Stellate Cells in Hepatic Immunological Tolerance

Gandhi, Chandrashekhar R.

doi:10.1016/b978-0-12-800134-9.00014-2

Cited by 9 publications

(22 citation statements)

References 140 publications

(197 reference statements)

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“…11–15 Because ConA-induced liver injury is attributed to mediators, such as TNF-α and IFN-γ, 17,18 and considering reduced hepatic levels of inflammatory and immune cells in ConA-treated HSC-depleted compared with HSC-sufficient mice, we examined the hepatic expression of various cytokines and chemokines. Expression of TNF-α and IFN-γ mRNA and protein increased strongly in ConA-treated HSC-sufficient but not in HSC-depleted mice (Figure 2, A and B).…”

Section: Resultsmentioning

confidence: 99%

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Stellate Cells Orchestrate Concanavalin A–Induced Acute Liver Damage

Rani

Tandon

Wang

et al. 2017

The American Journal of Pathology

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Concanavalin A (ConA) causes immune cell—mediated liver damage, but the contribution of resident nonparenchymal cells (NPCs) is also evident. Hepatic stellate cells (HSCs) induce hepatic inflammation and immunological reactions; we therefore investigated their role in ConA-induced liver injury. ConA was administered i.v. to control or HSC-depleted mice; hepatic histopathology and cytokines/chemokines were determined after 6 hours. In vitro, effects of ConA-conditioned HSC medium on hepatocytes were determined. ConA induced inflammation, sinusoidal congestion, and extensive midzonal hepatocyte death in control mice, which were strongly minimized in HSC-depleted mice. CD4 and natural killer T cells and neutrophils were markedly reduced in ConA-treated HSC-depleted mice compared with control mice. The increase in cytokines/chemokines of hepatic injury was much higher in ConA-treated control mice than in HSC-depleted mice. ConA-treated HSCs showed increased expression of interferon-β, tumor necrosis factor-α, and CXCL1, induced oxidative stress in hepatocytes, and caused hepatocyte apoptosis. ConA induced nuclear translocation of interferon-regulatory factor-1 (IRF1) in hepatocytes in vivo, and ConA/HSC induced a similar effect in cultured hepatocytes. IRF1-knockout mice were resistant to ConA-induced liver damage, and anti—interferon β antibody mitigated ConA/HSC-induced injury. In HSC-NPC co-culture, ConA-induced expression of inflammatory cytokines/chemokines was significantly augmented compared with NPCs alone. HSCs play an essential role in ConA-induced liver injury directly via the interferon-β/IRF1 axis, and by modulating properties of NPCs.

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Section: Resultsmentioning

confidence: 99%

“…10 By producing numerous cytokines, chemokines, and molecules of antigen presentation, HSCs influence characteristics of inflammatory cells and cells of the immune system. 11–15 Such bidirectional interactions between HSCs and inflammatory/immune cells can be critical to liver injury and immunological tolerance.…”

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confidence: 99%

Stellate Cells Orchestrate Concanavalin A–Induced Acute Liver Damage

Rani

Tandon

Wang

et al. 2017

The American Journal of Pathology

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“…Their activation by cytokines and inflammatory signals secondary to liver injury or inflammation initiates the fibrogenic process characterized by loss of vitamin A, myofibroblastic transformation, and excessive production of extracellular matrix components, notably type I collagen. In addition to their seminal role in liver fibrosis, HSCs are increasingly being recognized to have leucocyte‐like properties, including antigen presentation and immune stimulatory and regulatory functions depending on their activation status . HSCs express major histocompatiblity complex (MHC) class I and II and can take up and present antigens within the liver .…”

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confidence: 99%

“…In addition to their seminal role in liver fibrosis, HSCs are increasingly being recognized to have leucocyte‐like properties, including antigen presentation and immune stimulatory and regulatory functions depending on their activation status . HSCs express major histocompatiblity complex (MHC) class I and II and can take up and present antigens within the liver . They induce forkhead box protein 3 (Foxp3) + regulatory T cells (Tregs) through production of retinoic acid, promote their expansion in an MHC II‐dependent manner, and thus contribute to immunological tolerance within the liver .…”

