Upstream eventInfiltration, Inflammatory cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Lysosomal damage leading to liver inflammation||adjacent||High|
Life Stage Applicability
Key Event Relationship Description
Immune cells such as polymorphonuclear neutrophils (PMNs) or monocytes, circulate in the blood and become attracted towards a gradient of secreted pro-inflammatory cytokines. PMNs have a life span of only 7-12 hours. Therefore, around 1-2 x 1011 PMN are produced daily in the human body. They account for about 50-70 % of all blood leukocytes in the human body . Upon an inflammatory event, neutrophil production is upregulated, and its lifetime increases as a response to platelet activating factor (PAF), granulocyte-colony stimulating factor (G-CSF) or various pro-inflammatory cytokines, such as interleukin 1ß (IL-1ß) . In sterile tissue injury, for example as the result of apoptosis, there is no need for PMNs to function as antimicrobial effectors; instead, they clear debris and initiate the wound-healing process. Released damage-associated molecular patterns (see Relationship:924) stimulate Kupffer cells to produce IL-1ß which leads to intercellular adhesion molecular-1 (ICAM-1) upregulation on sinusoidal endothelial cells . ICAM-1 in turn mediates neutrophil adhesion to endothelial cells, as it interacts with ß2 integrin, which is expressed on the surface of PMNs. Subsequent to adhesion, neutrophils begin to migrate across the endothelium and towards the affected tissue . The transition of neutrophils from a resting state, as during circulation in the blood, to an activated state at the site of infection is triggered by an ordered sequence of signals from cytokines.
The aberrant activation of neutrophils and their extended lifespan upon an inflammatory stimulus can increase the probability of extracellular damage. PMNs are potent phagocytes, but they also lead to pathogen destruction upon oxidative bursting. The oxidative burst is marked by an increased consumption of molecular oxygen, resulting in the production of reactive oxygen species (ROS) such as H2O2 and OH•, and reactive nitrogen species (RNS). In general, the acute inflammatory response, as in the liver, is bi-phasic. The initial phase is characterised by a macrophage (Kupffer cell)-mediated phase, with the generation of reactive oxygen species aggravating the organ damage. The activated macrophages and subsequent infiltrating lymphocytes produce additional cytokines that further promote the inflammatory response, leading to a second phase, during which neutrophils become fully activated and secrete ROS, complement components, proteases, CXCL-1 and CXCL-2. The role of IL-1 and IL-17A in neutrophil activation and subsequent induction of inflammation has been confirmed by the use of knock-down models, showing that the absence of these mediators prevent neutrophil infiltration and subsequent onset of inflammation, inhibition of the latter also being shown by direct depletion of neutrophils.
Evidence Supporting this KER
The infiltration of immune cells to the infected or damaged tissue is initiated in order to repair the tissue or remove cell bodies or bacteria. However, if the trigger persists, an overstimulation of immune cells such as neutrophils, and the corresponding secretion of ROS can enhance the tissue damage, in turn leading to further infiltration of inflammatory cells and eventually manifest a chronic inflammation.
Include consideration of temporal concordance here
Infiltration of the hepatic parenchyma by neutrophils was found coinciding with chemokine induction. When chemokines have been neutralized by the addition of neutralizing monoclonal antibodies, a study found the chemokine KC mainly responsible for abrogating an inflammatory response to Fas-induced hepatic inflammation. When apoptosis was prevented by pre-treatment of the mice with a caspase-3 inhibitor, AP-1 activation and hepatic chemokine production were both significantly reduced, directly resulting in a reduction of the hepatic inflammation by 70%.
Neutrophils infiltration and subsequent liver inflammation and are drastically attenuated in IL-1R1 deficient mice or by using a neutralizing antibody, and also in the absence of IL-17RA signalling. The same study demonstrated that increased IL-17A was mainly expressed by CD4+ T cells, but also by neutrophils themselves, in the damaged liver, showing that these cells are critical for the further recruitment of circulating immune cells into the tissue. Depletion of neutrophils (by using the neutrophil depleting antibody NIMP-R14) directly resulted in a drastic reduction of the inflammation.
A general proof of the importance of infiltrated neutrophils is the fact that liver inflammation is usually clinically confirmed by analysis of histological features, marked by the influx of neutrophils (which can be stained by using Haematoxylin and eosin) .
Uncertainties and Inconsistencies
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?
Inhibition of messengers for the infiltration of inflammatory cells leads to a strong reduction of these. Furthermore, direct inhibition of neutrophils prevents the onset of liver inflammation.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Freitas M, Lima JL, Fernandes E. Optical probes for detection and quantification of neutrophils' oxidative burst. A review. Anal Chim Acta 2009;649(1):8-23
- Wessels I, Jansen J, Rink L, Uciechowski P. Immunosenescence of polymorphonuclear neutrophils. ScientificWorldJournal 2010;10:145-60
- Xu R, Huang H, Zhang Z, Wang FS. The role of neutrophils in the development of liver diseases. Cell Mol Immunol. 2014 May;11(3):224-31
- Drost EM, MacNee W. Potential role of IL-8, platelet-activating factor and TNF-alpha in the sequestration of neutrophils in the lung: effects on neutrophil deformability, adhesion receptor expression, and chemotaxis. Eur J Immunol 2002;32(2):393-403
- Wang Q, Doerschuk CM, Mizgerd JP. Neutrophils in innate immunity. Semin Respir Crit Care Med 2004;25(1):33-41
- Babior BM. Phagocytes and oxidative stress. Am J Med 2000;109(1):33-44
- Tan Z, Jiang R, Wang X, Wang Y, Lu L, Liu Q, Zheng SG, Sun B, Ryffel B. RORγt+IL-17+ neutrophils play a critical role in hepatic ischemia-reperfusion injury. J Mol Cell Biol. 2013 Apr;5(2):143-6
- 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
- Huebscher SG. Histological assessment of non-alcoholic fatty liver disease. Histopathol. 2006;49:450–465