Integrin α9β1 in airway smooth muscle suppresses exaggerated airway narrowing

Abstract

Exaggerated contraction of airway smooth muscle is the major cause of symptoms in asthma, but the mechanisms that prevent exaggerated contraction are incompletely understood. Here, we showed that integrin α 9 β 1 on airway smooth muscle localizes the polyamine catabolizing enzyme spermidine/spermine N 1 -acetyltransferase (SSAT) in close proximity to the lipid kinase PIP5K1γ. As PIP5K1γ is the major source of PIP2 in airway smooth muscle and its activity is regulated by higher-order polyamines, this interaction inhibited IP3-dependent airway smooth muscle contraction. Mice lacking integrin α 9 β 1 in smooth muscle had increased airway responsiveness in vivo, and loss or inhibition of integrin α 9 β 1 increased in vitro airway narrowing and airway smooth muscle contraction in murine and human airways. Contraction was enhanced in control airways by the higher-order polyamine spermine or by cell-permeable PIP2, but these interventions had no effect on airways lacking integrin α 9 β 1 or treated with integrin α 9 β 1 -blocking antibodies. Enhancement of SSAT activity or knockdown of PIP5K1γ inhibited airway contraction, but only in the presence of functional integrin α 9 β 1 . Therefore, integrin α 9 β 1 appears to serve as a brake on airway smooth muscle contraction by recruiting SSAT, which facilitates local catabolism of polyamines and thereby inhibits PIP5K1γ. Targeting key components of this pathway could thus lead to new treatment strategies for asthma.

Targeting integrin α5β1 ameliorates severe airway hyperresponsiveness in experimental asthma

“…One hour after administration, mice were anesthetized with ketamine (100 mg/kg), xylazine (10 mg/kg), and acepromazine (3 mg/kg). Pulmonary resistance was determined using invasive cannulation of the trachea as previously described (50). The scientists performing the experiment were blinded to the drug delivered throughout the experiment and during analysis of the experimental outcome.…”

The phosphatase CD148 promotes airway hyperresponsiveness through SRC family kinases

“…We therefore generated mice specifically lacking CD148 in smooth muscle by crossing our Ptprj TM-fl/TM-fl mice with mice expressing the reverse tetracycline transactivator under the control of the α-smooth muscle actin promoter (α-SMA-rTTA) and (tetO) 7 -Cre (35). The tissue specificity of deletion in smooth muscle has been previously confirmed (36). Mice carrying all 4 alleles will be referred to as Ptprj TM-fl/TM-fl ;SMA-rTTA Cre.…”

“…Conditional deletion of the CD148 floxed allele on hematopoietic and endothelial cells was achieved by crossing Ptprj TM-fl/TM-mice with Vav1-Cre (Vav-Cre) transgenic mice, as previously described (69). α-SMArTTA mice were provided by M. Shipley (Washington University School of Medicine, St. Louis, Missouri, USA) and have been previously described (36). The (TetO)7-Cre mouse line has been previously described (35).…”

“…Pulmonary resistance was determined using invasive cannulation of the trachea as previously described (36).…”

A Fungal Protease Allergen Provokes Airway Hyperresponsiveness in Asthma

“…Surprisingly, however, deficiency of α9β1 integrin in ASM by conditional genetic deletion of α9 (Itga9) in mice resulted in spontaneous AHR 22 . We observed markedly reduced surface expression and increased cytosolic localization of α9 integrin in Af-treated cells compared to controls by immunofluorescent staining (Fig.…”