PKCλ/ι regulates Th17 differentiation and house dust mite-induced allergic airway inflammation

Yang, Ying‐Ying; Dong, Panpan; Zhao, Jing; Zhou, Wei; Zhou, Yonghua; Xu, Yuping; Mei, Congjin; Guo, Fukun; Zheng, Yi; Yang, Jun‐Qi

doi:10.1016/j.bbadis.2018.01.001

Cited by 10 publications

(18 citation statements)

References 41 publications

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“…E). Of note, IL‐22 was even not efficiently induced by TGF‐β1 plus IL‐6 stimulation in WT Th17 cells, supporting the notion that additional stimulation by IL‐23 is needed to induce IL‐22 secretion from fully committed Th17 cells …”

Section: Resultsmentioning

confidence: 63%

“…We have developed a HDM‐induced model for allergic airway inflammation (Fig. A), in which Th17 and Th2 cells, Th17‐induced neutrophils and Th2‐induced eosinophils are among the dominant responders . Requirement of RhoA for airway inflammation was investigated in the next series of experiments (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Nonetheless, our finding that Y16 alleviated HDM‐induced murine allergic airway inflammation might demonstrate a proof‐of‐principle for pharmacological targeting of RhoA in prevention and therapy of asthma. Particularly, RhoA activity is increased in airway biopsies of asthma patients and HDM is a common indoor allergens that is a strong inducer of Th17 cells and neutrophils, 2 types of inflammatory cells important for the pathogenesis of severe asthma . Thus, Y16 might have important clinical implications in treatment of severe asthma that is refractory to current therapies.…”

Section: Discussionmentioning

confidence: 99%

“…Naïve T cells were activated with plate‐bound anti‐CD3 (clone 145‐2C11, 10 µg/mL) plus soluble anti‐CD28 (clone 37.51, 2 µg/mL) (BD Bioscience, San Jose, CA). For T‐cell differentiation, CD4 + T cells were differentiated into Th0, Th1, Th2, Th17, or iTreg cells, as previously reported . Briefly, CD4 + T cells were stimulated by anti‐CD3/CD28 for 4 days with IL‐2 (20 ng/mL) in the presence of anti‐IFN‐γ (clone 37895) and anti‐IL‐4 (clone 30340) (both 10 µg/mL, for Th0), anti‐IL‐4 and IL‐12 (20 ng/mL, for Th1), anti‐IFN‐γ and IL‐4 (20 ng/mL, for Th2).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, compelling evidence has demonstrated that Th17 cells are a major contributor to the pathogenesis of allergic airway inflammation, especially severe asthma. The latter is often characterized by mixed responses of Th2 and Th17 cells and resistant to the steroid therapy . To investigate the role of Th17 cells in the pathogenesis of asthma, we have recently established murine asthma models induced by house dust mites (HDM, Dermatophagoides sp .)…”

Section: Introductionmentioning

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: Resultsmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%