Sessile alveolar macrophages modulate immunity through connexin 43-based epithelial communication

Tissue-resident macrophages of barrier organs constitute the first line of defense against pathogens at the systemic interface with the ambient environment. In lung, resident alveolar macrophages (AMs) provide 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). However, since the AM-induced immune response could itself cause tissue injury, it is unclear how AMs modulate the response to prevent injury. Here, through real-time alveolar imaging in situ, we show that a subset of AMs attached to the alveolar wall, formed connexin 43 (Cx43)-containing gap junctional channels (GJCs) with the epithelium. During lipopolysaccharide (LPS)-induced inflammation, the AMs remained alveolus-attached and sessile, 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, since AM-specific knockout of Cx43 enhanced alveolar neutrophil recruitment and secretion of proinflammatory cytokines in the bronchoalveolar lavage (BAL). The picture emerges of a novel immunomodulatory process in which a subset of alveolus-attached AMs intercommunicates immunosuppressive signals to reduce endotoxin-induced lung inflammation.