Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity.
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. Bacterial constituents ligate Toll-like receptors (TLRs) on AMs, causing AMs to secrete proinflammatory cytokines that activate alveolar epithelial receptors, leading to recruitment of neutrophils that engulf pathogens. 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 Ca(2+) waves, using the epithelium as the conducting pathway. The intercommunication was immunosuppressive, involving Ca(2+)-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.
Lung Biology Laboratory, Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Columbia University Medical Center, New York, New York 10032, USA.
Kristin
K
Westphalen
Lung Biology Laboratory, Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Columbia University Medical Center, New York, New York 10032, USA.
Galina A
GA
Gusarova
Lung Biology Laboratory, Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Columbia University Medical Center, New York, New York 10032, USA.
Mohammad N
MN
Islam
Department of Medicine, Division of Molecular Medicine, Columbia University Medical Center, New York, New York 10032, USA.
Manikandan
M
Subramanian
Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA.
Taylor S
TS
Cohen
Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA.
Alice S
AS
Prince
1] Lung Biology Laboratory, Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Columbia University Medical Center, New York, New York 10032, USA [2] Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York 10032, USA.
Jahar
J
Bhattacharya
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D002450:Cell Communication; D018031:Connexin 43 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D017629:Gap Junctions / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000166:cytology* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000276:immunology*; D020545:Respiratory Mucosa / Q000166:cytology* / Q000276:immunology*
D018031:Connexin 43; D016207:Cytokines; D008070:Lipopolysaccharides; D002118:Calcium