflammatory responses [31,32], including the CD8 T cell apoptosis pathway [33]. Indeed, here we
Acknowledgements
This work was supported by the Natural Science Foundation of Guangdong Province (2018A030313576), and the Natural Science Foundation of Guangzhou city (201803010001), China. Key Program of Traditional Chinese Medicine of Guangdong Province (20173018), China.
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