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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJCI insight
Volume3
Issue number21
DOIs
StatePublished - Nov 2 2018

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Guanine Nucleotide Exchange Factors
Asthma
Inflammation
RNA Sequence Analysis
Therapeutics
Pyroglyphidae
GTP Phosphohydrolases
Smooth Muscle
Cytokines

Keywords

  • Asthma
  • Muscle Biology
  • Pulmonology

Cite this

Fong, V., Hsu, A., Wu, E., Looney, A. P., Ganesan, P., Ren, X., ... Bhattacharya, M. (2018). Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice. JCI insight, 3(21). https://doi.org/10.1172/jci.insight.123578

Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice. / Fong, Valerie; Hsu, Austin; Wu, Esther; Looney, Agnieszka P.; Ganesan, Previn; Ren, Xin; Sheppard, Dean; Wicher, Sarah A.; Thompson, Michael A.; Britt, Rodney Jr.; Prakash, Y.s.; Bhattacharya, Mallar.

In: JCI insight, Vol. 3, No. 21, 02.11.2018.

Research output: Contribution to journalArticle

Fong, V, Hsu, A, Wu, E, Looney, AP, Ganesan, P, Ren, X, Sheppard, D, Wicher, SA, Thompson, MA, Britt, RJ, Prakash, YS & Bhattacharya, M 2018, 'Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice', JCI insight, vol. 3, no. 21. https://doi.org/10.1172/jci.insight.123578
Fong, Valerie ; Hsu, Austin ; Wu, Esther ; Looney, Agnieszka P. ; Ganesan, Previn ; Ren, Xin ; Sheppard, Dean ; Wicher, Sarah A. ; Thompson, Michael A. ; Britt, Rodney Jr. ; Prakash, Y.s. ; Bhattacharya, Mallar. / Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice. In: JCI insight. 2018 ; Vol. 3, No. 21.
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