Identification of an immune-responsive mesolimbocortical serotonergic system: potential role in regulation of emotional behavior.

Peripheral immune activation can have profound physiological and behavioral effects including induction of fever and sickness behavior. One mechanism through which immune activation or immunomodulation may affect physiology and behavior is via actions on brainstem neuromodulatory systems, such as serotonergic systems. We have found that peripheral immune activation with antigens derived from the nonpathogenic, saprophytic bacterium, Mycobacterium vaccae, activated a specific subset of serotonergic neurons in the interfascicular part of the dorsal raphe nucleus (DRI) of mice, as measured by quantification of c-Fos expression following intratracheal (12 h) or s.c. (6 h) administration of heat-killed, ultrasonically disrupted M. vaccae, or heat-killed, intact M. vaccae, respectively. These effects were apparent after immune activation by M. vaccae or its components but not by ovalbumin, which induces a qualitatively different immune response. The effects of immune activation were associated with increases in serotonin metabolism within the ventromedial prefrontal cortex, consistent with an effect of immune activation on mesolimbocortical serotonergic systems. The effects of M. vaccae administration on serotonergic systems were temporally associated with reductions in immobility in the forced swim test, consistent with the hypothesis that the stimulation of mesolimbocortical serotonergic systems by peripheral immune activation alters stress-related emotional behavior. These findings suggest that the immune-responsive subpopulation of serotonergic neurons in the DRI is likely to play an important role in the neural mechanisms underlying regulation of the physiological and pathophysiological responses to both acute and chronic immune activation, including regulation of mood during health and disease states. Together with previous studies, these findings also raise the possibility that immune stimulation activates a functionally and anatomically distinct subset of serotonergic neurons, different from the subset of serotonergic neurons activated by anxiogenic stimuli or uncontrollable stressors. Consequently, selective activation of specific subsets of serotonergic neurons may have distinct behavioral outcomes.

Intragastric administration of Mycobacterium vaccae inhibits severe pulmonary allergic inflammation in a mouse model.

BACKGROUND: Coexistence with harmless microorganisms such as lactobacilli, saprophytic mycobacteria and some helminths, throughout evolution, may have shaped the host immune system. Exposure to such organisms may have therapeutic benefits by triggering immunoregulatory mechanisms that control inappropriate immune responses to self, gut contents or allergens. OBJECTIVE: We determined whether treatment with Mycobacterium vaccae by gavage influences the host immune response both locally and systemically. We also investigated whether delivery by this route prevents severe symptoms of disease in a murine model of pulmonary allergic inflammation. RESULTS: A single intragastric administration of M. vaccae induced a transient increase in the production of IL-10 and IFN-gamma by mesenteric lymph nodes cells and splenocytes. In addition, in a mouse model of pulmonary allergic inflammation, a single treatment with M. vaccae by gavage not only diminished the total cellular infiltrate and the eosinophilic component induced by subsequent intratracheal allergen challenge, but also biased local and systemic cytokine production towards IL-10. Delivery of M. vaccae by gavage was as effective as subcutaneous treatment. CONCLUSION: This is the first report to suggest that heat-killed mycobacteria can down-regulate symptoms of allergic inflammation by the intragastric route. These data suggest an alternative route of treatment with M. vaccae for patients with allergic conditions.