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Salud mental

versão impressa ISSN 0185-3325


HERNANDEZ, María Eugenia; BECERRIL, Luis; ALVAREZ, Liseth  e  PAVON-ROMERO, Lenin. Vías de neuroinmunomodulación. Primera parte. Salud Ment [online]. 2007, vol.30, n.6, pp.13-19. ISSN 0185-3325.

Inflammation is a normal response caused by physical stress like infection, injury and trauma; and processive or psychological stress like in psychiatric diseases such as major depression, schizophrenia and posttraumatic stress. The host responds with a complex series of immune, endocrine and nervous reactions to face the stressful stimuli named neuroendocrine immune interaction.

These interactions help us to maintain the homeostasis under stressful stimuli. Stress is a physicochemical or emotional process that induces tension. This process promotes the release of proinflammatory cytokines, hormones such as the corticotrophin-release hormone (CRH) and cortisol, and a wide number of neurotransmitters that are together responsible for some behavioral alterations. Both systemic and psychological stress elicits an equivalent response in an organism.

Particularly, the onset of inflammation is characterized by release of pro-inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-1, adhesion molecules, vasoactive mediators, and reactive oxygen species. The early release of pro-inflammatory cytokines by a widely variety of immune and no-immune cells has a pivotal role in triggering the local inflammatory response. Apart from their involvement in local inflammation, TNF-α and IL-1β are signal molecules for activation of brain derived neuroendocrine and immunomodulatory responses. Excessive production of cytokines, such as TNF-α and IL-1β however can be more injurious than the inciting event, initiating diffuse coagulation, tissue injury, hypotension, and death.

The inflammatory response is balanced by anti-inflammatory molecules like the cytokines IL-10 and IL-4, soluble TNF receptors, IL-1 receptor antagonists, and transforming growth factor (TGF)-β. Neuroendocrine pathways, such as the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic division of the Autonomic Nervous System (SNS) control the inflammation process by triggering anti-inflammatory balancing mechanisms.

The brain can monitor immune status and sense peripheral inflammation through two main pathways: neural and humoral. The neural mechanism relies upon activation of vagus nerve afferent sensory fibers that signal the brain that inflammation is occurring. Stressful stimuli activate vagal afferents either directly by cytokines released from dendritic cells, macrophages, and other vagal-associated immune cells, or indirectly through the chemoreceptive cells located in vagal paraganglia. The transmission of cytokine signals to the brain through the vagal sensory neurons depends upon the magnitude of the stressful challenge. Subdiaphragmatic vagotomy inhibits the stimulation of the HPA axis and noradrenaline (NA) release in hypothalamic nuclei in response to intraperitoneal administration of endotoxin or IL-1β. Intravenous endotoxin administration induces expression of the neural activation marker c-Fos in the brainstem medulla, regardless of the integrity of the vagus nerve. Vagotomy fails to suppress high dose endotoxininduced.

IL-1β immunoreactivity in the brain and increases blood corticosterone levels. It is likely that the vagal afferent neural pathway plays a dominant role in mild to moderate peripheral inflammatory responses, whereas acute, robust inflammatory responses signal the brain primarily via humoral mechanisms. By other hand, humoral pathway are supported by a large body of evidence, especially in cases of systemic immune challenge; circulatory cytokines like IL-1 β and TNF-α can cross the blood-brain barrier and enter cerebrospinal fluid and the interstitial fluid spaces of the brain and spinal cord by a saturable carrier mediated mechanism that may function only at very high plasma cytokine concentrations.

Cytokines also can bind to receptors at the surface of the endothelium of the brain capillaries and can enhance the synthesis and release of soluble mediators such as prostaglandins and nitric oxide, which diffuse into the brain parenchyma and modulate the activity of specific groups of neurons. It has been suggested that prostaglandins mediate fever and HPA axis activation.

Cytokine-to-brain communication also may occur via circumventricular organs that lack normal blood-brain barrier function. Among the circumventricular organs, the AP (area postrema) appears to represent the best candidate for such a transduction site. The AP is located in the floor of the caudal fourth ventricle and dendrites of neurons in the NTS (nucleus tractus solitarius) and DMN (dorsal motor nucleus) penetrate both the AP and floor of the fourth ventricle. The close proximity of AP to NTS and RVM (rostral ventrolateral medulla) and the existing neural connections provide a way of signaling the SNS and HPA axis. Cytokine-induced production of prostaglandins within the AP, NTS, and RVM may activate the catecholamine projections to the PVN, resulting in subsequent HPA axis activation. This is one possible interaction between the neural and humoral mechanisms of immune to brain communication through which the brain mediates anti-inflammatory responses.

Apart from their function in signaling the brain for immunomodulatory responses, cytokines play a multifunctional role in brain injury and neurodegenerative diseases.

Restoration of homeostasis as a logical resolution of inflammation does not always occur. For instance, a lack of adequate inflammatory responses may result in increased susceptibility to infections or cancer. On the other hand, excessive responses are associated with autoimmune diseases, diabetes, sepsis, psychiatric diseases with an important inflammatory response like major depression or schizophrenia and other debilitating conditions.

When control of local inflammatory responses is lost, pro-inflammatory mediators can spill into the circulation, resulting in systemic inflammation that may progress to shock, multiple organ failure, and death.

A recent discovery, showed that a novel neuroimmunomodulatory pathway that interface the brain and the immune system, referred as to the autonomic cholinergic anti-inflammatory pathway, mediate inhibitory responses during inflammation possibly by recruiting central mechanisms that modulate systemic or peripheral inflammatory responses. Still unclear, this neural circuit has been implicated in promoting sort of psychotherapeutical activities such as hypnosis, meditation, prayer, biofeedback, including acupuncture, but this mechanims still remain elusive.

The sympathetic and parasympathetic parts of the Autonomic Nervous System rarely operate alone; autonomic responses represent the interplay of both parts. A link between the parasympathetic part of the Autonomic Nervous System and immunoregulatory processes was suggested, when alleviation of T-lymphocyte cytotoxicity by muscarinic cholinergic stimulation was described.

Communication between the immune, nervous, and endocrine systems is essential for host defense and involves a variety of mediators including cytokines, neurotransmitters, hormones, and humoral factors. The influence of the brain on immune function and the mechanisms involved in these interactions have been elucidated over the past 3 decades, however, two important questions arise when describing the brain-derived immunomodulation: How is the specific brain initially signaled by cytokines to trigger corresponding neural and neuroendocrine responses?; and: How is immunomodulation achieved through these mechanisms? This review outlines brain-related control mechanisms of immune function in the regulation of inflammation.

Palavras-chave : Neuroimmunomodulation; sympathetic nerve; vagus nerve; cytokines and neurotransmitters.

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