Neuroimmune Interactions in Schizophrenia: Focus on Vagus Nerve Stimulation and Activation of the Alpha-7 Nicotinic Acetylcholine Receptor.

Schizophrenia is one of the most debilitating mental disorders and is aggravated by the lack of efficacious treatment. Although its etiology is unclear, epidemiological studies indicate that infection and inflammation during development induces behavioral, morphological, neurochemical, and cognitive impairments, increasing the risk of developing schizophrenia. The inflammatory hypothesis of schizophrenia is also supported by clinical studies demonstrating systemic inflammation and microglia activation in schizophrenic patients. Although elucidating the mechanism that induces this inflammatory profile remains a challenge, mounting evidence suggests that neuroimmune interactions may provide therapeutic advantages to control inflammation and hence schizophrenia. Recent studies have indicated that vagus nerve stimulation controls both peripheral and central inflammation via alpha-7 nicotinic acetylcholine receptor (α7nAChR). Other findings have indicated that vagal stimulation and α7nAChR-agonists can provide therapeutic advantages for neuropsychiatric disorders, such as depression and epilepsy. This review analyzes the latest results regarding: (I) the immune-to-brain pathogenesis of schizophrenia; (II) the regulation of inflammation by the autonomic nervous system in psychiatric disorders; and (III) the role of the vagus nerve and α7nAChR in schizophrenia.

Concanavalin-A induces IL-17 production during the course of Candida albicans infection.

In a previous study, our group verified that 100% of mice survived to a lethal dose of Candida albicans following pretreatment with concanavalin-A (Con-A) for 3 days. This work proposed to investigate whether treatment could mediate an adaptative immune response involving T(H) 17 cells. A significant increase in IL-17 levels at 6 h postinfection was observed and was maintained up to 18 h in the Con-A group, whereas in control mice, a reduction in this cytokine was verified. In addition, T(H) 17 cells develop in the presence of TGF-ß, IL-1 ß, and IL-6 that were increased significantly 2 h postinfection in Con-A-treated mice. Macrophages were involved in the process, engulfing greater numbers of yeast cells, and were activated through TNF-α and interferon-γ produced at significant levels at 2 h postinfection. A significant increase in IL-12 levels was also observed at 2 h postinfection. Thus, activated macrophages were probably more capable of killing and processing Candida antigens, signalizing an adaptative immune response. Macrophages from controls did not prevent yeast-to-hyphae transition and were partially destroyed, as shown in scanning microscopy. These results suggest that treatment with Con-A facilitated the triggering of T(H) 17 and T(H) 1 responses via IL-17 and IFN-γ production, leading to the resolution of C. albicans infection.

Artin M enhances TNF-α production and phagocytosis of Candida albicans mediated by dectin-1 and mannose receptors.

The activities of dectin-1 and mannose receptors on phagocytosis of Candida albicans and the production of TNF-α by macrophages from mice pretreated for 3 days with extract of Artocarpus intergrifolia seeds (jack extract), Artin M or jacalin were studied. Macrophages from these mice were coincubated with C. albicans CR15 (yeast), in the presence of mannose (50mM) plus mannan (100 µg) or laminarin (1mg). Phagocytosis was significantly enhanced to 52% in macrophages from mice pretreated intraperitoneally for 3 days with jack extract (500 µg/250 µl PBS). Reduction in phagocytosis from 52% to 34% (P<0.05) occurred in the presence of mannose receptor inhibitors and from 52% to 16% (P<0.01) in the presence of dectin-1 inhibitor laminarin, whereas only 20% of control macrophages phagocytosed blastoconidia. Similar results were verified for pretreatment of mice with Artin M (2.5 µg/250 µl PBS), but not for jacalin (25 µg/250 µl PBS). Macrophages from mice pretreated 3 days previously with jack extract or Artin M and then coincubated for 2h with C. albicans presented a significant increase in TNF-α production, correlating with significantly less transition of yeast to filamentous forms compared to pretreatment with jacalin. These results suggest that Artin M, but not jacalin present in jack extract significantly increased TNF-α production and the activity of mannose and dectin-1 receptors.