title: Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness.
abstract: Asthma is one of the most common chronic diseases globally and can be divided into presenting with or without an immune response. Current therapies have little effect on nonimmune disease, and the mechanisms that drive this type of asthma are poorly understood. Here, we have shown that loss of the transcription factors forkhead box P1 (Foxp1) and Foxp4, which are critical for lung epithelial development, in the adult airway epithelium evokes a non-Th2 asthma phenotype that is characterized by airway hyperresponsiveness (AHR) without eosinophilic inflammation. Transcriptome analysis revealed that loss of Foxp1 and Foxp4 expression induces ectopic expression of neuropeptide Y (Npy), which has been reported to be present in the airways of asthma patients, but whose importance in disease pathogenesis remains unclear. Treatment of human lung airway explants with recombinant NPY increased airway contractility. Conversely, loss of Npy in Foxp1- and Foxp4-mutant airway epithelium rescued the AHR phenotype. We determined that NPY promotes AHR through the induction of Rho kinase activity and phosphorylation of myosin light chain, which induces airway smooth muscle contraction. Together, these studies highlight the importance of paracrine signals from the airway epithelium to the underlying smooth muscle to induce AHR and suggest that therapies targeting epithelial induction of this phenotype may prove useful in treatment of noneosinophilic asthma.
authors.forename: Shanru
authors.initials: S
authors.lastname: Li
authors.forename: Cynthia
authors.initials: C
authors.lastname: Koziol-White
authors.forename: Joseph
authors.initials: J
authors.lastname: Jude
authors.forename: Meiqi
authors.initials: M
authors.lastname: Jiang
authors.forename: Hengjiang
authors.initials: H
authors.lastname: Zhao
authors.forename: Gaoyuan
authors.initials: G
authors.lastname: Cao
authors.forename: Edwin
authors.initials: E
authors.lastname: Yoo
authors.forename: William
authors.initials: W
authors.lastname: Jester
authors.forename: Michael P
authors.initials: MP
authors.lastname: Morley
authors.forename: Su
authors.initials: S
authors.lastname: Zhou
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Min Min
authors.initials: MM
authors.lastname: Lu
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.forename: Edward E
authors.initials: EE
authors.lastname: Morrisey
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects* / Q000235:genetics; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D009478:Neuropeptide Y / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; C472854:Foxp4 protein, mouse; D018994:Myosin Light Chains; D009478:Neuropeptide Y; D012097:Repressor Proteins; D054460:rho-Associated Kinases