title: Peripheral neural detection of danger-associated and pathogen-associated molecular patterns.
abstract: OBJECTIVE
  Bidirectional links between the nervous and immune systems modulate inflammation. The cellular mechanisms underlying the detection of danger-associated molecular patterns and pathogen-associated molecular patterns by the nervous system are not well understood. We hypothesized that the carotid body, a tissue of neural crest origin, detect pathogen associated molecular patterns and danger associated molecular patterns via an inflammasome-dependent mechanism similar to that described in immune cells.
  
  
  METHODS
  Randomized, controlled laboratory investigation.
  
  
  METHODS
  University laboratory.
  
  
  METHODS
  C57Bl/6J mice; juvenile Sprague-Dawley rats, primary human neutrophils.
  
  
  METHODS
  Rat carotid body chemosensitive cells, and human neutrophils, were treated with TLR agonists to activate inflammasome-dependent pathways. In mice, systemic inflammation was induced by the pathogen associated molecular pattern zymosan (intraperitoneal injection; 500 mg/kg). Isolated carotid body/carotid sinus nerve preparations were used to assess peripheral chemoafferent activity. Ventilation was measured by whole-body plethysmography.
  
  
  RESULTS
  Chemosensitive carotid body glomus cells exhibited toll-like receptor (TLR-2 and TLR-4), NLRP1, and NLRP3 inflammasome immunoreactivities. Zymosan increased NLRP3 inflammasome and interleukin-1β expression in glomus cells (p < 0.01). Human neutrophils demonstrated similar LPS-induced changes in inflammasome expression. Carotid body glomus cells also expressed IL-1 receptor and responded to application of IL-1β with increases in intracellular [Ca]. Four hours after injection of zymosan carotid sinus nerve chemoafferent discharge assessed in vitro (i.e., in the absence of acidosis/circulating inflammatory mediators) was increased five-fold (p < 0.001). Accordingly, zymosan-induced systemic inflammation was accompanied by enhanced respiratory activity.
  
  
  CONCLUSIONS
  In carotid body chemosensitive glomus cells, activation of toll-like receptors increases NLRP3 inflammasome expression, and enhances IL-1β production, which is capable of acting in an autocrine manner to enhance peripheral chemoreceptor drive.
authors.affiliation: Department of Medicine, Division of Medicine, Bloomsbury Institute of Intensive Care Medicine, University College London, London, United Kingdom. g.ackland@ucl.ac.UK
authors.forename: Gareth L
authors.initials: GL
authors.lastname: Ackland
authors.forename: Vitaly
authors.initials: V
authors.lastname: Kazymov
authors.forename: Nephtali
authors.initials: N
authors.lastname: Marina
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Gourine
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002344:Carotid Body / Q000187:drug effects*; D002346:Carotid Sinus / Q000276:immunology* / Q000294:innervation; D004195:Disease Models, Animal; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051193:Toll-Like Receptors / Q000819:agonists*; D015054:Zymosan / Q000494:pharmacology
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D015054:Zymosan; D002118:Calcium