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Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice
Valerie Fong, … , Y.S. Prakash, Mallar Bhattacharya
Valerie Fong, … , Y.S. Prakash, Mallar Bhattacharya
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e123578. https://doi.org/10.1172/jci.insight.123578.
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Research Article Muscle biology Pulmonology

Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice

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Abstract

Patients with severe, treatment-refractory asthma are at risk for death from acute exacerbations. The cytokine IL17A has been associated with airway inflammation in severe asthma, and novel therapeutic targets within this pathway are urgently needed. We recently showed that IL17A increases airway contractility by activating the procontractile GTPase RhoA. Here, we explore the therapeutic potential of targeting the RhoA pathway activated by IL17A by inhibiting RhoA guanine nucleotide exchange factors (RhoGEFs), intracellular activators of RhoA. We first used a ribosomal pulldown approach to profile mouse airway smooth muscle by qPCR and identified Arhgef12 as highly expressed among a panel of RhoGEFs. ARHGEF12 was also the most highly expressed RhoGEF in patients with asthma, as found by RNA sequencing. Tracheal rings from Arhgef12-KO mice and WT rings treated with a RhoGEF inhibitor had evidence of decreased contractility and RhoA activation in response to IL17A treatment. In a house dust mite model of allergic sensitization, Arhgef12-KO mice had decreased airway hyperresponsiveness without effects on airway inflammation. Taken together, our results show that Arhgef12 is necessary for IL17A-induced airway contractility and identify a therapeutic target for severe asthma.

Authors

Valerie Fong, Austin Hsu, Esther Wu, Agnieszka P. Looney, Previn Ganesan, Xin Ren, Dean Sheppard, Sarah A. Wicher, Michael A. Thompson, Rodney D. Britt Jr., Y.S. Prakash, Mallar Bhattacharya

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Figure 1

Riboprofiling identifies Arhgef12 as the most highly expressed RhoA guanine exchange factor in airway smooth muscle.

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Riboprofiling identifies Arhgef12 as the most highly expressed RhoA guan...
(A) Schematic of smooth muscle RNA riboprofiling of trachea from acta2-CreERT2/Rosa26loxpSTOPloxpRpl10a-mCherry mice. (B) Immunofluorescence of trachea from acta2-CreERT2/Rosa26loxpSTOPloxpRpl10a-mCherry mice. Scale bar: 200 μm. (C) Validation of smooth muscle specificity of riboprofiling by qPCR of smooth muscle and non–smooth muscle genes (n = 4 mice). PD, pulldown. (D) Riboprofiling of mouse tracheal RhoGEFs in healthy mice (n = 4 mice). (E) RhoGEF expression in airway smooth muscle from asthma patients (n = 7) and healthy controls (n = 12). Where 2 samples were available (4 of 7 asthma patients), counts were averaged. Box plots show minimum, maximum, and median, with 25th to 75th percentile range. *P < 0.01 by 1-tailed Student’s t test.

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