The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in controlling several aspects of immune responses, including the activation and differentiation of specific T ...cell subsets and antigen-presenting cells, thought to be relevant in the context of experimental Trypanosoma cruzi infection. The relevance of AhR for the outcome of T. cruzi infection is not known and was investigated here. We infected wild-type (WT) mice and AhR knockout (AhR KO) mice with T. cruzi (Y strain) and determined levels of parasitemia, myocardial inflammation and fibrosis, expression of AhR/cytokines/suppressor of cytokine signaling (SOCS) (spleen/heart), and production of nitric oxide (NO), reactive oxygen species (ROS), and peroxynitrite (ONOO(-)) (spleen). AhR expression was increased in the heart of infected WT mice. Infected AhR KO mice displayed significantly reduced parasitemia, inflammation, and fibrosis of the myocardium. This was associated with an anticipated increased immune response characterized by increased levels of inflammatory cytokines and reduced expression of SOCS2 and SOCS3 in the heart. In vitro, AhR deficiency caused impairment in parasite replication and decreased levels of ROS production. In conclusion, AhR influences the development of murine Chagas disease by modulating ROS production and regulating the expression of key physiological regulators of inflammation, SOCS1 to -3, associated with the production of cytokines during experimental T. cruzi infection.
Leukotriene B
(LTB
), a proinflammatory mediator produced by the enzyme 5-lipoxygenase (5-LO), is associated with the development of many inflammatory diseases. In this study, we evaluated the ...participation of the 5-LO/LTB
axis in graft-versus-host disease (GVHD) pathogenesis by transplanting 5-LO-deficient leukocytes and investigated the effect of pharmacologic 5-LO inhibition by zileuton and LTB
inhibition by CP-105,696. Mice that received allogeneic transplant showed an increase in nuclear 5-LO expression in splenocytes, indicating enzyme activation after GVHD. Mice receiving 5-LO-deficient cell transplant or zileuton treatment had prolonged survival, reduced GVHD clinical scores, reduced intestinal and liver injury, and decreased levels of serum and hepatic LTB
These results were associated with inhibition of leukocyte recruitment and decreased production of cytokines and chemokines. Treatment with CP-105,696 achieved similar effects. The chimerism or the beneficial graft-versus-leukemia response remained unaffected. Our data provide evidence that the 5-LO/LTB
axis orchestrates GVHD development and suggest it could be a target for the development of novel therapeutic strategies for GVHD treatment.
Innate immune signaling is critical for the development of protective immunity. Such signaling is, perforce, tightly controlled. Lipoxins (LXs) are eicosanoid mediators that play key ...counterregulatory roles during infection. The molecular mechanisms underlying LX-mediated control of innate immune signaling are of interest. In this study, we show that LX and aspirin (ASA)-triggered LX (ATL) inhibit innate immune signaling by inducing suppressor of cytokine signaling (SOCS) 2-dependent ubiquitinylation and proteasome-mediated degradation of TNF receptor-associated factor (TRAF) 2 and TRAF6, which are adaptor molecules that couple TNF and interleukin-1 receptor/Toll-like receptor family members to intracellular signaling events. LX-mediated degradation of TRAF6 inhibits proinflammatory cytokine production by dendritic cells. This restraint of innate immune signaling can be ablated by inhibition of proteasome function. In vivo, this leads to dysregulated immune responses, accompanied by increased mortality during infection. Proteasomal degradation of TRAF6 is a central mechanism underlying LX-driven immune counterregulation, and a hitherto unappreciated mechanism of action of ASA. These findings suggest a new molecular target for drug development for diseases marked by dysregulated inflammatory responses.
American trypanosomiasis, or Chagas disease, is a lifelong and persistent infection caused by the protozoan Trypanosoma cruzi and is the most significant cause of morbidity and mortality in South and ...Central America. Owing to immigration and additional risks from blood transfusion and organ transplantation, the number of reported cases of Chagas disease has increased recently in Europe and the USA. The disease is caused by a moderate to intense lasting inflammatory response that triggers local expression of inflammatory mediators and activates and recruits leukocytes to various tissues to eliminate the parasites.
This long-term inflammatory process triggers biochemical, physiological and morphological alterations and clinical changes in the digestive, nervous and cardiac (e.g. myocarditis, arrhythmias, congestive heart failure, autonomic dysfunctions and microcirculatory disturbances) systems. Indeed, the pathogenesis of Chagas disease is intricate and multifactorial, and the roles of the parasite and the immune response in initiating and maintaining the disease are still controversial.
