An NT4/TrkB‐dependent increase in innervation links early‐life allergen exposure to persistent airway hyperreactivity

Abstract

Children who are exposed to environmental respiratory insults often develop asthma that persists into adulthood. In this study, we used a neonatal mouse model of ovalbumin (OVA)-induced allergic airway inflammation to understand the long-term effects of early childhood insults on airway structure and function. We showed that OVA sensitization and challenge in early life led to a 2-fold increase in airway smooth muscle (ASM) innervation (P<0.05) and persistent airway hyperreactivity (AHR). In contrast, OVA exposure in adult life elicited short-term AHR without affecting innervation levels. We found that postnatal ASM innervation required neurotrophin (NT)-4 signaling through the TrkB receptor and that early-life OVA exposure significantly elevated NT4 levels and TrkB signaling by 5- and 2-fold, respectively, to increase innervation. Notably, blockade of NT4/TrkB signaling in OVA-exposed pups prevented both acute and persistent AHR without affecting baseline airway function or inflammation. Furthermore, biophysical assays using lung slices and isolated cells demonstrated that NT4 was necessary for hyperreactivity of ASM induced by early-life OVA exposure. Together, our findings show that the NT4/TrkB-dependent increase in innervation plays a critical role in the alteration of the ASM phenotype during postnatal growth, thereby linking early-life allergen exposure to persistent airway dysfunction.

Neurotrophins in Asthma

“…NT4 levels in mouse lungs peaked at postnatal day 14. In contrast, the BDNF levels were higher in the fetal lung than postnatal lungs [57••]. In addition, compared to BDNF −/− and TrkB −/− mice that die early postnatally, NT4 −/− mice mature into adulthood, breed normally, and exhibit no obvious behavior defects.…”

“…These findings indicate that BDNF and NT4 play distinct roles that may be explained at least in part by the difference in temporal expression. NT4 was expressed by ASM, PNECs, and mast cells in postnatal lungs of mouse, nonhuman primates, and humans [40••, 57••, 58••] (Fig. 3).…”

“…3). NT4 is required for the innervation of the lung, as NT4 −/− mice have significantly less nerve density in ASM and selective reduction of PNEC innervation by purinergic nerves [40••, 57••]. …”

“…These findings emphasize early life as a critical time window for the susceptibility to asthma. Notably, NT4 −/− mice were protected from early life allergen-induced airway hyperinnervation, hypercontractility, and mucus overproduction, while having no change in airway inflammation [57••, 59]. Lineage tracing of TrkB in mice showed highly selective TrkB expression in nerves (Fig.…”

Neurotrophin signaling and visceral hypersensitivity

“…In addition to its ability in affecting neuronal function via retrograde fashion, BDNF and receptor TrkB more likely undergo antergrade transport away from neuronal cell bodies (Tonra et al, 1998; Ng et al, 2007; Ha et al, 2008). NT-4, which is often interchangeable with BDNF in initiating TrkB-mediated signal transduction, also has a role in the periphery in sensitizing peripheral innervation and sensory sensitivity (Krimm et al, 2006; Aven et al, 2014; Huang and Krimm, 2014). …”