Immunoregulation by the sympathetic nervous system

Abstract

The neuroendocrine and autonomic nervous systems constitute efferent pathways through which the nervous system modulates peripheral immune responses. Regulation of glucocorticoid levels by the HPA axis is a primary component of the neural-immune regulatory system, whereas the role of the autonomic nervous system in the regulation of immune function is not fully elucidated. We have identified two paradigms, central inflammatory stimuli and stress, for which an immunosuppressive role of the sympathetic nervous system has been demonstrated. Since the spleen is exclusively innervated by sympathetic nerve fibers and is accessible for experimental manipulation, we have utilized this secondary immune organ as a model system for analyzing brain-immune interactions. Central injections of inflammatory stimuli (IL-1 or PGE2), as well as stress, produce an acute suppression of splenic macrophage function. Although the HPA axis and the sympathetic nervous system are jointly activated by these treatments, we have shown that the acute suppression of splenic macrophage function by central inflammatory stimuli and stress are still observed in adrenalectomized animals. Abrogation of this adrenal-independent immunosuppression in splenic immune function by surgically cutting the sympathetic nerve fibers innervating the spleen illustrates that the sympathetic nervous system constitutes an important pathway for the neural regulation of peripheral immune function. Although both stress and immune stimuli activate the same efferent system, they access this regulatory system via different neural pathways. The paraventricular nucleus (PVN) is proposed as an essential component of this regulatory network and a nodal region for the ingegration and regulation of both neuroendocrine and autonomic responses. Brain stem knife cuts or posterolateral deafferentation of the PVN indicate that activation of the PVN by immune stimuli are primarily, if not exclusively, mediated by ascending brain stem afferents to the PVN. stimuli are primarily, if not exclusively, mediated by ascending brain stem afferents to the PVN. These same brain stem knife cuts have a minimal effect on the activation of the PVN by stress and loss of posterior and lateral connections of the PVN only partially attenuates the activation of the PVN by stress. These results indicate that, in contrast to immune related, stimuli, rostral inputs to the PVN mediate a major portion of the activational effects of stress on the PVN. Thus, the HPA axis and the sympathetic nervous system are the two primary output pathways utilized by the neural-immune regulatory system to regulate peripheral immune responses.