Hepatic Natural Killer Cells: Organ-Specific Sentinels of Liver Immune Homeostasis and Physiopathology

Mikulak, Joanna; Bruni, Elena; Oriolo, Ferdinando; Vito, Clara Di; Mavilio, Domenico

doi:10.3389/fimmu.2019.00946

Cited by 115 publications

(124 citation statements)

References 152 publications

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“…More NK cells were activated and secreted more OPN in livers from mice on HFDs. The liver is populated by both transient cNK cells and trNK cell subsets that are phenotypically and functionally different . Compared with cNK cells, trNK cells are efficient at producing inflammatory cytokines including IFN‐γ, TNF‐α, and GM‐CSF .…”

Section: Discussionmentioning

confidence: 99%

“…The liver is populated by both transient cNK cells and trNK cell subsets that are phenotypically and functionally different. 10,29 Compared with cNK cells, trNK cells are efficient at producing inflammatory cytokines including IFN-, TNF-, and GM-CSF. 30 Here, we found that trNK cells produced more OPN than cNK cell subsets during diet-induced obesity.…”

Section: Discussionmentioning

confidence: 99%

“…It has been proposed that visceral adipose tissue‐resident NK (trNK) cells promote M1 macrophage polarization through the production of proinflammatory cytokines such as IFN‐γ and TNF‐α . Hepatic NK cells, including conventional NK (cNK) and trNK cell subsets, play an important role in liver metabolism and homeostasis . Previous studies demonstrate that NK cell depletion also improves insulin signaling in the liver and muscle of obese mice, but these studies were mainly focus on visceral adipose trNK cells .…”

Section: Introductionmentioning

confidence: 99%

“…7,8 Hepatic NK cells, including conventional NK (cNK) and trNK cell subsets, play an important role in liver metabolism and homeostasis. 9,10 Previous studies demonstrate that NK cell depletion also improves insulin signaling in the liver and muscle of obese mice, but these studies were mainly focus on visceral adipose trNK cells. 5,7 Whether hepatic NK cells can directly promote hepatic ER stress and IR remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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NK cells induce hepatic ER stress to promote insulin resistance in obesity through osteopontin production

Zhang

et al. 2019

Journal of Leukocyte Biology

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High‐fat diet (HFD) induced hepatic endoplasmic reticulum (ER) stress drives insulin resistance (IR) and steatosis. NK cells in adipose tissue play an important role in the pathogenesis of IR in obesity. Whether NK cells in the liver can induce hepatic ER stress and thus promote IR in obesity is still unknown. We demonstrate that HFD‐fed mice display elevated production of proinflammatory cytokine osteopontin (OPN) in hepatic NK cells, especially in CD49a+DX5– tissue‐resident NK (trNK) cells. Obesity‐induced ER stress, IR, and steatosis in the liver are ameliorated by ablating NK cells with neutralizing antibody in HFD‐fed mice. OPN treatment enhances the expression of ER stress markers, including p‐PERK, p‐eIF2, ATF4, and CHOP in both murine liver tissues and HL‐7702, a human liver cell line. Pretreatment of HL‐7702 cells with OPN promotes hyperactivation of JNK and subsequent decrease of tyrosine phosphorylation of insulin receptor substrate‐1 (IRS‐1), resulting in impaired insulin signaling, which can be reversed by inhibiting ER stress. Collectively, we demonstrate that hepatic NK cells induce obesity‐induced hepatic ER stress, and IR through OPN production.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NK cells induce hepatic ER stress to promote insulin resistance in obesity through osteopontin production

Zhang

et al. 2019

Journal of Leukocyte Biology

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“…However, the Ltbr ligand (Ltb) was effectively absent in KP1 cells (less than 1.5 TPM in bulk samples and pool-and-split controls from liver colonies). We searched Tabula Muris (40) and found that Ltb is abundantly expressed in hepatic natural killer (NK) cells, the most-prevalent lymphocyte population in the liver (65). Given that NK cell activity is retained or enhanced in athymic nude mice (66), their paracrine communication with KP1 cells is a plausible mechanism for heterogeneous NF-κB pathway activation in the liver.…”

