Journal
NATURE
Volume 506, Issue 7489, Pages 503-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature12902
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Funding
- US National Institutes of Health [HL78645, HL57556, HL64896, HL73989]
- Parker B. Francis Fellowships
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The tissue-resident macrophages of barrier organs constitute the first line of defence against pathogens at the systemic interface with the ambient environment. In the lung, resident alveolar macrophages (AMs) provide a sentinel function against inhaled pathogens(1). Bacterial constituents ligate Toll-like receptors (TLRs) on AMs(2), causing AMs to secrete proinflammatory cytokines(3) that activate alveolar epithelial receptors(4), leading to recruitment of neutrophils that engulf pathogens(5,6). Because the AM-induced response could itself cause tissue injury, it is unclear how AMs modulate the response to prevent injury. Here, using real-time alveolar imaging in situ, we show that a subset of AMs attached to the alveolar wall form connexin 43 (Cx43)-containing gap junction channels with the epithelium. During lipopolysaccharide-induced inflammation, the AMs remained sessile and attached to the alveoli, and they established intercommunication through synchronized Ca2+ waves, using the epithelium as the conducting pathway. The intercommunication was immunosuppressive, involving Ca2+-dependent activation of Akt, because AM-specific knockout of Cx43 enhanced alveolar neutrophil recruitment and secretion of proinflammatory cytokines in the bronchoalveolar lavage. A picture emerges of a novel immunomodulatory process in which a subset of alveolus-attached AMs intercommunicates immunosuppressive signals to reduce endotoxin-induced lung inflammation.
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