Modulation of Vagal Sensory Neurons via High Mobility Group Box-1 and Receptor for Advanced Glycation End Products: Implications for Respiratory Viral Infections

Stuart B Mazzone,Chen Chen,Brendan Y Chua,Seung-Kwon Yang,Aung Aung Kywe Moe,Luyi Tian,Kirsty R Short,Jaisy Arikkatt,Matthew E Ritchie,Juste Simanauskaite,Matthew W Trewella,Jennifer A Keller,Alice E Mcgovern,Simon Phipps,Matthew J Fogarty

doi:10.3389/fphys.2021.744812

Abstract

Vagal sensory neurons contribute to the symptoms and pathogenesis of inflammatory pulmonary diseases through processes that involve changes to their morphological and functional characteristics. The alarmin high mobility group box-1 (HMGB1) is an early mediator of pulmonary inflammation and can have actions on neurons in a range of inflammatory settings. We hypothesized that HMGB1 can regulate the growth and function of vagal sensory neurons and we set out to investigate this and the mechanisms involved. Culturing primary vagal sensory neurons from wildtype mice in the presence of HMGB1 significantly increased neurite outgrowth, while acute application of HMGB1 to isolated neurons under patch clamp electrophysiological investigation produced inward currents and enhanced action potential firing. Transcriptional analyses revealed the expression of the cognate HMGB1 receptors, Receptor for Advanced Glycation End products (RAGE) and Toll-like Receptor 4 (TLR4), in subsets of vagal sensory neurons. HMGB1-evoked growth and electrophysiological responses were significantly reduced in primary vagal sensory neurons harvested from RAGE deficient mice and completely absent in neurons from RAGE/TLR4 double deficient mice. Immunohistochemical analysis of vagal sensory neurons collected from mice after intranasal infection with murine pneumovirus or influenza A virus (IAV), or after intratracheal administration with the viral mimetic PolyI:C, revealed a significant increase in nuclear-to-cytoplasm translocation of HMGB1 compared to mock-inoculated mice. Neurons cultured from virus infected wildtype mice displayed a significant increase in neurite outgrowth, which was not observed for neurons from virus infected RAGE or RAGE/TLR4 deficient mice. These data suggest that HMGB1 can enhance vagal sensory neuron growth and excitability, acting primarily via sensory neuron RAGE. Activation of the HMGB1-RAGE axis in vagal sensory neurons could be an important mechanism leading to vagal hyperinnervation and hypersensitivity in chronic pulmonary disease.

Highlights

The airways and lungs are densely innervated by sensory neurons, the majority of which are derived from the nodose and jugular vagal sensory ganglia (Mazzone and Undem, 2016)
One neuron expressed detectable transcripts for both Ager and Tlr4, suggestive of largely different neuron subpopulations expressing these receptors for high mobility group box-1 (HMGB1)
High mobility group box-1 is present in the nucleus of most cells where it functions as a nonhistone DNA binding protein

Summary

Introduction

The airways and lungs are densely innervated by sensory neurons, the majority of which are derived from the nodose and jugular vagal sensory ganglia (Mazzone and Undem, 2016). The accompanying airways hyperresponsiveness in these animal models is reduced following the selective inhibition of specific bronchopulmonary sensory neuron subtypes (Trankner et al, 2014; Reznikov et al, 2016). These observations suggest that the pathological events occurring during pulmonary inflammation adversely affect sensory neuron biology leading to the sensory manifestations of lung diseases (Mazzone and Undem, 2016). The mechanisms leading to these inflammation-evoked alterations in vagal sensory biology remain poorly described

Methods

Results

Conclusion