title: Mast cell-derived neurotrophin 4 mediates allergen-induced airway hyperinnervation in early life.
abstract: Asthma often progresses from early episodes of insults. How early-life events connect to long-term airway dysfunction remains poorly understood. We demonstrated previously that increased neurotrophin 4 (NT4) levels following early-life allergen exposure cause persistent changes in airway smooth muscle (ASM) innervation and airway hyper-reactivity (AHR) in mice. Herein, we identify pulmonary mast cells as a key source of aberrant NT4 expression following early insults. NT4 is selectively expressed by ASM and mast cells in mice, nonhuman primates, and humans. We show in mice that mast cell-derived NT4 is dispensable for ASM innervation during development. However, upon insults, mast cells expand in number and degranulate to release NT4 and thus become the major source of NT4 under pathological condition. Adoptive transfer of wild-type mast cells, but not NT4-/-mast cells restores ASM hyperinnervation and AHR in KitW-sh/W-shmice following early-life insults. Notably, an infant nonhuman primate model of asthma also exhibits ASM hyperinnervation associated with the expansion and degranulation of mast cells. Together, these findings identify an essential role of mast cells in mediating ASM hyperinnervation following early-life insults by producing NT4. This role may be evolutionarily conserved in linking early insults to long-term airway dysfunction.
authors: The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: K R
authors: KR
authors: Patel
authors: The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: L
authors: L
authors: Aven
authors: The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: F
authors: F
authors: Shao
authors: Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: N
authors: N
authors: Krishnamoorthy
authors: Division of Critical Care Medicine, Department of Anesthesia, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.|Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: M G
authors: MG
authors: Duvall
authors: Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: B D
authors: BD
authors: Levy
authors: The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.|Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: X
authors: X
authors: Ai
mesh_terms: D000367:Age Factors; D000485:Allergens / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000378:metabolism; D015550:Cell Degranulation / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D011323:Primates; D012137:Respiratory System / Q000276:immunology* / Q000294:innervation* / Q000378:metabolism*
chemical_list: D000485:Allergens; D009414:Nerve Growth Factors; C073922:neurotrophin 4