Peripheral neural detection of danger-associated and pathogen-associated molecular patterns

• Published in: Critical care medicine Vol. 41; no. 6; p. e85
• Main Authors: Ackland, Gareth L, Kazymov, Vitaly, Marina, Nephtali, Singer, Mervyn, Gourine, Alexander V
• Format: Journal Article
• Language: English
• Published: United States 01.06.2013
• Subjects: Animals; Calcium - metabolism; Carotid Body - drug effects; Carotid Sinus - immunology; Carotid Sinus - innervation; Disease Models, Animal; Humans; Inflammation Mediators - immunology; Lipopolysaccharides - pharmacology; Mice; Mice, Inbred C57BL; Neutrophils; Random Allocation; Rats; Rats, Sprague-Dawley; Toll-Like Receptors - agonists; Zymosan - pharmacology
• ISSN: 1530-0293
• DOI: 10.1097/CCM.0b013e31827c0b05

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. Randomized, controlled laboratory investigation. University laboratory. C57Bl/6J mice; juvenile Sprague-Dawley rats, primary human neutrophils. 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. 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. 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.