Meningoencephalitic African trypanosomiasis: Brain IL-10 and IL-6 are associated with protection from neuro-inflammatory pathology

Sternberg, Jeremy M.; Rodgers, Jean; Bradley, Barbara; MacLean, Lorna; Murray, M.; Kennedy, Peter G. E.

doi:10.1016/j.jneuroim.2005.06.017

Cited by 76 publications

(93 citation statements)

References 26 publications

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“…Rather, human lethality results from infiltration of parasites through the blood-brain barrier resulting from changes in endothelial cell properties (41). Interestingly, a role for TNF and NO in increasing the permeability of the blood-brain barrier has been proposed (42) and high IL-10 levels in the brain are associated with reduced brain damage during human trypanosomiasis (43). Thus, whether M1, including TIP-DCs, and IL-10 modulate the pathogenic features of bovine or human natural infections deserves investigation.…”

Section: Discussionmentioning

confidence: 99%

IL-10 Dampens TNF/Inducible Nitric Oxide Synthase-Producing Dendritic Cell-Mediated Pathogenicity during Parasitic Infection

Guilliams

Movahedi

Bosschaerts

et al. 2009

The Journal of Immunology

107

156

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Antiparasite responses are associated with the recruitment of monocytes that differentiate to macrophages and dendritic cells at the site of infection. Although classically activated monocytic cells are assumed to be the major source of TNF and NO during Trypanosoma brucei brucei infection, their cellular origin remains unclear. In this study, we show that bone marrow-derived monocytes accumulate and differentiate to TNF/inducible NO synthase-producing dendritic cells (TIP-DCs) in the spleen, liver, and lymph nodes of T. brucei brucei-infected mice. Although TIP-DCs have been shown to play a beneficial role in the elimination of several intracellular pathogens, we report that TIP-DCs, as a major source of TNF and NO in inflamed organs, could contribute actively to tissue damage during the chronic stage of T. brucei brucei infection. In addition, the absence of IL-10 leads to enhanced differentiation of monocytes to TIP-DCs, resulting in exacerbated pathogenicity and early death of the host. Finally, we demonstrate that sustained production of IL-10 following IL-10 gene delivery treatment with an adeno-associated viral vector to chronically infected mice limits the differentiation of monocytes to TIP-DCs and protects the host from tissue damage.

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Section: Discussionmentioning

confidence: 99%

IL-10 Dampens TNF/Inducible Nitric Oxide Synthase-Producing Dendritic Cell-Mediated Pathogenicity during Parasitic Infection

Guilliams

Movahedi

Bosschaerts

et al. 2009

The Journal of Immunology

107

156

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“…Others have reported that endothelial cells do not produce IL-10 in response to exposure to B. burgdorferi (56), TNF, IFN-g, or LPS (57). An important protective role of IL-10 for the cerebral microcirculation has been shown in several systemic infections (58), including cerebral malaria (59,60) and African trypanosomiasis (61). It has been proposed that IL-10 protects the brain by reducing the synthesis of proinflammatory cytokines and modulating the expression of cytokine receptors.…”

Section: Discussionmentioning

confidence: 99%

IL-10 Prevents Apoptosis of Brain Endothelium during Bacteremia

Londoño

Carvajal

Strle

et al. 2011

The Journal of Immunology

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IL‐10 deficient mice infected with the relapsing fever bacterium Borrelia turicatae rapidly succumb to brain hemorrhage if they are unable to clear peak bacteremia. Here we investigated the protective role of IL‐10 during relapsing‐remitting bacterial infection and explored the molecular events involved in protection of brain endothelium by IL‐10. The results showed that severe endothelial cell injury leading to hemorrhage in the brain and other organs occurred in IL‐10 deficient mice during relapsing‐remitting infection. Human brain microvascular endothelial cells (HBMEC) upon exposure to whole bacteria or purified bacterial lipoprotein are rapidly killed by apoptosis and produced abundant pro‐inflammatory mediators but did not produce any IL‐10. HBMEC apoptosis during exposure to low number of bacteria was associated with down regulation of TNF and TNFAIP3 and upregulation of BAX. In contrast, exposure to high concentrations of purified outer membrane lipoprotein was associated with dramatic upregulation of FAS, FAS ligand, and the adaptor molecules RIPK1 and CFLAR. Exogenous IL‐10 reversed all the apoptotic signaling changes induced by whole bacteria or purified lipoprotein. The results indicate that IL‐10 prevent brain endothelial cell injury and point to a prominent role for bacterial lipoprotein mediated activation of different apoptosis pathways in this process.

