Acute Traumatic Brain Injury Induces CD4⁺ and CD8⁺ T Cell Functional Impairment by Upregulating the Expression of PD-1 via the Activated Sympathetic Nervous System

Abstract

Objective: Traumatic brain injury (TBI) induces immunosuppression in the acute phase, and the activation of the sympathetic nervous system (SNS) might play a role in this process, but the mechanism involved is unknown. Herein, we explored the impact of acute (a)TBI on the peripheral immune system and its correlation with the SNS and the T cell exhaustion marker, PD-1 (programmed cell death-1). Methods: Flow cytometry (FCM) was performed to analyze the expression of T cell markers and intracellular cytokines, interferon-γ and tumor necrosis factor-α, and the T cell exhaustion marker, PD-1, in the peripheral blood mononuclear cells (PBMCs) of TBI rats. Enzyme-linked immunosorbent assay (ELISA) was performed to analyze the concentration of norepinephrine (NE) in the serum. Propranolol was administrated to block the SNS in vivo and NE stimulation was used to imitate the activation of the SNS in vitro. Results: We found that the concentration of NE was significantly elevated after TBI, and the dysfunction of CD4⁺ and CD8⁺ T cells was reversed by the SNS blocker propranolol in vivo and imitated by the SNS neurotransmitter NE in vitro. The expression of PD-1 on CD4⁺ and CD8⁺ T cells was upregulated after aTBI, which was reversed by propranolol administration in vivo and imitated by NE stimulation in vitro. Furthermore, the PD-1 blocker reversed the dysfunction of CD4⁺ and CD8⁺T cells in vitro. Conclusion: Our findings demonstrated that aTBI activated the SNS, and further upregulated the expression of PD-1 on CD4⁺ and CD8⁺ T cells, which, in turn, impaired their function and contributed to immunosuppression.

Sepsis-associated encephalopathy: a vicious cycle of immunosuppression

“…Activation of β2-AR by NE triggers increased levels of cyclic AMP (cAMP) and activation of protein kinase A (PKA), which results in downregulation of proinflammatory cytokines by suppressing translocation of NF-κB [128]. Moreover, enhanced SNS activity is a major cause of the decreased ratio and antiinflammatory phenotype polarization of blood T cells through upregulating expression of cellular programmed cell death 1 (PD1) and promoting emigration and activation of Tregs in stroke [126,129]. Furthermore, these effects are established by increasing prostaglandin E 2 (PGE 2 ) levels and disrupting the stromal cell-derived factor-1 (SDF-1) axis after enhancing β-AR activation [126].…”

Metabolomics analysis of the hippocampus in a rat model of traumatic brain injury during the acute phase

“…Additionally, previous studies found that altered concentrations of metabolites in the hippocampus might be related to energy metabolism dysregulation and excitatory neurotransmission at later stages of traumatic injury by untargeted H-NMR metabolomics (McGuire et al, 2019;Viant, Lyeth, Miller, & Berman, 2005). Once TBI occurs, acute phase-based brain may suddenly experience concussion, contusion, bleeding, edema, inflammation, oxidative stress, and neurological dysfunction (Yang et al, 2019). Once TBI occurs, acute phase-based brain may suddenly experience concussion, contusion, bleeding, edema, inflammation, oxidative stress, and neurological dysfunction (Yang et al, 2019).…”

“…Traumatic brain injury is a severe cranial injury induced by sudden external force. Generally, we take 1-3 days after onset of TBI as time points to explore the effects of experimental acute TBI (Bentz et al, 2010;Yang et al, 2019;Zhang et al, 2014). Generally, we take 1-3 days after onset of TBI as time points to explore the effects of experimental acute TBI (Bentz et al, 2010;Yang et al, 2019;Zhang et al, 2014).…”

“…Traumatic brain injury is a severe cranial injury induced by sudden external force. Once TBI occurs, acute phase-based brain may suddenly experience concussion, contusion, bleeding, edema, inflammation, oxidative stress, and neurological dysfunction (Yang et al, 2019). Generally, we take 1-3 days after onset of TBI as time points to explore the effects of experimental acute TBI (Bentz et al, 2010;Yang et al, 2019;Zhang et al, 2014).…”

“…Once TBI occurs, acute phase-based brain may suddenly experience concussion, contusion, bleeding, edema, inflammation, oxidative stress, and neurological dysfunction (Yang et al, 2019). Generally, we take 1-3 days after onset of TBI as time points to explore the effects of experimental acute TBI (Bentz et al, 2010;Yang et al, 2019;Zhang et al, 2014). Even though some studies associated with brain metabolism in the hippocampus were established, only a few metabolic biomarkers were studied by a paucity of studies exploring the pathophysiology of its acute TBI.…”