In this review, we discuss the current knowledge of 'strategies' employed by the parasite to persist in the host and host defence mechanisms against Trypanosoma cruzi infection, which can result in equilibrium (absence of the disease) or disease development, mainly in the cardiac systems.
Chagas disease, caused by Trypanosoma cruzi (Tc), is an important cause of heart disease. Resistance to Tc infection is multifactorial and associated with Th1 response. IL-18 plays an important role ...in regulation of IFN-γ production/development of Th1 response. However, the role of IL-18 in the setting of Tc infection remains unclear. Therefore, we investigated the role of IL-18 in the modulation of immune response and myocarditis in Tc infection. C57BL/6 and IL-18 KO mice were infected with Tc (Y or Colombian strain) and parasitemia, immune response and pathology were evaluated. Y strain infection of IL-18 KO did not alter any parameters when compared with C57BL/6 mice. However, during the acute phase (20 and 40 days post infection-dpi), Colombian strain infected-IL-18 KO mice displayed higher serum levels of IL-12 and IFN-γ, respectively, and at the chronic phase (100 dpi) an increase in splenic IFN-γ-producing CD4+ and CD8+ T memory cells. There was an IL-10, FOXP3 and CD4+CD25+ cells reduction during acute infection in spleen. Additionally, there was a significant reduction in leukocyte infiltration and parasite load in myocardium of chronically infected IL-18 KO mice. Collectively, these data indicate that IL-18 contributes to the pathogenesis of Tc-induced myocarditis when infected with Colombian but not Y strain. These observations also underscore that parasite and host strain differences are important in evaluation of experimental Tc infection pathogenesis.
Cerebral malaria (CM) is debilitating and sometimes fatal. Disease severity has been associated with poor treatment access, therapeutic complexity and drug resistance and, thus, alternative therapies ...are increasingly necessary. In this study, the effect of the administration of Agaricus blazei, a mushroom of Brazilian origin in a model of CM caused by Plasmodium berghei, strain ANKA, was investigated in mice.
C57BL/6 mice were pre-treated with aqueous extract or fractions of A. blazei, or chloroquine, infected with P. berghei ANKA and then followed by daily administration of A. blazei or chloroquine. Parasitaemia, body weight, survival and clinical signs of the disease were evaluated periodically. The concentration of pro-and anti-inflammatory cytokines, histopathology and in vitro analyses were performed.
Mice treated with A. blazei aqueous extract or fraction C, that shows antioxidant activity, displayed lower parasitaemia, increased survival, reduced weight loss and protection against the development of CM. The administration of A. blazei resulted in reduced levels of TNF, IL-1β and IL-6 production when compared to untreated P. berghei-infected mice. Agaricus blazei (aqueous extract or fraction C) treated infected mice displayed reduction of brain lesions. Although chloroquine treatment reduced parasitaemia, there was increased production of proinflammatory cytokines and damage in the CNS not observed with A. blazei treatment. Moreover, the in vitro pretreatment of infected erythrocytes followed by in vivo infection resulted in lower parasitaemia, increased survival, and little evidence of clinical signs of disease.
This study strongly suggests that the administration of A. blazei (aqueous extract or fraction C) was effective in improving the consequences of CM in mice and may provide novel therapeutic strategies.
Arthralgia is a hallmark of chikungunya virus (CHIKV) infection and can be very debilitating and associated with a robust local inflammatory response. Many pathophysiological aspects associated with ...the disease remain to be elucidated. Here, we describe a novel model of CHIKV infection in immunocompetent mice and evaluate the role of tumour necrosis factor in the pathogenesis of the disease. C57BL/6 wild type (WT) or TNF receptor 1 deficient (TNFR1−/−) mice were inoculated with 1 × 106 PFU of CHIKV in the paw. Alternatively, etanercept was used to inhibit TNF in infected WT mice. Hypernociception, inflammatory and virological analysis were performed. Inoculation of CHIKV into WT mice induced persistent hypernociception. There was significant viral replication in target organs and local production of inflammatory mediators in early time‐points after infection. CHIKV infection was associated with specific humoral IgM and IgG responses. In TNFR1−/− mice, there was a decrease in the hypernociception threshold, which was associated with a milder local inflammatory response in the paw but delayed viral clearance. Local or systemic treatment with etanercept reduced CHIKV‐induced hypernociception. This is the first study to describe hypernociception, a clinical correlation of arthralgia, in immunocompetent mice infected with CHIKV. It also demonstrates the dual role of TNF in contributing to viral clearance but driving tissue damage and hypernociception. Inhibition of TNF may have therapeutic benefits but its role in viral clearance suggests that viral levels must be monitored in CHIKV‐infected patients and that TNF inhibitors should ideally be used in combination with anti‐viral drugs.
