Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis

Tran, Sophie; Baba, Inès; Poupel, Lucie; Dussaud, Sébastien; Moreau, Martine; Gélineau, Adélaïde; Marcelin, Geneviève; Magréau-Davy, Elissa; Ouhachi, Melissa; Lesnik, Philippe; Boissonnas, Alexandre; Goff, Wilfried Le; Clausen, Björn E.; Yvan‐Charvet, Laurent; Sennlaub, Florian; Huby, Thierry; Gautier, Emmanuel L.

doi:10.1016/j.immuni.2020.06.003

Cited by 260 publications

(299 citation statements)

References 37 publications

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“…Despite these differences, our observation that ResKCs were gradually lost from the tissue in MAFLD is consistent with the other recent studies ( Seidman et al., 2020 ; Tran et al., 2020 ). Regarding why ResKCs fail to self-maintain in MAFLD, one hypothesis is that they are no longer correctly adapted to the niche.…”

Section: Discussionsupporting

confidence: 93%

“…However, further work is required to better understand the precise signals at play. With the knowledge that ResKCs have been suggested to be protective in NASH ( Tran et al., 2020 ), our data suggesting a lack of ResKCs in HCC and the finding that osteopontin expression correlates with worse disease ( Glass et al., 2018 ), perhaps if we can understand the signals driving ResKC loss and LAM generation in MAFLD, this could open the door to therapeutic options for patients to prevent and/or reverse progression to NASH and HCC.…”

Section: Discussionmentioning

confidence: 82%

“…Notably, the gene expression profile of Mac1s somewhat resembles moKCs ( Figure 5 A) and macs en route to becoming moKCs ( Bonnardel et al., 2019 ). While this manuscript was under review, Clec1b (encoding CLEC2) was proposed to be a good marker of moKCs that appeared to be expressed earlier than CLEC4F ( Tran et al., 2020 ). To confirm this, we examined expression of CLEC4F and CLEC2 in Clec4f -DTR mice ( Scott et al., 2016 ) 3 and 6 days post-ResKC depletion during the generation of moKCs ( Scott et al., 2016 ).…”

Section: Resultsmentioning

confidence: 99%

“…However, LAMs were predominantly found in regions characterized by increased Desmin expression, suggestive of fibrosis. During reviewing, two additional papers were published investigating macs in MAFLD ( Seidman et al., 2020 ; Tran et al., 2020 ). It is currently unclear exactly how the populations identified here correlate to those described by Seidman et al.…”

Section: Discussionmentioning

confidence: 99%

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Osteopontin Expression Identifies a Subset of Recruited Macrophages Distinct from Kupffer Cells in the Fatty Liver

et al. 2020

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Summary Metabolic-associated fatty liver disease (MAFLD) represents a spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs), are suggested to play important roles in the pathogenesis of MAFLD through their activation, although the exact roles played by these cells remain unclear. Here, we demonstrated that KCs were reduced in MAFLD being replaced by macrophages originating from the bone marrow. Recruited macrophages existed in two subsets with distinct activation states, either closely resembling homeostatic KCs or lipid-associated macrophages (LAMs) from obese adipose tissue. Hepatic LAMs expressed Osteopontin, a biomarker for patients with NASH, linked with the development of fibrosis. Fitting with this, LAMs were found in regions of the liver with reduced numbers of KCs, characterized by increased Desmin expression. Together, our data highlight considerable heterogeneity within the macrophage pool and suggest a need for more specific macrophage targeting strategies in MAFLD.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Osteopontin Expression Identifies a Subset of Recruited Macrophages Distinct from Kupffer Cells in the Fatty Liver

et al. 2020

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“…The striking accumulation of immune cells is one hallmark characteristic of NASH and has been associated with ongoing hepatic inflammation and NAFLD progression (68,69). With the NAFLD progression, it has been recently reported that the number of resident-Kupffer cells from embryonic progenitors is decreased causing by elevated cell death and are replaced by monocyte-derived Kupffer cells (70). This new pool of kupffer cells are more inflammatory and are important contributor of the impairment of liver responses during NASH (70).…”

Section: Liver Macrophages Are Important Drivers Of Hepatic Inflammationmentioning

confidence: 99%

Chronic Inflammation in Non-Alcoholic Steatohepatitis: Molecular Mechanisms and Therapeutic Strategies

et al. 2020

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Non-Alcoholic Steatohepatitis (NASH) is the progressive form of Non-Alcoholic Fatty Liver Disease (NAFLD), the main cause of chronic liver complications. The development of NASH is the consequence of aberrant activation of hepatic conventional immune, parenchymal, and endothelial cells in response to inflammatory mediators from the liver, adipose tissue, and gut. Hepatocytes, Kupffer cells and liver sinusoidal endothelial cells contribute to the significant accumulation of bone-marrow derived-macrophages and neutrophils in the liver, a hallmark of NASH. The aberrant activation of these immune cells elicits harmful inflammation and liver injury, leading to NASH progression. In this review, we highlight the processes triggering the recruitment and/or activation of hepatic innate immune cells, with a focus on macrophages, neutrophils, and innate lymphoid cells as well as the contribution of hepatocytes and endothelial cells in driving liver inflammation/fibrosis. On-going studies and preliminary results from global and specific therapeutic strategies to manage this NASH-related inflammation will also be discussed.

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Gasdermin‐E‐Dependent Non‐Canonical Pyroptosis Promotes Drug‐Induced Liver Failure by Promoting CPS1 deISGylation and Degradation

Ouyang,

Zhu,

Cao

et al. 2024

Advanced Science

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Drug‐induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non‐canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP‐DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP‐DILI. Mice with hepatocyte‐specific rescue of GSDME reproduced APAP‐induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP‐induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte‐derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte‐specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon‐stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase‐1 (CPS1), promoted its degradation via K48‐linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl‐fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP‐DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP‐DILI.

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Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis

Cited by 260 publications

References 37 publications

Osteopontin Expression Identifies a Subset of Recruited Macrophages Distinct from Kupffer Cells in the Fatty Liver

Osteopontin Expression Identifies a Subset of Recruited Macrophages Distinct from Kupffer Cells in the Fatty Liver

Chronic Inflammation in Non-Alcoholic Steatohepatitis: Molecular Mechanisms and Therapeutic Strategies

Gasdermin‐E‐Dependent Non‐Canonical Pyroptosis Promotes Drug‐Induced Liver Failure by Promoting CPS1 deISGylation and Degradation

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