KLRG1+ natural killer cells exert a novel antifibrotic function in chronic hepatitis B

Wijaya, Ratna Sari; Read, Scott A.; Schibeci, Stephen D.; Eslam, Mohammed; Azardaryany, Mahmoud Karimi; El-Khobar, Korri Elvanita; Poorten, David van der; Lin, Rita; Yuen, Lawrence; Lam, Vincent; George, Jacob; Douglas, Mark W.; Ahlenstiel, Golo

doi:10.1016/j.jhep.2019.03.012

Cited by 39 publications

(38 citation statements)

References 93 publications

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“…103 Nevertheless, in patients with chronic HBV infection, enriched hepatic KLRG1 + NK cells with a mature phenotype of elevated expression of CD57 and DNAM-1 and reduced expression of NKp46 and NKG2A exerted antifibrotic functions by killing activated HSCs in a TRAIL-dependent manner and CD44-osteopontin-dependent manner. 104 The level of elevation of ILC1s, but not ILC2s, was closely related to hepatic damage in patients with CHB, suggesting potential proinflammatory roles of ILC1s in the pathogenesis of CHB. 105 NK cells are involved in the whole process of HCV infection, from providing innate protection to contributing to viral clearance induced by treatments.…”

Section: Viral Infectionmentioning

confidence: 85%

Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer

Chen

Tian

2020

Cell Mol Immunol

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The liver is a lymphoid organ with unique immunological properties, particularly, its predominant innate immune system. The balance between immune tolerance and immune activity is critical to liver physiological functions and is responsible for the sensitivity of this organ to numerous diseases, including hepatotropic virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, autoimmune liver disease, and liver cancer, which are major health problems globally. In the past decade, with the discovery of liver-resident natural killer cells, the importance of innate lymphocytes with tissue residency has gradually become the focus of research. In this review, we address the current knowledge regarding hepatic innate lymphocytes with unique characteristics, including NK cells, ILC1/2/3s, NKT cells, γδ T cells, and MAIT cells, and their potential roles in liver homeostasis maintenance and the progression of liver diseases and cancer. A better understanding of the immunopathogenesis of hepatic innate lymphocytes will be helpful for proposing effective treatments for liver diseases and cancer.

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Section: Viral Infectionmentioning

confidence: 85%

Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer

Chen

Tian

2020

Cell Mol Immunol

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“…This interaction can be modulated by regulatory CD4 T cells (Langhans et al 2015). Furthermore, NK cells contribute to the defense of viral infections in the liver (Kramer et al 2012;Mantovani et al 2015;Wijaya et al 2019). However, much is still unknown about specific roles and interactions.…”

Section: Discussionmentioning

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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“…Importantly, NK cells can kill multiple targets in a serial fashion, using granule exocytosis for initial killing events, and the death-receptor pathway for later events when perforin and granzyme reserves are exhausted [41]. Further, target cytotoxicity can be mediated via antibody-dependent cellular cytotoxicity (ADCC) through the FcγRIII receptor CD16 [42]. In addition, secretion of immunomodulatory cytokines such as interferon-gamma (IFN-γ), and TNF-α also act to enhance NK cytotoxicity [43].…”

Section: Natural Killer Cellsmentioning

confidence: 99%

“…Phase 5 represents circulating NK cells, and is characterised by an observable spike in CD56 expression representing the relatively young CD56 bright population, as well as the more mature CD56 dim population that co-express CD16 and killer immunoglobulin-like receptor (KIR) (CD158). Phase 6 represents terminal maturation gaining expression of CD57 and may include the generation of "adaptive" or "memory-like" NK cells following antigen exposure, gaining expression of NKG2C and KLRG1 [42,50].…”

Section: Natural Killer Cellsmentioning

confidence: 99%

“…A number of studies have identified the liver as a key reservoir for memory NK cells [114,115], and yet they have been overlooked in the context of hepatic viral infections. While there are no published studies examining the memory response to HBV or HCV, our group has identified an expanded population of KLRG1+ NK cells in chronic HBV (CHB) patients that possess antifibrotic activity [42]. We have since further characterized this population and have identified a memory population of NK cells in CHB patients that degranulate in response to HBV antigen [116].…”

Section: Nk Cell Memory In Hcvmentioning

confidence: 99%

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Immunomodulation of the Natural Killer Cell Phenotype and Response during HCV Infection

Njiomegnie

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et al. 2020

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Hepatitis C virus (HCV) infection develops into chronic hepatitis in over two-thirds of acute infections. While current treatments with direct-acting antivirals (DAAs) achieve HCV eradication in >95% of cases, no vaccine is available and re-infection can readily occur. Natural killer (NK) cells represent a key cellular component of the innate immune system, participating in early defence against infectious diseases, viruses, and cancers. When acute infection becomes chronic, however, NK cell function is altered. This has been well studied in the context of HCV, where changes in frequency and distribution of NK cell populations have been reported. While activating receptors are downregulated on NK cells in both acute and chronic infection, NK cell inhibiting receptors are upregulated in chronic HCV infection, leading to altered NK cell responsiveness. Furthermore, chronic activation of NK cells following HCV infection contributes to liver inflammation and disease progression through enhanced cytotoxicity. Consequently, the NK immune response is a double-edged sword that is a significant component of the innate immune antiviral response, but persistent activation can drive tissue damage during chronic infection. This review will summarise the role of NK cells in HCV infection, and the changes that occur during HCV therapy.

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KLRG1+ natural killer cells exert a novel antifibrotic function in chronic hepatitis B

Cited by 39 publications

References 93 publications

Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer

Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer

Enhanced activation of human NK cells by drug-exposed hepatocytes

Immunomodulation of the Natural Killer Cell Phenotype and Response during HCV Infection

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