Absence of TNF receptor is associated with an improvement in clinical and inflammatory parameters of CHIKV infection.
Chagas disease caused by
Trypanosoma cruzi
remains an important neglected tropical disease and a cause of significant morbidity and mortality. No longer confined to endemic areas of Latin America, it ...is now found in non-endemic areas due to immigration. The parasite may persist in any tissue, but in recent years, there has been increased recognition of adipose tissue both as an early target of infection and a reservoir of chronic infection. The major complications of this disease are cardiomyopathy and megasyndromes involving the gastrointestinal tract. The pathogenesis of Chagas disease is complex and multifactorial involving many interactive pathways. The significance of innate immunity, including the contributions of cytokines, chemokines, reactive oxygen species, and oxidative stress, has been emphasized. The role of the components of the eicosanoid pathway such as thromboxane A
2
and the lipoxins has been demonstrated to have profound effects as both pro- and anti-inflammatory factors. Additionally, we discuss the vasoconstrictive actions of thromboxane A
2
and endothelin-1 in Chagas disease. Human immunity to
T. cruzi
infection and its role in pathogen control and disease progression have not been fully investigated. However, recently, it was demonstrated that a reduction in the anti-inflammatory cytokine IL-10 was associated with clinically significant chronic chagasic cardiomyopathy.
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Experimental Autoimmune Encephalomyelitis (EAE) is the most widely used animal model for the study of MS. The ...Suppressor of Cytokine Signaling (SOCS) 2 protein plays a critical role in regulating the immune responses. The role of SOCS2 during EAE has not been explored. EAE was induced in WT and SOCS2-/- mice using myelin oligodendrocyte glycoprotein (MOG35-55) peptide. Brain and spinal cord were examined during the peak (day 14) and recovery phase (day 28) of the disease. SOCS2 was upregulated in the brain of WT mice at the peak and recovery phase of EAE. The development of the acute phase was slower in onset in SOCS2-/- mice and was associated with reduced number of Th1 (CD3+CD4+IFN-γ+) cells in the spinal cord and brain. However, while in WT mice, maximal clinical EAE score was followed by a progressive recovery; the SOCS2-/- mice were unable to recover from locomotor impairment that occurred during the acute phase. There was a prolonged inflammatory response (increased Th1 and decreased Th2 and T regulatory cells) in the late phase of EAE in the CNS of SOCS2-/- mice. Transplantation of bone marrow cells from SOCS2-/- into irradiated WT mice resulted in higher lethality at the early phase of EAE. Altogether, these results suggest that SOCS2 plays a dual role in the immune response during EAE. It is necessary for damage during the acute phase damage but plays a beneficial role in the recovery stage of the disease.
Infection with Plasmodium falciparum may result in severe disease affecting various organs, including liver, spleen, and brain, resulting in high morbidity and mortality. Plasmodium berghei Anka ...infection of mice recapitulates many features of severe human malaria. The aryl hydrocarbon receptor (AhR) is an intracellular receptor activated by ligands important in the modulation of the inflammatory response. We found that AhR-knockout (KO) mice infected with P. berghei Anka displayed increased parasitemia, earlier mortality, enhanced leukocyte-endothelial cell interactions in the brain microvasculature, and increased inflammation in brain (interleukin-17 IL-17 and IL-6) and liver (gamma interferon IFN-γ and tumor necrosis factor alpha TNF-α) compared to infected wild-type (WT) mice. Infected AhR-KO mice also displayed a reduction in cytokines required for host resistance, including TNF-α, IL-1β, and IFN-γ, in the brain and spleen. Infection of AhR-KO mice resulted in an increase in T regulatory cells and transforming growth factor β, IL-6, and IL-17 in the brain. AhR modulated the basal expression of SOCS3 in spleen and brain, and P. berghei Anka infection resulted in enhanced expression of SOCS3 in brain, which was absent in infected AhR-KO mice. These data suggest that AhR-mediated control of SOCS3 expression is probably involved in the phenotype seen in infected AhR-KO mice. This is, to our knowledge, the first demonstration of a role for AhR in the pathogenesis of malaria.
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