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Crit Care Med. 2013 Jun;41(6):e85-92. doi: 10.1097/CCM.0b013e31827c0b05.

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

Author information

1
Department of Medicine, Division of Medicine, Bloomsbury Institute of Intensive Care Medicine, University College London, London, United Kingdom. g.ackland@ucl.ac.UK

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.

DESIGN:

Randomized, controlled laboratory investigation.

SETTING:

University laboratory.

SUBJECTS:

C57Bl/6J mice; juvenile Sprague-Dawley rats, primary human neutrophils.

INTERVENTIONS:

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.

MEASUREMENTS AND MAIN 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.

PMID:
23507714
PMCID:
PMC4154842
DOI:
10.1097/CCM.0b013e31827c0b05
[Indexed for MEDLINE]
Free PMC Article

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