Interferon-γ induced nitric oxide mediates in vitro neuronal damage by Trypanosoma cruzi-infected macrophages

Abstract

Neuronal lesions and peripheral denervation in Chagas' disease are related to local inflammation; however, the pathogenic mechanisms of neuronal lesions in the heart and megavisceras are still unclear. We investigated the involvement of nitric oxide (NO) on neuronal lesion in co-cultures of neurons and macrophages. Trypanosoma cruzi-infected and interferon-gamma (IFN-gamma)-activated co-cultures of neurons and wild-type (WT) macrophages showed significant reduction of both neuronal survival and neurite density. These findings correlated with the levels of NO and the expression of inducible nitric oxide synthase (iNOS). Accordingly, neuronal survival rate in the co-cultures was recovered to control levels by treatment of the cultures with the iNOS inhibitor, aminoguanidine. Moreover, neither neuronal survival nor the neurite density was affected in the co-cultures when the macrophages were harvested from iNOS-deficient mice. These results demonstrate that iNOS-derived NO is the major molecule involved in neuronal damage mechanism in our in vitro model of Chagas' disease neuropathology.

Neurodegeneration and Increased Production of Nitrotyrosine, Nitric Oxide Synthase, IFN-γ and S100β Protein in the Spinal Cord of IL-12p40-Deficient Mice Infected with <i>Trypanosoma cruzi</i>

“…Of note, Arantes et al [63] reported intrinsic intestinal denervation in T. cruziinfected mice, due to IFN-␥ -induced NO. In line with this, in vitro neurodegeneration by IFN-␥ -induced NO released from T. cruzi -infected peritoneal macrophages was also reported [64] . Likewise, here we suggest that infiltrating and resident glial cells stimulated by IFN-␥ and S100 ␤ were able to overproduce NO, which contributed to the neurodegenerative process seen in T. cruzi -infected IL-12p40KO spinal cord.…”

Sympathetic glial cells and macrophages develop different responses to Trypanosoma cruzi infection or lipopolysaccharide stimulation

“…Our group has studied SCG neurons (Almeida-Leite et al 2007) and glial cells (Almeida-Leite & Arantes 2010) due to their participation in the neuronal degenerative changes induced by T. cruzi . This parasite has a tropism to nervous tissues in intracardiac ganglia (Machado & Ribeiro 1989) and the intramural myenteric plexus, a site where glia parasitism has been reported, whereas neuronal infection is rarely observed (Tafuri 1970, Arantes et al 2004).…”

“…Many studies have elucidated crucial roles for glial cells in neuropathological situations through the release of trophic factors, neuroprotective molecules or neurotoxic chemicals that mediate neuronal survival, function, lesion or death (Garden & Moller 2006, Giaume et al 2007). Glial cells are in close contact with neurons in both the central and peripheral nervous systems and are believed to affect them to a greater degree than inflammatory cells and their products (Arantes et al 2000, Almeida-Leite et al 2007, Dewil et al 2007, von Bernhardi 2007). In intestinal Chagas disease, parasitised glial cells and neuronal cells in close proximity to damaged myenteric ganglia is a frequent finding (Tafuri 1970, Arantes et al 2004).…”

“…Resistance to T. cruzi infection is associated with the capacity of lymphocytes to generate interferon-γ (IFN-γ), which activates macrophages to produce nitric oxide (NO), the main effector molecule that controls intracellular T. cruzi multiplication (Gazzinelli et al 1992, Vespa et al 1994). NO is also related to tissue damage (Vespa et al 1994, Chandra et al 2002), myenteric denervation (Arantes et al 2004), neuronal death and reduced neurite density in T. cruzi infection (Almeida-Leite et al 2007). …”

Primary culture of glial cells from mouse sympathetic cervical ganglion: A valuable tool for studying glial cell biology

“…Our group has a previous experience in obtaining neuronal primary cultures from sympathetic superior cervical ganglion (SCG) of newborn mice (Arantes et al, 2000;Almeida-Leite et al, 2007). These cultures are dependent on Matrigel, an artificial extracellular matrix used in various types of cell cultures (Kleinman et al, 1982(Kleinman et al, , 1987McGuire and Seeds, 1989;Katz et al, 1992;Vukicevic et al, 1992;Mackay et al, 1993).…”