The role of pulmonary mast cells in neurotrophin 4 mediated cholinergic neuroplasticity in neonatal asthma
Patel, Kruti Rajan
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Asthma is a chronic inflammatory lung disease characterized by recurrent wheezing, coughing and difficulties in breathing. Asthma affects 25.7 million people in the USA including 8 million children. Asthma is often associated with early-life exposure to environmental insults. However, mechanisms that link early-life insults to persistent airway dysfunction are unknown. Our previous studies in mice showed that early-life allergen exposure increases the levels of neurotrophin 4 (NT4) causing airway smooth muscle (ASM) hyper innervation and persistent airway hyper reactivity (AHR). I show that early-life allergen exposure selectively increases cholinergic innervation. Notably, cholinergic nerves release acetylcholine, a potent airway constrictor that signals through the M3 receptor in ASM. Building upon these findings, my thesis encompasses two components. Firstly, how is NT4 expression aberrantly up regulated following early-life allergen exposure? Secondly, what is the effect of enhanced cholinergic innervation on the neonatal ASM? I find that NT4 is selectively expressed by ASM and mast cells in mice, nonhuman primates and humans. We show in mice that while NT4 expression in ASM remains unchanged upon allergen exposure, mast cells expand in number and degranulate to release NT4 thereby increasing NT4 levels in the lung. Adoptive transfer of wild-type mast cells, but not NT4-/- mast cells restores ASM innervation and AHR in KitW-sh/W-sh mice following early-life insults. In an infant primate model of asthma, the increased ASM innervation is also associated with the expansion and degranulation of mast cells. Therefore, pulmonary mast cells are a key source of aberrant NT4 expression following early-life insults in both mice and possibly primates. Next, I speculated that an increased cholinergic output in the neonatal lung might lead to persistent AHR. Using recurrent methacholine exposure and M3 receptor blocker, 4-DAMP, I show that enhanced cholinergic signaling in neonatal mice leads to persistent AHR without inflammation. In contrast, methacholine exposure in adult mice has no prolonged effects on airway reactivity. Together, my findings support a model in which deregulated neural activities following early-life insults cause persistent ASM hyper contractility. Thus, early-life interventions to block mast cell degranulation and the cholinergic pathway may benefit children with recurrent wheezing.