The Role of Kinin Receptors in Preventing Neuroinflammation and Its Clinical Severity during Experimental Autoimmune Encephalomyelitis in Mice

Abstract

BackgroundMultiple sclerosis (MS) is a demyelinating and neuroinflammatory disease of the human central nervous system (CNS). The expression of kinins is increased in MS patients, but the underlying mechanisms by which the kinin receptor regulates MS development have not been elucidated.Methodology/Principal FindingsExperimental autoimmune encephalomyelitis (EAE) was induced in female C57BL/6 mice by immunization with MOG35–55 peptide emulsified in complete Freund's adjuvant and injected with pertussis toxin on day 0 and day 2. Here, we report that blockade of the B1R in the induction phase of EAE markedly suppressed its progression by interfering with the onset of the immune response. Furthermore, B1R antagonist suppressed the production/expression of antigen-specific TH1 and TH17 cytokines and transcription factors, both in the periphery and in the CNS. In the chronic phase of EAE, the blockade of B1R consistently impaired the clinical progression of EAE. Conversely, administration of the B1R agonist in the acute phase of EAE suppressed disease progression and inhibited the increase in permeability of the blood-brain barrier (BBB) and any further CNS inflammation. Of note, blockade of the B2R only showed a moderate impact on all of the studied parameters of EAE progression.Conclusions/SignificanceOur results strongly suggest that kinin receptors, mainly the B1R subtype, play a dual role in EAE progression depending on the phase of treatment through the lymphocytes and glial cell-dependent pathways.

Carboxypeptidase N-deficient mice present with polymorphic disease phenotypes on induction of experimental autoimmune encephalomyelitis

“…Subsequently, it was shown that bradykinin exerted anti-inflammatory effects on LPS-treated microglia and astrocytes in a B1 receptor-dependent fashion (Noda et al, 2007a; Noda et al, 2007b). More recent studies have demonstrated an important role for the B1 receptor in controlling inflammation and leukocyte infiltration into the CNS during EAE (Dutra et al, 2011; Gobel et al, 2011; Schulze-Topphoff et al, 2009). It is possible that the des-Arg form of these kinins contribute to the early phase mortality we observed after induction of EAE.…”

The kallikrein-kinin system in experimental Chagas disease: a paradigm to investigate the impact of inflammatory edema on GPCR-mediated pathways of host cell invasion by Trypanosoma cruzi

“…Ongoing studies in chagasic mice treated with BK 1 R blockers may clarify whether this therapeutic strategy may reduce parasite tissue load as well as myocardial fibrosis. Moreover, it is conceivable that BK 1 R antagonists may reduce chronic inflammation by preventing microvascular leakage and/or blocking parasite-induced recruitment of pathogenic subsets of anti-parasite CD8 T effector cells into the myocardium (Silverio et al, 2012), as reported in EAE (Dutra et al, 2011; Göbel et al, 2011). …”

“…Studies in mice subjected to traumatic brain injury revealed that blood-brain leakage and recruitment of inflammatory leukocytes to the CNS is blocked by a specific BK 1 R antagonist (Raslan et al, 2010). Although inflammation is usually initiated through the signaling of the constitutive BK 2 R, the sustenance of the inflammatory response depends on the signaling of endothelial BK 1 R. McLean et al (2000) were the first to report that the trans-endothelial leukocyte migration is enhanced as result of up-regulated expression/signaling of endothelial BK 1 R. Recent progress in studies of experimental autoimmune encephalitis (EAE) demonstrated that BK 1 R increases the recruitment of pathogenic effector T cells into the CNS (Dutra et al, 2011; Göbel et al, 2011; Table 1 ).…”

Exacerbation of DSS‐induced colitis in mice lacking kinin B1 receptors through compensatory up‐regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis

“…and all of the other antagonists were administered i.p. twice a day, as previously described (Costa et al ., ; Dutra et al ., ). To induce colitis, animals received a solution of filtered water containing 250 mL of 3% DSS ad libitum over a 5‐day period.…”