Section: Mifmentioning

confidence: 99%

Fragmentation of Small-cell Lung Cancer Regulatory States in Heterotypic Microenvironments

Schaff

Singh

Kim

et al. 2020

Preprint

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Small-cell lung cancers derive from pulmonary neuroendocrine cells, which have stemlike properties to reprogram into other cell types upon lung injury. It is difficult to uncouple the plasticity of these transformed cells from heritable changes that evolve in primary tumors or select in metastases to distant organs. Approaches to single-cell profiling are also problematic if the required sample dissociation activates injury-like signaling and reprogramming. Here, we defined cell-state heterogeneities in situ through laser capture microdissection-based 10-cell transcriptomics coupled with stochastic-profiling fluctuation analysis. Using labeled cells from a small-cell lung cancer mouse model initiated by neuroendocrine deletion of p53 and Rb, we profiled cell-to-cell transcriptional-regulatory heterogeneity in spheroid cultures and liver colonies seeded intravenously. Fluctuating transcripts in vitro were partly shared with other epithelial-spheroid models, and candidate heterogeneities increased considerably when cells were delivered to the liver. Colonization of immunocompromised animals drove the fractional appearance of alveolar type II-like markers and poised cells for paracrine stimulation from immune cells and hepatocytes. Immunocompetency further exaggerated the fragmentation of tumor states in the liver, yielding mixed stromal signatures evident in bulk sequencing from autochthonous tumors and metastases. We identified dozens of transcript heterogeneities that recur irrespective of biological context; their mapped orthologs brought together observations of murine and human small-cell lung cancer. Candidate heterogeneities recurrent in the liver also stratified primary human tumors into discrete groups not readily explained by molecular subtype.We conclude that heterotypic interactions in the liver and lung are an accelerant for intratumor heterogeneity in small-cell lung cancer. Statement of significanceThe single-cell regulatory heterogeneity of small-cell lung cancer becomes increasingly elaborate in the liver, a common metastatic site for the disease.

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Immune landscape of hepatocellular carcinoma: From dysregulation of the immune responses to the potential immunotherapies

Pourbagheri‐Sigaroodi,

Momeny,

Rezaei

et al. 2024

Cell Biochemistry & Function

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Hepatocellular carcinoma (HCC) presents a considerable global health burden due to its late diagnosis and high morbidity. The liver's specific anatomical and physiological features expose it to various antigens, requiring precise immune regulation. To the best of our knowledge, this is the first time that a comprehensive overview of the interactions between the immune system and gut microbiota in the development of HCC, as well as the relevant therapeutic approaches are discussed. Dysregulation of immune compartments within the liver microenvironment drives HCC pathogenesis, characterized by elevated regulatory cells such as regulatory T cells (Tregs), myeloid‐derived suppressor cells, and M2 macrophages as well as suppressive molecules, alongside reduced number of effector cells like T cells, natural killer cells, and M1 macrophages. Dysbiosis of gut microbiota also contributes to HCC by disrupting intestinal barrier integrity and triggering overactivated immune responses. Immunotherapy approaches, particularly immune checkpoint inhibitors, have exhibited promise in HCC management, yet adoptive cell therapy and cancer vaccination research are in the early steps with relatively less favorable outcomes. Further understanding of immune dysregulation, gut microbiota involvement, and therapeutic combination strategies are essential for advancing precision immunotherapy in HCC.

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Hepatic Natural Killer Cells: Organ-Specific Sentinels of Liver Immune Homeostasis and Physiopathology

Cited by 115 publications

References 152 publications

NK cells induce hepatic ER stress to promote insulin resistance in obesity through osteopontin production

NK cells induce hepatic ER stress to promote insulin resistance in obesity through osteopontin production

Fragmentation of Small-cell Lung Cancer Regulatory States in Heterotypic Microenvironments

Immune landscape of hepatocellular carcinoma: From dysregulation of the immune responses to the potential immunotherapies

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