Diverse macrophage populations mediate acute lung inflammation and resolution

Abstract

Acute respiratory distress syndrome (ARDS) is a devastating disease with distinct pathological stages. Fundamental to ARDS is the acute onset of lung inflammation as a part of the body's immune response to a variety of local and systemic stimuli. In patients surviving the inflammatory and subsequent fibroproliferative stages, transition from injury to resolution and recovery is an active process dependent on a series of highly coordinated events regulated by the immune system. Experimental animal models of acute lung injury (ALI) reproduce key components of the injury and resolution phases of human ARDS and provide a methodology to explore mechanisms and potential new therapies. Macrophages are essential to innate immunity and host defense, playing a featured role in the lung and alveolar space. Key aspects of their biological response, including differentiation, phenotype, function, and cellular interactions, are determined in large part by the presence, severity, and chronicity of local inflammation. Studies support the importance of macrophages to initiate and maintain the inflammatory response, as well as a determinant of resolution of lung inflammation and repair. We will discuss distinct roles for lung macrophages during early inflammatory and late resolution phases of ARDS using experimental animal models. In addition, each section will highlight human studies that relate to the diverse role of macrophages in initiation and resolution of ALI and ARDS.

Keywords: ARDS; activation; inflammation; macrophage.

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.