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confidence: 99%

“…1,2 HSCs express major histocompatiblity complex (MHC) class I and II and can take up and present antigens within the liver. 2,3 They induce forkhead box protein 3 (Foxp3) 1 regulatory T cells (Tregs) through production of retinoic acid, promote their expansion in an MHC II-dependent manner, and thus contribute to immunological tolerance within the liver. 4,5 HSCs may also interact with hepatotropic pathogens that induce their activation.…”

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A novel role for hepatic stellate cells in pathogenesis of visceral leishmaniasis

2015

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Differential recruitment of monocyte‐derived macrophages in control and stellate cell‐depleted mice during recurrent carbon tetrachloride‐induced acute liver injury

Sharma

Kudira

Wang

et al. 2022

Journal Cellular Physiology

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Liver depleted of hepatic stellate cells (HSCs) is resistant to ischemia/reperfusion-, concanavalin A-, and acetaminophen-induced acute injury. Whether HSCs regulate carbon tetrachloride (CCl 4 )-induced acute liver injury is not known. CCl 4 treatment damages pericentral hepatocytes that express CCl 4 -metabolizing Cyp2E1 and activates HSCs. We investigated whether HSC-depletion in mice transgenic for thymidine kinase under the glial fibrillary acidic protein promoter (GFAP-TK-Tg) confers resistance to injury and inflammation due to CCl 4 rechallenge. GFAP-TK-Tg or wild type (WT) mice were administered 0.16 ml/kg CCl 4 (3× at 3 days intervals), then 40 μg/g/day ganciclovir for 10 days. The treatment depletes ~70%-75% HSCs from GFAP-TK-Tg but not WT mice while the liver recovers from earlier CCl 4induced injury. Mice were then administered CCl 4 , and liver injury and inflammation were determined at 24 h. HSC-depleted and HSC-sufficient mice showed similar CCl 4 -induced hepatocyte necrosis and oxidative stress. However, increase in F4/80 + macrophages, but not CD68 + cells, was greater in CCl 4 rechallenged HSC-depleted compared to HSC-sufficient mice. Expression of tumor necrosis factor-α (TNF-α), CCL2, and CXCL1 increased similarly, whereas increase in interleukin-6 (IL6), IL1β, and IL10 expression was higher in CCl 4 rechallenged HSC-depleted compared to HSC-sufficient mice. CCl 4 rechallenge of HSC-sufficient mice rapidly activated HSCs causing significant fibrosis with increased expression of Col1a1, transforming growth factor β1 (TGFβ1), tissue inhibitors of metalloproteinases 1 (TIMP1); increase in TIPM1 was much lower and metalloproteinases 13 (MMP13) greater in CCl 4 rechallenged HSC-depleted mice. Interestingly, hepatic recruitment of both profibrogenic (Ly6C hi ) and antifibrogenic restorative (Ly6C lo ) macrophages, and neutrophils was significantly greater in CCl 4 rechallenged HSC-depleted mice. These data suggest that CCl 4 directly damages hepatocytes but HSCs regulate inflammation. Rapid fibrogenesis in CCl 4 rechallenged HSC-sufficient mice recovered from earlier injury indicates that even transiently activated HSCs that had reverted to the quiescent phenotype remain primed to become reactivated.

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Stellate Cells in Hepatic Immunological Tolerance

Cited by 9 publications

References 140 publications

Stellate Cells Orchestrate Concanavalin A–Induced Acute Liver Damage

Stellate Cells Orchestrate Concanavalin A–Induced Acute Liver Damage

A novel role for hepatic stellate cells in pathogenesis of visceral leishmaniasis

Differential recruitment of monocyte‐derived macrophages in control and stellate cell‐depleted mice during recurrent carbon tetrachloride‐induced acute liver injury

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