Interleukin-33 in the pathogenesis of liver fibrosis: alarming ILC2 and hepatic stellate cells

Weiskirchen, Ralf; Tacke, Frank

doi:10.1038/cmi.2016.62

Cited by 40 publications

(45 citation statements)

References 19 publications

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“…Recent studies have similarly implicated IL‐33 or its receptor ST2 in the pathogenesis of fibrosis in various organs such as the lung parenchyma, the liver, the heart and the skin . Interleukin‐33 transgenic mice develop pulmonary fibrosis .…”

Section: Discussionmentioning

confidence: 99%

The effects of interleukin‐33 on airways collagen deposition and matrix metalloproteinase expression in a murine surrogate of asthma

Zhang

Wang

et al. 2018

Immunology

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It has been suggested that interleukin-33 (IL-33) plays an important role in the pathogenesis of asthma through a variety of pathways, but its role in airways fibrosis in asthma has not been fully elucidated. In the present study we evaluated changes in the expression of extracellular matrix proteins (ECMs) as well as matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in an IL-33-induced, antigen-independent murine surrogate of asthma as well as a conventional surrogate employing per-nasal challenge of mice previously sensitized to produce an IgE response to ovalbumin (OVA). In addition, in in vitro experiments we explored the direct effects of IL-33 on the proliferation and function of murine fibroblasts. Per-nasal administration of IL-33 alone was sufficient to induce airways deposition of ECMs, including collagens I, III, V and fibronectin, to a degree comparable with that observed in the OVA-sensitized and challenged mice. These changes were associated with a local imbalance between the expression of extracellular MMPs and TIMPs. Per-nasal challenge of mice with IL-33 also induced elevated airways expression of connective tissue growth factor and fibroblast growth factor receptor 4, two key facilitators of local fibrosis, again to a degree compatible with that observed in OVA-sensitized and challenged mice. Deletion of the ST2 gene, which encodes the IL-33 receptor, abrogated these fibrotic changes in the airways in the OVA surrogate. In vitro, IL-33 significantly increased the proliferation and expression of collagen III by murine lung fibroblasts. These data suggest that direct exposure of murine airways to IL-33 is able to induce local fibrotic changes, at least partially through effects of signalling through the IL-33/ST2 axis on fibroblast function and local expression of MMPs and their inhibitors, and other fibrosis-related proteins.

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Section: Discussionmentioning

confidence: 99%

The effects of interleukin‐33 on airways collagen deposition and matrix metalloproteinase expression in a murine surrogate of asthma

Zhang

Wang

et al. 2018

Immunology

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“…Furthermore, it has been found that ST2L deficient mice did not increase collagen production when challenged with carbon tetrachloride, an organic compound with pro-fibrotic effects ( 24 , 28 ). Similarly, the absence of ST2L prevented liver inflammation both in the acute and chronic phases, with attenuated activation of mitogen-activated protein kinase (MEK)\extracellular signal-regulated kinase(ERK)/p38- mitogen-activated protein kinase (MAPK) signaling cascade( 25 , 232 ).…”

Section: Il-33/st2 Axis In Liver Fibrosismentioning

confidence: 99%

IL-33/ST2 Axis in Organ Fibrosis

2018

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Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis.

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“…While the killing of hepatocytes by NK cells represents a direct injury to the liver, the removal of stressed or damaged hepatocytes by NK cells could also be beneficial. Stressed hepatocytes produce IL-33, which activates ILC2 (McHedlidze et al 2013;Weiskirchen and Tacke 2017). The production and release of IL-5 and IL-13 by ILC2 contributes to liver injury.…”

Section: Figmentioning

confidence: 99%

Enhanced activation of human NK cells by drug-exposed hepatocytes

et al. 2020

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Drug-induced liver injury (DILI) represents one of the major causes why drugs have to be withdrawn from the market. In this study, we describe a new interaction between drug-exposed hepatocytes and natural killer (NK) cells. In a previous genome-wide expression analysis of primary human hepatocytes that had been exposed to clinically relevant concentrations of 148 drugs, we found that several activating ligands for NK cell receptors were regulated by various drugs (e.g., valproic acid, ketoconazole, promethazine, isoniazid). Especially expression of the activating NKG2D ligands (MICA, MICB and ULBPs) and the NKp30 ligand B7-H6 were upregulated in primary human hepatocytes upon exposure to many different drugs. Using the human hepatocyte cell lines Huh7 and HepG2, we confirmed that protein levels of activating NK cell ligands were elevated after drug exposure. Hepatocyte cell lines or primary human hepatocytes co-cultivated with NK cells caused enhanced NK cell activation after pretreatment with drugs at in vivo relevant concentrations compared to solvent controls. Enhanced NK cell activation was evident by increased cytotoxicity against hepatocytes and interferon (IFN)-γ production. NK cell activation could be blocked by specific antibodies against activating NK cell receptors. These data support the hypothesis that NK cells can modulate drug-induced liver injury by direct interaction with hepatocytes resulting in cytotoxicity and IFN-γ production.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Interleukin-33 in the pathogenesis of liver fibrosis: alarming ILC2 and hepatic stellate cells

Cited by 40 publications

References 19 publications

The effects of interleukin‐33 on airways collagen deposition and matrix metalloproteinase expression in a murine surrogate of asthma

The effects of interleukin‐33 on airways collagen deposition and matrix metalloproteinase expression in a murine surrogate of asthma

IL-33/ST2 Axis in Organ Fibrosis

Enhanced activation of human NK cells by drug-exposed hepatocytes

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