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

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.

Cough hypersensitivity and chronic cough

“…Animal studies also suggest that neural plasticity during pulmonary pathologies may relate to neuroinflammation within the vagus nerve or ganglia, characterized by increased inflammatory cell influx, upregulated inflammatory gene transcription and the release of inflammatory molecules from sensory neurons and resident or infiltrating immune cells 88 – 90 . The cause of this neuroinflammation is unclear, but likely relates to both peripheral vagal detection of tissue inflammation and adverse effects of inflammation-induced persistent firing of action potentials in sensory neurons 88 , 91 .…”

Evidence for vagal sensory neural involvement in influenza pathogenesis and disease

“…We have previously shown that severe pulmonary IAV infections in mice are accompanied by a neuroinflammatory phenotype in the vagal sensory ganglia [19, 20]. To investigate whether peripheral sensory neuron activation in the lungs is involved in the development of vagal neuroinflammation, we compared the expression of inflammatory genes and inflammatory cell densities in the vagal sensory ganglia of IAV infected mice administered via inhalation from day 3 post IAV infection with either vehicle or QX-314 (Fig 2A).…”

“…We have previously shown that severe pulmonary IAV infections in mice are accompanied by a neuroinflammatory phenotype in the vagal sensory ganglia [19,20]…”

“…This neuropathy is characterized by an infiltration of immune cells into the vagus nerve and the upregulation of genes in the sensory neurons associated with host defense and inflammation [19]. In addition, these neurons respond by translocating the alarmin high mobility group box-1 (HMGB1) from the nucleus to the cytoplasm, which could serve as a mediator of hyperinnervation and prolonged hypersensitivity by promoting vagal sensory neurite growth and excitability [20].…”

Cough hypersensitivity and chronic cough

“…However, clinical trials employing antagonists acting at each of these channels have so far failed to demonstrate any benefit against natural cough in human patient populations 15,90 , suggesting animal studies of reflex cough hypersensitivity may not adequately reflect cough hypersensitivity leading to chronic cough in humans. Animal studies also suggest that neural plasticity during pulmonary pathologies may relate to a neuroinflammatory state (neuropathy) within the vagus nerve or ganglia characterized by increased inflammatory cell influx, upregulated inflammatory gene transcription and the release of inflammatory molecules from sensory neurons and resident or infiltrating immune cells [91][92][93] . The cause of this vagal neuropathy is unclear, but likely relates to both peripheral vagal detection of tissue inflammation and adverse effects associated with inflammation-induced persistent firing of action potentials in sensory neurons 91,94 .…”