Abstract
BackgroundAcute traumatic brain injury (TBI) represents one of major causes of mortality and disability in the USA. Neuroinflammation has been regarded both beneficial and detrimental, probably in a time-dependent fashion.MethodsTo address a role for neuroinflammation in brain injury, C57BL/6 mice were subjected to a closed head mild TBI (mTBI) by a standard controlled cortical impact, along with or without treatment of sphingosine 1-phosphate (S1P) or rolipram, after which the brain tissue of the impact site was evaluated for cell morphology via histology, inflammation by qRT-PCR and T cell staining, and cell death with Caspase-3 and TUNEL staining. Circulating lymphocytes were quantified by flow cytometry, and plasma hydrocortisone was analyzed by LC-MS/MS. To investigate the mechanism whereby cortisol lowered the number of peripheral T cells, T cell egress was tracked in lymph nodes by intravital confocal microscopy after hydrocortisone administration.ResultsWe detected a decreased number of circulating lymphocytes, in particular, T cells soon after mTBI, which was inversely correlated with a transient and robust increase of plasma cortisol. The transient lymphocytopenia might be caused by cortisol in part via a blockade of lymphocyte egress as demonstrated by the ability of cortisol to inhibit T cell egress from the secondary lymphoid tissues. Moreover, exogenous hydrocortisone severely suppressed periphery lymphocytes in uninjured mice, whereas administering an egress-promoting agent S1P normalized circulating T cells in mTBI mice and increased T cells in the injured brain. Likewise, rolipram, a cAMP phosphodiesterase inhibitor, was also able to elevate cAMP levels in T cells in the presence of hydrocortisone in vitro and abrogate the action of cortisol in mTBI mice. The investigation demonstrated that the number of circulating T cells in the early phase of TBI was positively correlated with T cell infiltration and inflammatory responses as well as cell death at the cerebral cortex and hippocampus beneath the impact site.ConclusionsDecreases in intracellular cAMP might be part of the mechanism behind cortisol-mediated blockade of T cell egress. The study argues strongly for a protective role of cortisol-induced immune suppression in the early stage of TBI.
Highlights
Acute traumatic brain injury (TBI) represents one of major causes of mortality and disability in the USA
Elevation of cortisol but reduction of circulating lymphocytes following TBI Our previous study showed that introduction of inflammation worsened secondary brain damage following mild TBI (mTBI) [7]
The mTBI was created by a gentle hit of the brain with an intact skull and scalp by a standard controlled impact, which resulted in extensive cell death at the impact site and significant neurologic severity score (NSS) ranging from 3 to 5 [7]
Summary
Acute traumatic brain injury (TBI) represents one of major causes of mortality and disability in the USA. Acute traumatic brain injury (TBI) is a major cause of mortality and disability in the early decades of life in many developed countries. Tremendous efforts have been made in the past decades toward exploring the cellular and molecular mechanisms underlying secondary brain damage as well as identification of specific targets for prevention and/or therapeutics against this disorder [2]. It is believed that a cascade of molecular, neurochemical, neuronal cell apoptosis, cellular, and immune processes contribute to secondary brain damage as a consequence of mitochondrial dysfunction, cerebral hypoxia, and disruption of calcium homeostasis in cells at the impact site [2, 3]
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