Regulation of alveolar macrophage death in acute lung inflammation

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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.

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Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis.

Jie ZHAO, Siriporn Jitkaew, Zhenyu Cai … (2012)

Tumor necrosis factor (TNF) is an important inflammatory cytokine and induces many cellular responses, including inflammation, cell proliferation, apoptosis, and necrosis. It is known that receptor interacting protein (RIP) kinases, RIP1 and RIP3, are key effectors of TNF-induced necrosis, but little is known about how these two RIP kinases mediate this process, although reactive oxygen species (ROS) generation and JNK activation have been suggested to be two downstream events of RIP kinases. Here we report the identification of mixed lineage kinase domain-like, MLKL, as a key RIP3 downstream component of TNF-induced necrosis. Through screening a kinase/phosphatase shRNA library in human colon adenocarcinoma HT-29 cells, we found that knockdown of MLKL blocked TNF-induced necrosis. Our data suggest that MLKL functions downstream of RIP1 and RIP3 and is recruited to the necrosome through its interaction with RIP3. Finally, we found that MLKL is required for the generation of ROS and the late-phase activation of JNK during TNF-induced necrosis. However, because these two events are not involved in TNF-induced necrosis in HT-29 cells, the target of MLKL during TNF-induced necrosis remains elusive. Taken together, our study suggests that MLKL is a key RIP3 downstream component of TNF-induced necrotic cell death.

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Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death

Xin-Xin Chen, Wenjuan Li, Junming Ren … (2013)

Mixed lineage kinase domain-like protein (MLKL) was identified to function downstream of receptor interacting protein 3 (RIP3) in tumor necrosis factor-α (TNF)-induced necrosis (also called necroptosis). However, how MLKL functions to mediate necroptosis is unknown. By reconstitution of MLKL function in MLKL-knockout cells, we showed that the N-terminus of MLKL is required for its function in necroptosis. The oligomerization of MLKL in TNF-treated cells is essential for necroptosis, as artificially forcing MLKL together by using the hormone-binding domain (HBD*) triggers necroptosis. Notably, forcing together the N-terminal domain (ND) but not the C-terminal kinase domain of MLKL causes necroptosis. Further deletion analysis showed that the four-α-helix bundle of MLKL (1-130 amino acids) is sufficient to trigger necroptosis. Both the HBD*-mediated and TNF-induced complexes of MLKL(ND) or MLKL are tetramers, and translocation of these complexes to lipid rafts of the plasma membrane precedes cell death. The homo-oligomerization is required for MLKL translocation and the signal sequence for plasma membrane location is located in the junction of the first and second α-helices of MLKL. The plasma membrane translocation of MLKL or MLKL(ND) leads to sodium influx, and depletion of sodium from the cell culture medium inhibits necroptosis. All of the above phenomena were not seen in apoptosis. Thus, the MLKL oligomerization leads to translocation of MLKL to lipid rafts of plasma membrane, and the plasma membrane MLKL complex acts either by itself or via other proteins to increase the sodium influx, which increases osmotic pressure, eventually leading to membrane rupture.

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Selective autophagy mediated by autophagic adapter proteins.

Terje Johansen, Trond Lamark (2011)

Mounting evidence suggests that autophagy is a more selective process than originally anticipated. The discovery and characterization of autophagic adapters, like p62 and NBR1, has provided mechanistic insight into this process. p62 and NBR1 are both selectively degraded by autophagy and able to act as cargo receptors for degradation of ubiquitinated substrates. A direct interaction between these autophagic adapters and the autophagosomal marker protein LC3, mediated by a so-called LIR (LC3-interacting region) motif, their inherent ability to polymerize or aggregate as well as their ability to specifically recognize substrates are required for efficient selective autophagy. These three required features of autophagic cargo receptors are evolutionarily conserved and also employed in the yeast cytoplasm-to-vacuole targeting (Cvt) pathway and in the degradation of P granules in C. elegans. Here, we review the mechanistic basis of selective autophagy in mammalian cells discussing the degradation of misfolded proteins, p62 bodies, aggresomes, mitochondria and invading bacteria. The emerging picture of selective autophagy affecting the regulation of cell signaling with consequences for oxidative stress responses, tumorigenesis and innate immunity is also addressed.

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Author and article information

Contributors

Jie Fan:

ORCID: http://orcid.org/0000-0002-0090-2704

jif7@pitt.edu

Journal

Journal ID (nlm-ta): Respir Res

Journal ID (iso-abbrev): Respir. Res

Title: Respiratory Research

Publisher: BioMed Central (London )

ISSN (Print): 1465-9921

ISSN (Electronic): 1465-993X

Publication date (Electronic): 27 March 2018

Publication date PMC-release: 27 March 2018

Publication date (Print): 2018

Volume: 19

Electronic Location Identifier: 50

Affiliations

[1 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Kenneth P. Dietrich School of Arts & Sciences, University of Pittsburgh, ; Pittsburgh, PA 15260 USA

[2 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Department of Surgery, , University of Pittsburgh School of Medicine, ; Pittsburgh, PA 15213 USA

[3 ]ISNI 0000 0004 0420 3665, GRID grid.413935.9, Research and Development, , Veterans Affairs Pittsburgh Healthcare System, ; Pittsburgh, PA 15240 USA

[4 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, McGowan Institute for Regenerative Medicine, , University of Pittsburgh, ; Pittsburgh, PA 15219 USA

Author information

Jie Fan http://orcid.org/0000-0002-0090-2704

Article

Publisher ID: 756

DOI: 10.1186/s12931-018-0756-5

PMC ID: 5872399

PubMed ID: 29587748

SO-VID: 8aa810ff-bc36-4564-baf6-9a75b88bfbff

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 17 January 2018

Date accepted : 5 March 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;

Award ID: HL-079669

Award ID: HL076179-09

Award Recipient : Jie Fan

Funded by: FundRef http://dx.doi.org/10.13039/100000738, U.S. Department of Veterans Affairs;

Award ID: 1I01BX002729

Award Recipient : Jie Fan

Custom metadata

ScienceOpen disciplines: Respiratory medicine

Keywords: acute lung injury,macrophages,cell death,pyroptosis,necroptosis,autophagy

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ScienceOpen disciplines: Respiratory medicine

Keywords: acute lung injury, macrophages, cell death, pyroptosis, necroptosis, autophagy

Regulation of alveolar macrophage death in acute lung inflammation

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Abstract

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Inflamed lung in vitro co-culture models

Most cited references 69

Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis.

Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death

Selective autophagy mediated by autophagic adapter proteins.

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