A Tilted Axis: Maladaptive Inflammation and HPA Axis Dysfunction Contribute to Consequences of TBI

Abstract

Each year approximately 1.7 million people sustain a traumatic brain injury (TBI) in the US alone. Associated with these head injuries is a high prevalence of neuropsychiatric symptoms including irritability, depression, and anxiety. Neuroinflammation, due in part to microglia, can worsen or even cause neuropsychiatric disorders after TBI. For example, mounting evidence demonstrates that microglia become “primed” or hyper-reactive with an exaggerated pro-inflammatory phenotype following multiple immune challenges. Microglial priming occurs after experimental TBI and correlates with the emergence of depressive-like behavior as well as cognitive dysfunction. Critically, immune challenges are various and include illness, aging, and stress. The collective influence of any combination of these immune challenges shapes the neuroimmune environment and the response to TBI. For example, stress reliably induces inflammation and could therefore be a gateway to altered neuropathology and behavioral decline following TBI. Given the increasing incidence of stress-related psychiatric disorders after TBI, the degree in which stress affects outcome is of particular interest. This review aims to highlight the role of the hypothalamic-pituitary-adrenal (HPA) axis as a key mediator of stress-immune pathway communication following TBI. We will first describe maladaptive neuroinflammation after TBI and how stress contributes to inflammation through both anti- and pro-inflammatory mechanisms. Clinical and experimental data describing HPA-axis dysfunction and consequences of altered stress responses after TBI will be discussed. Lastly, we will review common stress models used after TBI that could better elucidate the relationship between HPA axis dysfunction and maladaptive inflammation following TBI. Together, the studies described in this review suggest that HPA axis dysfunction after brain injury is prevalent and contributes to the dynamic nature of the neuroinflammatory response to brain injury. Experimental stressors that directly engage the HPA axis represent important areas for future research to better define the role of stress-immune pathways in mediating outcome following TBI.

Opposite regulation of piRNAs, rRNAs and miRNAs in the blood after subarachnoid hemorrhage

“…In an ischemic stroke model, Courties et al demonstrated that activation of HPAA with high systemic levels of GCs affected lymphopoiesis by inducing GR-dependent apoptosis in thymic T cells and in B-cell progenitors [34]. Similar effects of traumatic brain injury on T cells were reported [35]. Our results suggest that GR may also play a regulatory role by interacting with some sRNAs.…”

Sex-Dependent Pathology in the HPA Axis at a Sub-acute Period After Experimental Traumatic Brain Injury

“…Activated microglia can play a role in regulation of cytokines, synaptic reorganization, neuron morphology and survival, and glial scarring (110). We previously reported that neuropathology was not apparent at 7 DPI in males (42), indicating that this response is likely mediated by the TBI-induced activation of the HPA axis as reported after stress paradigms (75). Previous publications indicate that activation of microglia in the PVN can be associated with excitation of the sympathetic nervous system and hypertension (111,112).…”

“…Morphological markers of microglial activation include decreased number of endpoints and shorter branch length and occur alongside the increase in cell numbers, both of which are indicators of a neuroinflammatory response (64,72). There is clinical evidence that microglia can remain activated at least 17 years after TBI (73), where they are capable of instigating processes that can influence the HPA axis (74,75). ; p = 0.002], with 7 DPI males losing more weight than their sex-matched sham controls (p = 0.0003; male 7 DPI n = 10; female 7 DPI n = 11).…”

Cosyntropin Attenuates Neuroinflammation in a Mouse Model of Traumatic Brain Injury

“…In contrast to GCs, ACTH 1–24 increases glucose uptake in neurons through stimulation of transport protein synthesis, and MC4R-agonists increase BDNF in vitro , suggesting melanocortin receptor signaling may counteract deleterious effects of GC signaling (Daval et al, 1985 ; Saba et al, 2019 ). The delicate balance between CRF, ACTH, and GCs in the maintenance of homeostasis and response to stress is vital for normal functioning and is disrupted following TBI (Tapp et al, 2019 ). Additional research is needed to evaluate the effect of synthetic ACTH as a post-TBI therapeutic specifically addressing if its effects are dependent on its GC-inducing capacity or extend beyond this mechanism of action, potentially counteracting the side effects of supraphysiological or prolonged GC activation.…”