Efferocytosis and lung disease

Abstract

In healthy individuals, billions of cells die by apoptosis each day. Clearance of these apoptotic cells, termed "efferocytosis," must be efficient to prevent secondary necrosis and the release of proinflammatory cell contents that disrupt tissue homeostasis and potentially foster autoimmunity. During inflammation, most apoptotic cells are cleared by macrophages; the efferocytic process actively induces a macrophage phenotype that favors tissue repair and suppression of inflammation. Several chronic lung diseases, particularly airways diseases such as chronic obstructive lung disease, asthma, and cystic fibrosis, are characterized by an increased lung burden of uningested apoptotic cells. Alveolar macrophages from individuals with these chronic airways diseases have decreased efferocytosis relative to alveolar macrophages from healthy subjects. These two findings have led to the hypothesis that impaired apoptotic cell clearance may contribute causally to sustained lung inflammation and that therapies to enhance efferocytosis might be beneficial. This review of the English-language scientific literature (2006 to mid-2012) explains how such existing therapies as corticosteroids, statins, and macrolides may act in part by augmenting apoptotic cell clearance. However, efferocytosis can also impede host defenses against lung infection. Thus, determining whether novel therapies to augment efferocytosis should be developed and in whom they should be used lies at the heart of efforts to differentiate specific phenotypes within complex chronic lung diseases to provide appropriately personalized therapies.

Figure 1.

Interplay between controlling factors and consequences of decreased efferocytosis in the lung. A, Processes increasing AC accumulation in inflammatory lung diseases. Although the basal efferocytic capacity of resident AMøs is low, oxidant stress and proteolytic events during inflammation can further reduce concentrations of efferocytic opsonins and cleave efferocytic receptors, leading to greater apoptotic cell accumulation. Uncleared apoptotic cells undergo secondary necrosis, which can expose autoantigens. Uningested apoptotic cells can also stimulate NKT cells to activate DCs, driving maturation of T cells, which can be proinflammatory or even autoreactive. The resulting release of inflammatory cytokines can both increase DC activation and further decrease efferocytosis. B, Feedback loops resulting from decreased efferocytosis. Oxidant stress, inflammatory cytokines, and autoimmunity can all amplify alveolar destruction, a potential source of ACs. Alveolar destruction itself amplifies inflammatory cytokine release and oxidant stress. Decreased efferocytic opsonins and increased inflammatory cytokines enhance leukocyte recruitment. Evidence linking a specific disease to any of these factors or consequences is noted with colored circles. AC = apoptotic cell; ALI = acute lung injury; AMø = alveolar macrophage; CF = cystic fibrosis; DC = dendritic cell; NKT = natural killer T; TNF = tumor necrosis factor. (Illustration by Haderer & Muller Biomedical Art, LLC.)

Figure 2.

Theoretical positive and negative effects of therapeutic enhancement of efferocytosis. Increasing efferocytosis could accelerate tissue repair and resolution of inflammation, helping to break the destructive cycle of inflammatory lung disease. Conversely, increasing efferocytosis may leave the phagocyte that ingested apoptotic cells less able to recognize and kill pathogenic microbes, as has been demonstrated in a murine model. PAMP = pathogen-associated molecular pattern. See Figure 1 legend for expansion of other abbreviation. (Illustration by Haderer & Muller Biomedical Art, LLC.)

Figure 3.

Surfactant therapy and antioxidants work through the same pathway to enhance efferocytosis. Oxidant stress activates RhoA, an inhibitor of Rac-dependent actin rearrangement that is required for engulfment of ACs; antioxidants suppress RhoA, allowing Rac activation and permitting apoptotic cell engulfment (shown on the left). Surfactant therapy decreases oxidant stress and may favor antioxidant production, shifting the balance toward RhoA inhibition and apoptotic cell ingestion (shown on the right). See Figure 1 legend for expansion of abbreviation. (Illustration by Haderer & Muller Biomedical Art, LLC.)