Effect of Anti-IL17 Antibody Treatment Alone and in Combination With Rho-Kinase Inhibitor in a Murine Model of Asthma

Santos, Tabata Maruyama Dos; Righetti, Renato Fraga; Camargo, Leandro do Nascimento; Saraiva-Romanholo, Beatriz Mangueira; Aristóteles, Luciana R. C. R. B.; Souza, Flávia Castro Ribas de; Fukuzaki, Silvia; Alonso-Vale, Maria Isabel Cardoso; Cruz, Maysa Mariana; Prado, Carla M.; Leick, Edna Aparecida; Martins, Mílton A.; Tibério, Iolanda F.L.C.

doi:10.3389/fphys.2018.01183

Cited by 35 publications

(56 citation statements)

References 73 publications

(114 reference statements)

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“…In addition, RhoA functions through activation of its immediate downstream effectors such as Rho‐associated protein kinase (ROCK), mDia, and protein kinase N . Blockade of ROCK activity by its specific inhibitors Y27632 or fasudil is associated with the downregulation of Th17 function and improvement for several autoimmune and inflammatory diseases, such as systemic lupus erythematosus, OVA‐induced murine allergic lung inflammation, and viral myocarditis . Thus, ROCK likely contributes to RhoA‐regulated Th17 signaling and differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…42 As we have shown that RhoA promotes mTOR signaling in activated T cells and RhoA promotes Th2 differentiation through glycolysis, 11 it will be interesting to determine whether mTOR-regulated glycolysis contributes to RhoA-mediated Th17 differentiation in future. In addition, RhoA functions through activation of its immediate downstream effectors such as Rho-associated protein kinase (ROCK), mDia, and protein kinase N. 43 Blockade of ROCK activity by its specific inhibitors Y27632 or fasudil is associated with the downregulation of Th17 function and improvement for several autoimmune and inflammatory diseases, such as systemic lupus erythematosus, 44 OVA-induced murine allergic lung inflammation, 45 and viral myocarditis. 46 Thus, ROCK likely contributes to RhoA-regulated Th17 signaling and differentiation.…”

Section: Discussionmentioning

confidence: 99%

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Ablation of RhoA impairs Th17 cell differentiation and alleviates house dust mite-triggered allergic airway inflammation

Yang

Kalim

et al. 2019

Journal of Leukocyte Biology

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Asthma is a heterogeneous chronic airway inflammation in which Th2 and Th17 cells are key players in its pathogenesis. We have reported that RhoA of Rho GTPases orchestrated glycolysis for Th2 cell differentiation and allergic airway inflammation by the use of a conditional RhoA‐deficient mouse line. However, the role of RhoA in Th17 cells remains to be elucidated. In this study, we investigated the effects of RhoA deficiency on Th17 cells in the context of ex vivo cell culture systems and an in vivo house dust mites (HDM)‐induced allergic airway inflammation. We found that RhoA deficiency inhibited Th17 differentiation and effector cytokine secretion, which was associated with the downregulations of Stat3 and Rorγt, key Th17 transcription factors. Furthermore, loss of RhoA markedly suppressed Th17 and neutrophil‐involved airway inflammation induced by HDM in mice. The infiltrating inflammatory cells in the lungs and bronchoalveolar lavage (BAL) fluids were dramatically reduced in conditional RhoA‐deficient mice. Th17 as well as Th2 effector cytokines were suppressed in the airways at both protein and mRNA levels. Interestingly, Y16, a specific RhoA inhibitor, was able to recapitulate the most phenotypes of RhoA genetic deletion in Th17 differentiation and allergic airway inflammation. Our data demonstrate that RhoA is a key regulator of Th17 cell differentiation and function. RhoA might serve as a potential novel therapeutic target for asthma and other inflammatory disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ablation of RhoA impairs Th17 cell differentiation and alleviates house dust mite-triggered allergic airway inflammation

Yang

Kalim

et al. 2019

Journal of Leukocyte Biology

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“…Similarly, Y16, a specific RhoA inhibitor, also suppressed Th17 response and allergic airway inflammation. In addition, Rho‐kinase inhibitor in conjunction with anti‐IL‐17 alleviated airway responsiveness, airway inflammation and remodelling, and oxidative stress in mice with chronic allergic lung inflammation 102 …”

