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

JCI Insight. 2018 Nov 2;3(21):e123578. doi: 10.1172/jci.insight.123578.

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.

Keywords: Asthma; Muscle Biology; Pulmonology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Animals
  • Asthma / drug therapy
  • Asthma / metabolism*
  • Asthma / physiopathology
  • Disease Progression
  • Female
  • Guanine Nucleotide Exchange Factors / antagonists & inhibitors
  • Guanine Nucleotide Exchange Factors / pharmacology
  • Humans
  • Interleukin-17 / metabolism*
  • Male
  • Mice
  • Middle Aged
  • Muscle Contraction / drug effects*
  • Muscle Contraction / physiology
  • Respiratory Hypersensitivity / drug therapy
  • Respiratory Hypersensitivity / metabolism*
  • Rho Guanine Nucleotide Exchange Factors / metabolism*
  • Sequence Analysis, RNA / methods
  • Severity of Illness Index
  • rhoA GTP-Binding Protein / drug effects*
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Arhgef12 protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Interleukin-17
  • Rho Guanine Nucleotide Exchange Factors
  • rhoA GTP-Binding Protein