• Gareth L Ackland, Vitaly Kazymov, Nephtali Marina, Mervyn Singer, and Alexander V Gourine.
• Department of Medicine, Division of Medicine, Bloomsbury Institute of Intensive Care Medicine, University College London, London, United Kingdom. g.ackland@ucl.ac.UK
• Crit. Care Med. 2013 Jun 1; 41 (6): e85-92.

ObjectiveBidirectional 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.DesignRandomized, controlled laboratory investigation.SettingUniversity laboratory.SubjectsC57Bl/6J mice; juvenile Sprague-Dawley rats, primary human neutrophils.InterventionsRat 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.Measurements And Main ResultsChemosensitive 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.ConclusionsIn 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.

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