Acute lung injury: how macrophages orchestrate resolution of inflammation and tissue repair

Abstract

Lung macrophages are long living cells with broad differentiation potential, which reside in the lung interstitium and alveoli or are organ-recruited upon inflammatory stimuli. A role of resident and recruited macrophages in initiating and maintaining pulmonary inflammation in lung infection or injury has been convincingly demonstrated. More recent reports suggest that lung macrophages are main orchestrators of termination and resolution of inflammation. They are also initiators of parenchymal repair processes that are essential for return to homeostasis with normal gas exchange. In this review we will discuss cellular cross-talk mechanisms and molecular pathways of macrophage plasticity which define their role in inflammation resolution and in initiation of lung barrier repair following lung injury.

Keywords: inflammation; lung; macrophage; repair; resolution.

Figure 1

Macrophages terminate and resolve alveolar inflammation after acute inflammatory lung injury and coordinate structural and functional parenchymal repair processes that are essential for return to homeostasis. Inflammation resolution and tissue repair after injury involve a variety of timely coordinated, active processes in which lung macrophages are directly or indirectly involved: Inhibition of granulocyte (PMN) and monocyte recruitment from the circulation, phagocytosis of apoptotic neutrophils or parenchymal cells, removal of fibrin, clearance of alveolar edema fluid, and repair of the endo- and epithelial barrier by junctional sealing and induction of angiogenesis and proliferation/differentiation of epithelial progenitor cells including type II alveolar epithelial cells (AEC).

Figure 2

Different extracellular signals are integrated to shape pulmonary macrophage phenotypes during lung inflammation. First, growth factors such as GM-CSF, M-CSF, or type I interferons (IFN) drive differentiation and activation of macrophage progenitors or lineage precursors (1), second, macrophages obtain signals from chemokines or cellular adhesion molecules upon transendo/epithelial recruitment to the alveoli (2), third, macrophages receive signals from cytokines like GM-CSF and interferons (M1) or IL-4, IL-13, IL-25, or IL-33 (M2) (3); fourth, pathogens, PAMPs, or DAMPs deliver signals via TLR, NLR, or other pattern recognition receptors (4). Later on, cell–cell communications during phagocytosis of apoptotic neutrophils (PMN) or via CD200–CD200R interaction with AEC add on these signals and may support an anti-inflammatory macrophage phenotype (5). JAMs, junctional adhesion molecules; HSP, heat shock proteins; HMGB-1, high mobility group box-1; S. pn., Streptococcus pneumoniae; K. pn., Klebsiella pneumoniae; AEC, alveolar epithelial cells.