Relationship:924

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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
Cell injury/death, N/A Cytokine, Release

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
Lysosomal damage leading to liver inflammation Directly Leads to Strong Weak

Taxonomic Applicability

Name Scientific Name Evidence Links
mouse Mus musculus Strong NCBI
human Homo sapiens Moderate NCBI

How Does This Key Event Relationship Work

Apoptosis is a complex process that regulates whether cell death leads to the induction of inflammation or quiet removal of a damaged cell, for example during development or normal tissue turnover. This most likely depends on the severity of the effect[1]. Additional cell death mechanisms are known to be potent inducers of inflammation, such as necrosis (including secondary necrosis which can follow apoptosis if the removal of apoptotic cells by phagocytic cells fails). Necrosis leads to the release of intracellular contents into the extracellular milieu, thus inducing an inflammatory response[2].

The induction of inflammation by apoptosis is usually linked to infiltration of neutrophils, which are recruited by secreted CXC chemokines. Dying hepatocytes can release intracellular molecules known as damage-associated molecular patterns (DAMPs), which, if persistent, can induce the so-called sterile inflammation. This occurs in the absence of pathogens and is a key factor for the development of (liver) inflammation [3][4]. Mitochondrial DNA (mtDNA) and mitochondria-derived formyl peptides are examples of mitochondria-derived DAMPs which bind to pattern recognition receptors (PPRs) such as toll-like receptors (TLRs). TLRs are found expressed in most liver cells, including hepatocytes, Kupffer cells (KCs) or hepatic stellate cells (HPCs) [3]. Specifically, mtDNA-activated TLR9 has recently been described to play a role in the development of liver inflammation and accompanied induction of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-a) [5].

Fas is a cell surface glycoprotein that belongs to the tumor necrosis factor receptor family. It is known that ligation of the Fas receptor promotes the proteolytic cleavage of intracellular caspases and thus leads to the induction of apoptosis[6]. Activation of Fas directly leads to the activation of caspase-3 and induction of a variety of cytokines such as macrophage inflammatory protein-2 (MIP-2)/IL-8, KC, IL-6, MCP-1/CCL2 and sICAM-1. However, when caspase-3 was inhibited, the chemokine-induction was significantly reduced. Faouzi and coworkers could also show that the transcription factor AP-1, and not NF-kB, was involved in the onset of apoptosis-induced liver inflammation[6][7].

Weight of Evidence

Biological Plausibility

The severity of cell death activation determines the outcome for the cell: inflammation is part of the tissue regeneration process, and intermediate apoptotic stimuli are able to trigger this response. Recruitment of inflammatory cells such as neutrophils is meant as a beneficial process, as for example apoptotic bodies of bacteria-infected cells can be removed. Thus the apoptotic cells can secrete soluble "find-me" factors that trigger infiltration of immune cells. However, if this becomes chronic it has the potential to enhance tissue damage and ultimately induce fibrosis[1][7].

Empirical Support for Linkage

Include consideration of temporal concordance here

A high fat diet increases the amount of plasma mtDNA levels, which were shown to induce TLR9, accompanied by the induction of TNF-a. TLR9 knock-out mice were shown to show less severe symptoms for developing liver inflammation when put on a high fat diet compared to control mice [5].

Induction of apoptosis by using an anti-Fas antibody was found to lead to upregulation and secretion of KC and MIP-2 in liver tissue, while inhibition of caspase-3 significantly reduced chemokine-induction[6].

Uncertainties or Inconsistencies

No dose-response or time dependency is described; proof is presented mainly by using respective inhibitors.

Quantitative Understanding of the Linkage

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Currently, there is no quantitative understanding of this KER. The use of Fas-inhibitors has led to understanding this mechanism. Interestingly, an increase of the stimulus (increased concentrations of anti-Fas) has led to decreased cytokine formation which is explained by a potential caspase-3-dependent block in chemokine translation[6].

Evidence Supporting Taxonomic Applicability

[6][5][7]: mouse [7]: human

References

  1. 1.0 1.1 Jaeschke H. Inflammation in response to hepatocellular apoptosis. Hepatology. 2002 Apr;35(4):964-6
  2. Hirsova P, Gores GJ. Death Receptor-Mediated Cell Death and Proinflammatory Signaling in Nonalcoholic Steatohepatitis. Cell Mol Gastroenterol Hepatol. 2015 Jan;1(1):17-27
  3. 3.0 3.1 Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate Immunity and Inflammation in NAFLD/NASH. Dig Dis Sci. 2016 May;61(5):1294-303
  4. Miura K, Yang L, van Rooijen N, Brenner DA, Ohnishi H, Seki E. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology. 2013 Feb;57(2):577-89
  5. 5.0 5.1 5.2 Garcia-Martinez I, Santoro N, Chen Y, Hoque R, Ouyang X, Caprio S, Shlomchik MJ, Coffman RL, Candia A, Mehal WZ. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest. 2016 Mar 1;126(3):859-64
  6. 6.0 6.1 6.2 6.3 6.4 Faouzi S, Burckhardt BE, Hanson JC, Campe CB, Schrum LW, Rippe RA, Maher JJ. Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-kappa B-independent, caspase-3-dependent pathway. J Biol Chem. 2001 Dec 28;276(52):49077-82
  7. 7.0 7.1 7.2 7.3 Cullen SP, Henry CM, Kearney CJ, Logue SE, Feoktistova M, Tynan GA, Lavelle EC, Leverkus M, Martin SJ. Fas/CD95-induced chemokines can serve as "find-me" signals for apoptotic cells. Mol Cell. 2013 Mar 28;49(6):1034-48