Targeting of Rac1 prevents bronchoconstriction and airway hyperresponsiveness

André-Grégoire, Gwennan; Dilasser, Florian; Chesné, Julie; Braza, Faouzi; Magnan, A.; Loirand, Gervaise; Sauzeau, Vincent

doi:10.1016/j.jaci.2017.09.049

Cited by 30 publications

(39 citation statements)

References 33 publications

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“…The murine airway hyperresponsiveness was induced according to our recent reports 26,27 with modifications. 28,29 Briefly, mice were inoculated intratracheally (i.t.) with 40 μg of house dust mite (HDM;…”

Section: House Dust Mite (Hdm)-induced Allergic Airway Inflammationmentioning

confidence: 99%

Rational targeting Cdc42 restrains Th2 cell differentiation and prevents allergic airway inflammation

Yang

Kalim

et al. 2018

Clin Experimental Allergy

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Background: Asthma is an allergic airway inflammation-driven disease that affects more than 300 million people worldwide. Targeted therapies for asthma are largely lacking. Although asthma symptoms can be prevented from worsening, asthma development can’t be prevented. Cdc42 GTPase has been shown to regulate actin cytoskeleton, cell proliferation and survival. Objectives: To investigate the role and targeting of Cdc42 in Th2 cell differentiation and Th2-mediated allergic airway inflammation. Methods: Post-thymic Cdc42-deficient mice were generated by crossing Cdc42flox/flox mice with dLckicre transgenic mice in which Cre expression is driven by distal Lck promoter. Effects of post-thymic Cdc42 deletion and pharmacological targeting Cdc42 on Th2 cell differentiation were evaluated in vitro under Th2-polarized culture conditions. Effects of post-thymic Cdc42 deletion and pharmacological targeting Cdc42 on allergic airway inflammation were evaluated in ovalbumin- and/or house dust mite-induced mouse models of asthma. Results: Post-thymic deletion of Cdc42 led to reduced peripheral CD8+ T cells and attenuated Th2 cell differentiation, with no effect on closely related Th1, Th17 and induced regulatory T (iTreg) cells. Post-thymic Cdc42 deficiency ameliorated allergic airway inflammation. The selective inhibition of Th2 cell differentiation by post-thymic deletion of Cdc42 was recapitulated by pharmacological targeting of Cdc42 with CASIN, a Cdc42 activity-specific chemical inhibitor. CASIN also alleviated allergic airway inflammation. CASIN-treated Cdc42-deficient mice showed comparable allergic airway inflammation to vehicle-treated Cdc42-deficient mice, indicative of negligible off-target effect of CASIN. CASIN had no effect on established allergic airway inflammation. Conclusion & Clinical Relevance: Cdc42 is required for Th2 cell differentiation and allergic airway inflammation and rational targeting Cdc42 may serve as a preventive but not therapeutic approach for asthma control.

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Section: House Dust Mite (Hdm)-induced Allergic Airway Inflammationmentioning

confidence: 99%

Rational targeting Cdc42 restrains Th2 cell differentiation and prevents allergic airway inflammation

Yang

Kalim

et al. 2018

Clin Experimental Allergy

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“…Recently, André‐Grégoire et al demonstrated that Rac1 activation is caused by CCh stimulation in murine and human airway smooth muscle cells. The Rac1 activation induced by CCh acts via phospholipase (PLC) β 2 to induce intracellular Ca 2+ signalling and hence contraction.…”

Section: Discussionmentioning

confidence: 99%

“…In the presence of atropine (1 μmol/L), force development was observed in response to all constriction‐inducing agents administered, with the exception of CCh. The Rac1 inhibitor EHT1864 reportedly inhibits Rac1 activation selectively in vitro, and 10 μmol/L EHT1864 is used by many studies . Therefore, 10 μmol/L EHT1864 was used in this study.…”

Section: Methodsmentioning

confidence: 99%

“…In rat BSMs, Rac1 is involved in the Ca 2+ ‐sensitive MLCP pathway, which mediates muscle contractions. Moreover, the inhibition of Rac1 prevents bronchoconstriction and AHR . In the current study, we investigated the role of Rac1 in the BSM contractions of AHR mice.…”

Section: Introductionmentioning

confidence: 96%

“…Moreover, the inhibition of Rac1 prevents bronchoconstriction and AHR. 12 In the current study, we investigated the role of Rac1 in the BSM contractions of AHR mice.…”

Section: Introductionmentioning

confidence: 99%

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Up‐regulation of Rac1 in the bronchial smooth muscle of murine experimental asthma

Kai

Motegi

Suzuki

et al. 2019

Basic Clin Pharma Tox

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There has been considerable research on the involvement of RhoA/Rho kinase signalling in smooth muscle contractions. However, only a few reports have addressed the specific role of Rac1, which is a member of the Rho GTPase superfamily. Therefore, this study investigated the role of Rac1‐related pathways in bronchial smooth muscle (BSM) contractions. Bronchial rings isolated from mice were suspended in an organ bath, and the isometric contractions of circular smooth muscles were monitored. The phosphorylation of myosin light chains (MLCs) was analysed by immunoblotting. The Rac1 inhibitor EHT1864 inhibited carbachol (CCh)‐induced BSM contractions, although high K+ depolarization‐induced BSM contractions were not significantly attenuated by EHT1864. Moreover, high K+‐ and phorbol 12,13‐dibutyrate (PDBu; PKC activator)‐induced contractions were not attenuated by Rac1 inhibition, whereas sodium fluoride (NaF)‐induced force development was inhibited by EHT1864. The gene and protein expression of Rac1 was increased in the BSM of a murine model with antigen‐induced airway hyper‐responsiveness (AHR). In addition, an increased force of the BSM contractions in AHR was suppressed by EHT1864 treatment, suggesting that the up‐regulation of Rac1 is involved in AHR. These findings suggest that an increase in Rac1‐mediated signalling is involved in the augmented contractions of BSMs in antigen‐induced AHR mice.

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MicroRNA-98-5p Inhibits IL-13-Induced Proliferation and Migration of Human Airway Smooth Muscle Cells by Targeting RAC1

et al. 2022

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Targeting of Rac1 prevents bronchoconstriction and airway hyperresponsiveness

Cited by 30 publications

References 33 publications

Rational targeting Cdc42 restrains Th2 cell differentiation and prevents allergic airway inflammation

Rational targeting Cdc42 restrains Th2 cell differentiation and prevents allergic airway inflammation

Up‐regulation of Rac1 in the bronchial smooth muscle of murine experimental asthma

MicroRNA-98-5p Inhibits IL-13-Induced Proliferation and Migration of Human Airway Smooth Muscle Cells by Targeting RAC1

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