Section: Rhoa/rho‐kinase and Airway Inflammationmentioning

confidence: 96%

RhoA/Rho‐kinases in asthma: from pathogenesis to therapeutic targets

et al. 2020

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Asthma is a chronic and heterogeneous disease characterised by airway inflammation and intermittent airway narrowing. The key obstacle in the prevention and treatment of asthma has been our incomplete understanding of its aetiology and biological mechanisms. The ras homolog family member A (RhoA) of the Rho family GTPases has been considered to be one of the most promising and novel therapeutic targets for asthma. It is well known that RhoA/Rho-kinases play an important role in the pathophysiology of asthma, including airway smooth muscle contraction, airway hyper-responsiveness, b-adrenergic desensitisation and airway remodelling. However, recent advances have suggested novel roles for RhoA in regulating allergic airway inflammation. Specifically, RhoA has been shown to regulate allergic airway inflammation through controlling Th2 or Th17 cell differentiation and to regulate airway remodelling through regulating mesenchymal stem cell (MSC) differentiation. In this review, we evaluate the literature regarding the recent advances in the activation of RhoA/Rho-kinase, cytokine and epigenetic regulation of RhoA/Rho-kinase, and the role of RhoA/Rho-kinase in regulating major features of asthma, such as airway hyperresponsiveness, remodelling and inflammation. We also discuss the importance of the newly identified role of RhoA/Rho-kinase signalling in MSC differentiation and bronchial epithelial barrier dysfunction. These findings indicate the functional significance of the RhoA/Rho-kinase pathway in the pathophysiology of asthma and suggest that RhoA/Rho-kinase signalling may be a promising therapeutic target for the treatment of asthma.

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“…The lack of studies with ROCK inhibitors is surprising because it has been suggested that these agents may act synergistically with other classes of bronchodilators, although this remains to be investigated [68]. Furthermore, ROCK inhibitors in conjunction with anti-IL-17 treatment are able to modulate airway responsiveness in mice with chronic allergic lung inflammation [69].…”

Section: Rho Kinase Inhibitorsmentioning

confidence: 99%

The future of bronchodilation: looking for new classes of bronchodilators

2019

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@ERSpublicationsThere is a real interest among researchers and the pharmaceutical industry in developing novel bronchodilators. There are several new opportunities; however, they are mostly in a preclinical phase. They could better optimise bronchodilation. http://bit.ly/2lW1q39Cite this article as: Cazzola M, Rogliani P, Matera MG. The future of bronchodilation: looking for new classes of bronchodilators.ABSTRACT Available bronchodilators can satisfy many of the needs of patients suffering from airway disorders, but they often do not relieve symptoms and their long-term use raises safety concerns. Therefore, there is interest in developing new classes that could help to overcome the limits that characterise the existing classes. At least nine potential new classes of bronchodilators have been identified: 1) selective phosphodiesterase inhibitors; 2) bitter-taste receptor agonists; 3) E-prostanoid receptor 4 agonists; 4) Rho kinase inhibitors; 5) calcilytics; 6) agonists of peroxisome proliferator-activated receptor-γ; 7) agonists of relaxin receptor 1; 8) soluble guanylyl cyclase activators; and 9) pepducins. They are under consideration, but they are mostly in a preclinical phase and, consequently, we still do not know which classes will actually be developed for clinical use and whether it will be proven that a possible clinical benefit outweighs the impact of any adverse effect.It is likely that if developed, these new classes may be a useful addition to, rather than a substitution of, the bronchodilator therapy currently used, in order to achieve further optimisation of bronchodilation.

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Effect of Anti-IL17 Antibody Treatment Alone and in Combination With Rho-Kinase Inhibitor in a Murine Model of Asthma

Cited by 35 publications

References 73 publications

Ablation of RhoA impairs Th17 cell differentiation and alleviates house dust mite-triggered allergic airway inflammation

Ablation of RhoA impairs Th17 cell differentiation and alleviates house dust mite-triggered allergic airway inflammation

RhoA/Rho‐kinases in asthma: from pathogenesis to therapeutic targets

The future of bronchodilation: looking for new classes of bronchodilators

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