Abstract
The consequences of systemic inflammation are a significant burden after traumatic brain injury (TBI), with almost all organs affected. This response consists of inflammation and concurrent immunosuppression after injury. One of the main immune regulatory organs, the spleen, is highly interactive with the brain. Along this brain–spleen axis, both nerve fibers as well as brain-derived circulating mediators have been shown to interact directly with splenic immune cells. One of the most significant comorbidities in TBI is acute ethanol intoxication (EI), with almost 40% of patients showing a positive blood alcohol level (BAL) upon injury. EI by itself has been shown to reduce proinflammatory mediators dose-dependently and enhance anti-inflammatory mediators in the spleen. However, how the splenic immune modulatory effect reacts to EI in TBI remains unclear. Therefore, we investigated early splenic immune responses after TBI with and without EI, using gene expression screening of cytokines and chemokines and fluorescence staining of thin spleen sections to investigate cellular mechanisms in immune cells. We found a strong FLT3/FLT3L induction 3 h after TBI, which was enhanced by EI. The FLT3L induction resulted in phosphorylation of FLT3 in CD11c+ dendritic cells, which enhanced protein synthesis, maturation process, and the immunity of dendritic cells, shown by pS6, peIF2A, MHC-II, LAMP1, and CD68 by immunostaining and TNF-α expression by in-situ hybridization. In conclusion, these data indicate that TBI induces a fast maturation and immunity of dendritic cells which is associated with FLT3/FLT3L signaling and which is enhanced by EI prior to TBI.
Highlights
Brain injury results in a systemic increase of inflammatory mediators and cytokines in both patients [7–9] and rodent models of traumatic brain injury (TBI) [10–12], there remains ample evidence pointing toward systemic immunosuppression post-TBI, with a decrease in immune cells in the periphery [13–18]
We set out to verify if any rapid modification in the splenic immune responses would take place upon mild/moderate TBI and, most importantly, if the comorbidity of ethanol intoxication (EI) would significantly interact with such responses
Ethanol intoxication before TBI resulted in a significant further enhancement of the expression of FLT3L (ST vs. ET; 163 ± 44 vs. 233 ± 56; p = 0.026; Figure 1I) and CX3CL1 (ST vs. ET; 98 ± 25 vs. 168 ± 53; p = 0.006; Figure 1K), whereas FLT3 and CX3CR1 were unaltered in ET compared with ST (FLT3: ST vs. ET, 239 ± 119 vs. 266 ± 124, p = 0.93, Figure 1J; CX3CR1: ST vs. ET, 134 ± 18 vs. 146 ± 34, p = 0.52, Figure 1L)
Summary
Traumatic injury to the brain has acute, large-scale systemic consequences [1] that affect almost all organs and may lead to a compromised function of the heart, lung, gastrointestinal tract, liver, kidney, bones, lymphoid organs, and others, without direct systemic injury or infection [2, 3]. Brain injury results in a systemic increase of inflammatory mediators and cytokines in both patients [7–9] and rodent models of TBI [10–12], there remains ample evidence pointing toward systemic immunosuppression post-TBI, with a decrease in immune cells in the periphery [13–18]. Prior investigation of the brain–spleen axis has revealed the interaction and regulation of splenic responses initiated by the central nervous system by either circulating mediators whose receptors are located on APCs [20] or by autonomic nerve fibers associated with splenic immune cells [21]. Vagus nerve stimulation can reduce macrophage-induced TNF alpha release in the spleen through a so-called cholinergic anti-inflammatory pathway [23].
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