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Review
. 2018 Mar 27;19(1):50.
doi: 10.1186/s12931-018-0756-5.

Regulation of alveolar macrophage death in acute lung inflammation

Erica K Y Fan  1 , Jie Fan  2   3   4
Affiliations
Review

Regulation of alveolar macrophage death in acute lung inflammation

Erica K Y Fan et al. Respir Res. .

Abstract

Acute lung injury (ALI) and its severe form, known as acute respiratory distress syndrome (ARDS), are caused by direct pulmonary insults and indirect systemic inflammatory responses that result from conditions such as sepsis, trauma, and major surgery. The reciprocal influences between pulmonary and systemic inflammation augments the inflammatory process in the lung and promotes the development of ALI. Emerging evidence has revealed that alveolar macrophage (AM) death plays important roles in the progression of lung inflammation through its influence on other immune cell populations in the lung. Cell death and tissue inflammation form a positive feedback cycle, ultimately leading to exaggerated inflammation and development of disease. Pharmacological manipulation of AM death signals may serve as a logical therapeutic strategy for ALI/ARDS. This review will focus on recent advances in the regulation and underlying mechanisms of AM death as well as the influence of AM death on the development of ALI.

Keywords: Acute lung injury; Autophagy; Cell death; Macrophages; Necroptosis; Pyroptosis.

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Figures

Fig. 1
Fig. 1
IL-1β-IL-1RI-mediateded AM pyroptosis and lung inflammation in response to LPS. In AM LPS-TLR4 signaling not only activates Nlrp3 inflammasome activation and subsequent release of IL-1β, but also up-regulates IL-1RI cell surface expression through MyD88 and NF-κB dependent signaling. The upregulated IL-1RI, therefore, sensitizes AM to IL-1β and results in pyroptosome activation, which in turn leads to AM pyroptosis, a type of caspase-1-dependent inflammatory cell death, and subsequent exaggerated lung inflammation (This figure is adapted from the Ref. [36]. Adapted with permission)
Fig. 2
Fig. 2
Endocytosis of HMGB1 induces pyroptosis. HMGB1 acting through RAGE on macrophages triggers dynamin-dependent endocytosis of HMGB1, which in turn initiates a cascade of cellular and molecular events. These include CatB activation and release from ruptured lysosome followed by pyroptosome formation and caspase-1 activation, which serves as a mechanism underlying the HMGB1-induced pyroptosis (This figure is adapted from the Ref. [21]. Adapted with permission)
Fig. 3
Fig. 3
Trauma-induced mtDNA fragmentation regulates macrophage death. Trauma through CIRP-TLR4-MyD88 signaling induces NADPH oxidase activation and release of ROS, which activate endonuclease G. Endonuclease G directly fragments mtDNA, which triggers macrophage autophagy, as well as necroptosis by separate pathways. However, autophagy also suppresses macrophage necroptosis to limit local inflammation (This figure is adapted from the Ref. [96]. Adapted with permission)
Fig. 4
Fig. 4
Model of the mechanism underlying tissue damage regulation of LPS-induced macrophage necroptosis. LPS acting through TLR4 promotes macrophage necroptosis. However, damaged tissue through HMGB1/RAGE signaling upregulates caveolin-1 expression in macrophage, which, in turn, induces caveolae-mediated TLR4 internalization and desensitization, thereby, ameliorates LPS-TLR4-induced macrophage necroptosis. RAGE-MyD88 signal activation of Cdc42 and the consequent nuclear translocation of Sp1 serve the mechanism of upregulation of caveolin-1 (This figure is adapted from the Ref. [22]. Adapted with permission)
Fig. 5
Fig. 5
The complexity of AM death Regulation following infection, trauma, and HS. LPS, an important PAMP molecule derived from Gram negative bacteria acting through TLR4 promotes AM necroptosis. However, DAMP molecules released from tissue damage, which is a resultant of severe trauma and HS, significantly influence the regulation of AM death. For example, DAMP molecule HMGB1 acting through cell surface RAGE and MyD88-dependent pathway (as illustrated in Fig. 3) ameliorates the TLR4-mediated AM necroptosis. On the other aspect, HMGB1triggers RAGE-dynamin-dependent endocytosis of HMGB1, which promotes AM pyroptosis. HMGB1/TLR4 signaling upregulates NOD2 expression in AM and sensitizes them to subsequent NOD2 ligand MDP to induces autophagy in AM, which negatively regulates lung inflammation through feedback suppression of NOD2-RIP2 signaling and inflammasome activation. DAMP molecule CIRP acts through TLR4-MyD88 signaling to induce mtDNA fragmentation in AM, via a pathway in which NADPH oxidase-derived ROS served as a major mediator for the induction of endonuclease G, which, in turn, directly mediates mtDNA fragmentation. Fragmented mtDNA then triggered AM autophagy and necroptosis through separate signaling pathways, although autophagy also suppressed AM necroptosis, to attenuate propagation of local inflammation. Therefore, AM autophagy represents an intracellular negative regulation of AM death, whereas, pyroptosis serves as a dominant AM death form in a condition combined with infection, trauma and hemorrhage
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