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“…However, the relevance of this cytokine as an antiviral mediator in the mouse model is questionable, since neutralization of TNF-␣ has no effect on virus resolution following genital HSV-2 infection (33). However, elevated expression of TNF-␣ has been associated with other CNS infections, including rabies and trypanosomiasis, ultimately resulting in encephalitis and meningoencephalitis, respectively (39,50). TNF-␣ is also a neurodegenerative cytokine due to its augmentation of glutamate neurotoxicity (57).…”

Section: Discussionmentioning

confidence: 99%

Susceptibility of CCR5-Deficient Mice to Genital Herpes Simplex Virus Type 2 Is Linked to NK Cell Mobilization

Thapa¹,

Kuziel

Carr

2007

J Virol

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With greater than 1.6 million Americans infected annually (4), herpes simplex virus type 2 (HSV-2) is a sexually transmitted pathogen with a significant impact on public health. Typically, infection results in a lifelong latent infection of the host (15, 52). Causes for the success of HSV-2 in the human population include asymptomatic shedding of the virus even in the presence of CD8 ϩ cytotoxic T lymphocytes and the production of a viral glycoprotein that indirectly elicits NK cell death (8,44,51). There is also evidence to suggest that genital HSV-2 infection increases the susceptibility of individuals to other sexually transmitted diseases, including human immunodeficiency virus (6,20). Consequently, it is imperative to characterize the host response to infection and identify key components that contribute to virus resistance to devise a strategy that will significantly reduce viral prevalence.The development of a mouse model of genital HSV-2 infection (7, 40) has contributed to our understanding of the innate and adaptive immune response to infection. Specifically, the application of progesterone to mice prior to infection enhances susceptibility through the direct immunosuppressive action of the hormone and expression of a herpesvirus entry receptor, nectin 1 (20,25,34). In this rodent model, investigators have demonstrated the importance of the innate immune response, including neutrophils, NK cells, NKT cells, and the production of alpha/beta interferon (IFN-␣/␤), interleukin-12 (IL-12), IL-15, and IL-18 in suppressing HSV-2 replication and reducing virus-mediated mortality (5,13,16,30,36). Relative to the adaptive immune response, T and B cells are involved in controlling virus infection, although T cells appear to be more critical in this process (12,28,29,31,35,41). The contribution of IFN-␥ produced by CD4 ϩ T cells in reducing HSV-2 pathogenesis has been demonstrated using CD4-deficient mice and CD4 T cell, CD8 T cell, and IFN-␥ depletion studies (17,32,42). Such results are consistent with a supportive role in the development of a Th1 response (55) and a detrimental role in the development of a Th2 response (38) in the host following HSV-2 infection.Mobilization of T and B cells between the vaginal epithelium and the draining (iliac) lymph nodes during genital HSV-2 infection have been described previously (22). However, the role of chemokines in regulating this process is relatively unknown. CCR5 and CCR1 have been implicated in resistance to intraperitoneal infection, with HSV-2 impacting NK cell recruitment and activity at the site of infection (3, 49). Using a more conventional site of infection, RANTES/CCL5 (regulated on activation, normal T-cell expressed, and secreted) was found to reduce HSV-2-induced morbidity and mortality associated with an increase in IL-2 and IFN-␥ production in vaccinated mice when administered in the form of a DNA vaccine adjuvant (48). Since it has been reported that CCR5-deficient mice show a decrease in Th1 responses as measured by a decrease in IFN-␥ and IL-12 pro...

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Meningoencephalitic African trypanosomiasis: Brain IL-10 and IL-6 are associated with protection from neuro-inflammatory pathology

Cited by 76 publications

References 26 publications

IL-10 Dampens TNF/Inducible Nitric Oxide Synthase-Producing Dendritic Cell-Mediated Pathogenicity during Parasitic Infection

IL-10 Dampens TNF/Inducible Nitric Oxide Synthase-Producing Dendritic Cell-Mediated Pathogenicity during Parasitic Infection

IL-10 Prevents Apoptosis of Brain Endothelium during Bacteremia

Susceptibility of CCR5-Deficient Mice to Genital Herpes Simplex Virus Type 2 Is Linked to NK Cell Mobilization

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