IL33 regulates airway neuronal plasticity in vitro

Abstract

Rationale: In recent years, more evidence has become available showing that airway nerves may undergo remodeling in asthma. The mechanisms involved in this response remain largely unknown. We aimed to assess the role of IL13 and IL33 in neuronal plasticity via secretion of ASM-derived neurotrophic factors (NTFs) such as BDNF and its receptor TrkB.

Methods: Primary bovine airway smooth muscle (bASM) or human (hASM) cells were stimulated with IL13 or IL33, either in mono-cultures or in co-cultures with neuronal SH-SY5Y cells. Single-cell RNA seq data from airway biopsies of asthma patients was mined to assess the expression of NTFs and their receptors.

Results: IL33 stimulation of bASM/SH-SY5Y and hASM/SH-SY5Y co-cultures increased BDNF expression, whereas IL13 stimulation did not alter BDNF/TrkB expression. IF staining showed an increased neuronal density upon IL33 stimulation in bASM/SH-SY5Y and hASM/SH-SY5Y co-cultures. Inhibiting the IL33 receptor ST2/IL1RL1 abolished the effect, whereas anti-BDNF partially prevented the augmented neuronal network formation. Single-cell seq data from asthma patients indicated TrkB being primarily expressed in ASM and increased in expression in asthmatic donors. Furthermore, in biopsies from asthma patients, a correlation was found between IL33 receptor IL1RL1 and TrkB mRNA expression.

Conclusions: IL33 is a potential link between airway inflammation and airway neuronal plasticity, as IL-33 increased BDNF and TrkB expression and neuronal density in vitro. Increased neuronal density could be inhibited by anti-ST2 and is partially mediated via TrkB/BDNF. Importantly, patient data showed a correlation between IL1RL1 and TrkB, suggesting a critical role for IL33 in neuronal plasticity in asthma.