Diverse macrophage populations mediate acute lung inflammation and resolution - PubMed (original) (raw)

Fig. 1.

A schematic displaying major alveolar macrophage phenotypes and functions during steady state, inflammation, and resolution. During quiescence, macrophages are tethered to epithelial cells, with persistent expression of pattern recognition (TLRs) and scavenger (Dectin-1) receptors. Turnover is slow and driven primarily by M-CSF/GM-CSF induced local proliferation, with minimal recruitment from circulating monocytes. With increased foreign antigen stimulation (PAMPs, DAMPs), macrophage activation occurs, skewing resident macrophages toward an M1 activation state (transcription factors NF-κB, STAT1, IRF-5; cytokines IFN-γ, TNF-α, IL-1β, IL-12) hallmarked by secretion of proinflammatory cytokines capable of neutrophil (MIP-2/KC) and inflammatory monocyte/macrophage recruitment (MCP-1/CCL2), as well as stimulation of alveolar epithelial cells (TNF-α) and effector T cells (CD86-CD28) to help promote and sustain the inflammatory response. With sufficient control of foreign antigen, macrophages reprogram toward an M2 activation state (transcription factors STAT6, STAT3, IRF-4, 15-LO; cytokines IL-4, IL-13, IL-10) and coordinate a series of regulated responses to abrogate inflammation, and enhance resolution/repair. Key processes include cessation of inflammatory cell recruitment (IL-1ra, MMPs); apoptosis of inflammatory cells (IL-1ra, TRAIL, IL-10, TGF-β); interaction with Tregs; and secretion of lipoxins, resolvins, and growth factors to promote epithelial repair and type II to type I AEC transition. AEC, alveolar epithelial cell; CCL2, chemokine (C-C motif) ligand 2; CCR2, chemokine (C-C motif) receptor 2; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN-γ, interferon-γ; IL, interleukin; IL-1ra, interleukin 1 receptor antagonist; iNOS, inducible nitric oxide synthase; IRF, interferon regulator factor; LO, lipoxygenase; M-CSF, macrophage colony-stimulating factor; MCP-1, monocyte chemoattractant protein-1; MIP-2, macrophage inflammatory protein-2; MMPs, matrix metalloproteinases; MR, mannose receptor (MRC1); NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; PMN, polymorphonuclear leukocyte (neutrophil); STAT, signal transducer and activator of transcription; TGF-β, transforming growth factor β; TLRs, Toll-like receptors; TNF-α, tumor necrosis factor-α; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; Treg, regulatory T cell.