Stress-Immune Communication
Stress broadly refers to the disruption of homeostatic balance by a stressor. There are many different types of stressors (e.g. physical, psychological, immunological, etc.) that can result in a stress response. This stress response is characterized by activation of the hypothalamic-pituitary-adrenal (HPA) axis. The neural and non-neural components of the HPA axis has many regulatory controls to ensure that the reactivity is appropriate for stressful as well as non-stressful stimuli such as sexual experience, appetite, or even light.
Allostasis is the process by which homeostasis is maintained through change. Allostasis is accomplished through coordinated activation and regulation of the HPA-axis, which releases stress hormones when activated. Clinical data indicate endocrine dysfunction in all HPA-axes following TBI. These clinical studies demonstrate that TBI induces baseline changes in neuroendocrine function but do not provide insight to whether or not these changes influence post-injury response to and recovery from stressful stimuli, i.e. allostasis.
Post-TBI HPA axis dysfunction leads to inappropriate responses to stress, which in turn can dysregulate inflammation. Both processes have been implicated in the development of psychiatric disorders after TBI; however, the cross-talk between stress-immune pathways after brain injury remains underexplored in both experimental and clinical studies. Long-term effects of TBI-induced HPA axis dysfunction on inflammation are currently unknown, but evidence suggests that the stress-immune axis breakdown after injury could contribute to the development or worsening of psychiatric disorders and altered behavioral responses. Application of stress models after experimental TBI could better elucidate a mechanism by which post-injury inflammation can both modulate and be modulated by HPA axis dysfunction. Studying the breakdowns in bi-directional communication between the immune and stress axes could identify target mechanisms or molecules for clinical intervention in the treatment of TBI.
Allostasis is the process by which homeostasis is maintained through change. Allostasis is accomplished through coordinated activation and regulation of the HPA-axis, which releases stress hormones when activated. Clinical data indicate endocrine dysfunction in all HPA-axes following TBI. These clinical studies demonstrate that TBI induces baseline changes in neuroendocrine function but do not provide insight to whether or not these changes influence post-injury response to and recovery from stressful stimuli, i.e. allostasis.
Post-TBI HPA axis dysfunction leads to inappropriate responses to stress, which in turn can dysregulate inflammation. Both processes have been implicated in the development of psychiatric disorders after TBI; however, the cross-talk between stress-immune pathways after brain injury remains underexplored in both experimental and clinical studies. Long-term effects of TBI-induced HPA axis dysfunction on inflammation are currently unknown, but evidence suggests that the stress-immune axis breakdown after injury could contribute to the development or worsening of psychiatric disorders and altered behavioral responses. Application of stress models after experimental TBI could better elucidate a mechanism by which post-injury inflammation can both modulate and be modulated by HPA axis dysfunction. Studying the breakdowns in bi-directional communication between the immune and stress axes could identify target mechanisms or molecules for clinical intervention in the treatment of TBI.
A Titled Axis: Maladaptive Inflammation and HPA Axis Dysfunction Contribute to Consequences of TBI
Tapp, Godbout, & Kokiko-Cochran, 2019
Frontiers in Neurology, 10:345
Hypothalamic-pituitary-adrenal axis before and after TBI. (A) In response to stressors, excitatory neuronal inputs activate the HPA axis and are transformed into hormonal communication, represented by solid black lines, to produce a physiological stress response. Activation via excitatory neuronal inputs to the hypothalamic PVN releases CRH and AVP via the median eminence into hypothalamic hypophyseal portal circuitry to the anterior pituitary. CRH induces corticotropes in the anterior pituitary to stimulate production of ACTH. ACTH is released into the blood and travels to the adrenal glands, superior to the kidneys. In the adrenal glands, ACTH initiates synthesis of CORT. CORT is then released into the blood to act on multiple tissues such as the lungs, heart, and muscles to induce a stress response. Represented by dashed red lines, CORT acts through GR-mediated feedback at every level to negatively regulate HPA activation and reduce CORT production. (B) TBI, represented as a lightning bolt, induces hypopituitarism and results in suppressed HPA activation in response to a stressor, represented by dotted black lines. Hypopituitarism indicates decreased production of ACTH, thus there is decreased stimulation of the adrenal glands and less CORT production. Suppressed CORT levels cannot inhibit continued HPA activation through GR-mediated negative feedback, as depicted by dashed red lines, resulting in impaired GR-mediated negative feedback and perpetuation of the stress response that leads to longer recovery time after exposure to a stressor. Decreased CORT is associated with increased inflammation which could contribute to psychiatric sequelae, thus injury-induced suppression of the HPA axis depicts a mechanism through which post-TBI consequences may occur. Sagittal brain schematic: Patrick J. Lynch, medical illustrator [CC BY 2.5 (https://creativecommons.org/licenses/by/2.5)].