Hepatic damage caused by long-term high cholesterol intake induces a dysfunctional restorative macrophage population in experimental NASH

Maretti-Mira, Ana C.; Salomon, Matthew P.; Hsu, Angela M.; Kanel, Gary C.; Golden–Mason, Lucy

doi:10.3389/fimmu.2022.968366

Cited by 7 publications

(6 citation statements)

References 67 publications

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“…Conversely, the chronic tissue insult dysregulates the inflammatory response and favors fibrosis development ( 34 ). Fibrosis progression is marked by the activation of hepatic stellate cells (HSC) and hepatic macrophages, which secrete high levels of extracellular matrix compounds, unbalancing the restoration of the damaged tissue ( 35 , 36 ). At this stage, NK cells play a critical role in inducing early activated HSCs to apoptosis via cytotoxicity or IFN-γ secretion, thus delaying the progression of fibrogenesis ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Etiology of end-stage liver cirrhosis impacts hepatic natural killer cell heterogenicity

et al. 2023

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The natural killer (NK) cell population is a critical component of the innate immune compartment of the liver, and its functions are deeply affected by the surrounding environment. In the late stage of fibrosis, NK cells become dysfunctional, but the influence of disease etiology on NK cell behavior during cirrhosis remains unclear. Using single-cell RNA sequencing (scRNA-seq), we characterized the hepatic NK cells from end-stage cirrhotic livers from subjects with non-alcoholic steatohepatitis (NASH), chronic hepatitis C infection (HCV) and primary sclerosing cholangitis (PSC). Here, we show that although NK cells shared similar dysfunctions, the disease etiology impacts hepatic NK cell heterogeneity. Therapeutical strategies targeting NK cells for the prevention or treatment of fibrosis should consider liver disease etiology in their design.

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Section: Discussionmentioning

confidence: 99%

Etiology of end-stage liver cirrhosis impacts hepatic natural killer cell heterogenicity

et al. 2023

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“…Therefore, strategies devoted to improving NKT cell-mediated immune responses might represent a possible therapeutic approach to control HCC development in NASH. Cholesterol accumulation also fosters the differentiation of dysfunctional restorative macrophages which persists even after cholesterol restriction [ 121 ]. Metabolic factors in combination with chronic antigen stimulation also impact on T-cells by favoring the hepatic accumulation of CD4 + and CD8 + T-cells expressing the thymocyte selection associated high mobility group box protein (TOX), a nuclear factor leading to the acquisition of an exhausted phenotype.…”

Section: Immunomodulating Mechanisms Underlying Nash-related Hccmentioning

confidence: 99%

Inflammatory processes involved in NASH-related hepatocellular carcinoma

et al. 2023

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Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. In the recent years nonalcoholic fatty liver disease (NAFLD) is becoming a growing cause of HCCs and the incidence of NAFLD-related HCCs is expected to further dramatically increase by the next decade. Chronic inflammation is regarded as the driving force of NAFLD progression and a key factor in hepatic carcinogenesis. Hepatic inflammation in NAFLD results from the persistent stimulation of innate immunity in response to hepatocellular injury and gut dysbiosis as well as by the activation of adaptive immunity. However, the relative roles of innate and adaptive immunity in the processes leading to HCC are still incompletely characterized. This is due to the complex interplay between different liver cell populations, which is also strongly influenced by gut-derived bacterial products, metabolic/nutritional signals. Furthermore, carcinogenic mechanisms in NAFLD/NASH appear to involve the activation of signals mediated by hypoxia inducible factors. This review discusses recent data regarding the contribution of different inflammatory cells to NAFLD-related HCC and their possible impact on patient response to current treatments.

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“…In addition, it was discovered that systemic cholesterol levels influence cellular cholesterol homeostasis in lipid-laden KCs ( 100 ). During hypercholesterolemia, macrophage cholesterol efflux is impaired, this drives their polarization towards a proinflammatory phenotype ( 115 , 116 ). The association is strong between dietary cholesterol intake and hepatic cholesterol in the development of NASH in both human and animal models.…”

Section: Macrophage Lipid Processing In Nafldmentioning

confidence: 99%

“…This is supported by large scale epidemiological studies, where dietary cholesterol consumption was independently associated with the development of NASH and cirrhosis ( 118 , 119 ). It has also been shown that the beginning of hypercholesterolemia might affect membrane fluidity, which, in turn, can cause changes in phagocytic capacity, a process known to be disrupted in murine models of NASH ( 115 , 119 – 121 ). It is speculated that the KCs scavenged free cholesterol (including crystals), cholesterol esters, and triglycerides from the remaining big lipid droplets of dying hepatocytes.…”

Section: Macrophage Lipid Processing In Nafldmentioning

confidence: 99%

Macrophages and the development and progression of non-alcoholic fatty liver disease

Alabdulaali,

Al-rashed,

Al-Onaizi

et al. 2023

Front. Immunol.

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The liver is the site of first pass metabolism, detoxifying and metabolizing blood arriving from the hepatic portal vein and hepatic artery. It is made up of multiple cell types, including macrophages. These are either bona fide tissue-resident Kupffer cells (KC) of embryonic origin, or differentiated from circulating monocytes. KCs are the primary immune cells populating the liver under steady state. Liver macrophages interact with hepatocytes, hepatic stellate cells, and liver sinusoidal endothelial cells to maintain homeostasis, however they are also key contributors to disease progression. Generally tolerogenic, they physiologically phagocytose foreign particles and debris from portal circulation and participate in red blood cell clearance. However as immune cells, they retain the capacity to raise an alarm to recruit other immune cells. Their aberrant function leads to the development of non-alcoholic fatty liver disease (NAFLD). NAFLD refers to a spectrum of conditions ranging from benign steatosis of the liver to steatohepatitis and cirrhosis. In NAFLD, the multiple hit hypothesis proposes that simultaneous influences from the gut and adipose tissue (AT) generate hepatic fat deposition and that inflammation plays a key role in disease progression. KCs initiate the inflammatory response as resident immune effectors, they signal to neighbouring cells and recruit monocytes that differentiated into recruited macrophages in situ. Recruited macrophages are central to amplifying the inflammatory response and causing progression of NAFLD to its fibro-inflammatory stages. Given their phagocytic capacity and their being instrumental in maintaining tissue homeostasis, KCs and recruited macrophages are fast-becoming target cell types for therapeutic intervention. We review the literature in the field on the roles of these cells in the development and progression of NAFLD, the characteristics of patients with NAFLD, animal models used in research, as well as the emerging questions. These include the gut-liver-brain axis, which when disrupted can contribute to decline in function, and a discussion on therapeutic strategies that act on the macrophage-inflammatory axis.

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Hepatic damage caused by long-term high cholesterol intake induces a dysfunctional restorative macrophage population in experimental NASH

Cited by 7 publications

References 67 publications

Etiology of end-stage liver cirrhosis impacts hepatic natural killer cell heterogenicity

Etiology of end-stage liver cirrhosis impacts hepatic natural killer cell heterogenicity

Inflammatory processes involved in NASH-related hepatocellular carcinoma

Macrophages and the development and progression of non-alcoholic fatty liver disease

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