Neurobiology of the stress response: contribution of the sympathetic nervous system to the neuroimmune axis in traumatic injury

Abstract

Acute injury produces an immediate activation of neuroendocrine mechanisms aimed at restoring hemodynamic and metabolic counter-regulatory responses. These counter-regulatory responses are mediated by the systemic and tissue-localized release of neuroendocrine-signaling molecules known to affect immune function. This has led to the recognition of the importance of neuroendocrine-immune modulation during acute injury as well as throughout the recovery period. The period immediately after acute injury is characterized by upregulation of proinflammatory cytokine expression leading to a later period of generalized immunosuppression. The course and progression of the host recovery from traumatic injury and the integrity of its response to a secondary challenge is directly related to the effective control of the immediate proinflammatory responses to the initial insult. Among the neuroendocrine mechanisms involved in restoring homeostasis, the sympathetic nervous system plays a central role in mediating acute counter-regulatory stress responses to injury. In addition to its recognized cardiovascular, hemodynamic, and metabolic effects, the neurotransmitters released by the sympathetic nervous system have been shown to affect immune function through specific adrenergic receptor-mediated pathways. In turn, cells of the immune system and their products have been shown to influence peripheral and central neurotransmission, leading to the conceptualization of a bidirectional neuroimmune communication system. The reflex activation of this bidirectional neuroimmune pathway in response to injury, integrated with the parasympathetic nervous system, and opioid and glucocorticoid pathways responsible for orchestrating the counterregulatory stress response, results in dynamic regulation of host defense mechanisms vital for immune competence and tissue repair. This review provides the biological framework for the integration of our understanding of the neuroendocrine mechanisms involved in mediating the stress response and their role in modulating immune function during and after traumatic injury.