Publications by authors named "Michael Karin"

377 Publications

Concurrent Disruption of Ras/MAPK and NF-κB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis.

Mol Cancer Res 2021 Nov 22. Epub 2021 Nov 22.

Department of Pathology, and Division of Biological Sciences, University of California, San Diego

The Ras/Erk and NF-κB pathways play critical roles in cell proliferation and are known to drive oncogenesis when over-activated. Herein we report a gatekeeper function of the two pathways by working in synergy to suppress liver tumorigenesis. Hepatocyte-specific deletion of both Shp2/Ptpn11 and Ikkβ in mice, which promote Ras/Erk and NF-κB signaling, respectively, exacerbated chemical carcinogenesis and even triggered spontaneous development of hepatocellular carcinoma (HCC). We show that the unanticipated severe tumor phenotype was contributed collectively by severe cholestasis, metabolic changes, upregulated cell cycle progression and disruption of circadian rhythm in mutant hepatocytes. Remarkably, human HCCs with dysregulated circadian gene expression displayed downregulation of Ras/Erk and NF-κB signaling and poor prognosis. Together, these data indicate that at the ground state, the two central pathways, previously known as oncogenic, cooperate to sustain tumor-suppressive physiological homeostasis and to prevent hepatic damage. Disruption of this intricate signaling network is carcinogenic in the liver. Implications: We demonstrate here that basal levels of the Ras/MAPK and NF-κB pathways, while promoting tumorigenesis if overactivated, are required to maintain physiological homeostasis and regulate circadian rhythm in the liver, which are anti-tumorigenic.
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http://dx.doi.org/10.1158/1541-7786.MCR-21-0479DOI Listing
November 2021

"Sweet death": Fructose as a metabolic toxin that targets the gut-liver axis.

Cell Metab 2021 Sep 30. Epub 2021 Sep 30.

Department of Pharmacology, School of Medicine, University of California, San Diego, San Diego, CA, USA. Electronic address:

Glucose and fructose are closely related simple sugars, but fructose has been associated more closely with metabolic disease. Until the 1960s, the major dietary source of fructose was fruit, but subsequently, high-fructose corn syrup (HFCS) became a dominant component of the Western diet. The exponential increase in HFCS consumption correlates with the increased incidence of obesity and type 2 diabetes mellitus, but the mechanistic link between these metabolic diseases and fructose remains tenuous. Although dietary fructose was thought to be metabolized exclusively in the liver, evidence has emerged that it is also metabolized in the small intestine and leads to intestinal epithelial barrier deterioration. Along with the clinical manifestations of hereditary fructose intolerance, these findings suggest that, along with the direct effect of fructose on liver metabolism, the gut-liver axis plays a key role in fructose metabolism and pathology. Here, we summarize recent studies on fructose biology and pathology and discuss new opportunities for prevention and treatment of diseases associated with high-fructose consumption.
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http://dx.doi.org/10.1016/j.cmet.2021.09.004DOI Listing
September 2021

Regulation of antitumor immunity by inflammation-induced epigenetic alterations.

Cell Mol Immunol 2021 Aug 31. Epub 2021 Aug 31.

Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Chronic inflammation promotes tumor development, progression, and metastatic dissemination and causes treatment resistance. The accumulation of genetic alterations and loss of normal cellular regulatory processes are not only associated with cancer growth and progression but also result in the expression of tumor-specific and tumor-associated antigens that may activate antitumor immunity. This antagonism between inflammation and immunity and the ability of cancer cells to avoid immune detection affect the course of cancer development and treatment outcomes. While inflammation, particularly acute inflammation, supports T-cell priming, activation, and infiltration into infected tissues, chronic inflammation is mostly immunosuppressive. However, the main mechanisms that dictate the outcome of the inflammation-immunity interplay are not well understood. Recent data suggest that inflammation triggers epigenetic alterations in cancer cells and components of the tumor microenvironment. These alterations can affect and modulate numerous aspects of cancer development, including tumor growth, the metabolic state, metastatic spread, immune escape, and immunosuppressive or immunosupportive leukocyte generation. In this review, we discuss the role of inflammation in initiating epigenetic alterations in immune cells, cancer-associated fibroblasts, and cancer cells and suggest how and when epigenetic interventions can be combined with immunotherapies to improve therapeutic outcomes.
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http://dx.doi.org/10.1038/s41423-021-00756-yDOI Listing
August 2021

Autophagy-mitophagy induction attenuates cardiovascular inflammation in a murine model of Kawasaki disease vasculitis.

JCI Insight 2021 Sep 22;6(18). Epub 2021 Sep 22.

Department of Pediatrics, Division of Infectious Diseases and Immunology.

Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Murine and human data suggest that the NLRP3-IL-1β pathway is the main driver of KD pathophysiology. NLRP3 can be activated during defective autophagy/mitophagy. We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to examine the role of autophagy/mitophagy on cardiovascular lesion development. LCWE-injected mice had impaired autophagy/mitophagy and increased levels of ROS in cardiovascular lesions, together with increased systemic 8-OHdG release. Enhanced autophagic flux significantly reduced cardiovascular lesions in LCWE-injected mice, whereas autophagy blockade increased inflammation. Vascular smooth muscle cell-specific deletion of Atg16l1 and global Parkin-/- significantly increased disease formation, supporting the importance of autophagy/mitophagy in this model. Ogg1-/- mice had significantly increased lesions with increased NLRP3 activity, whereas treatment with MitoQ reduced vascular tissue inflammation, ROS production, and systemic 8-OHdG release. Treatment with MN58b or Metformin (increasing AMPK and reducing ROS) resulted in decreased cardiovascular lesions. Our results demonstrate that impaired autophagy/mitophagy and ROS-dependent damage exacerbate the development of murine KD vasculitis. This pathway can be efficiently targeted to reduce disease severity. These findings enhance our understanding of KD pathogenesis and identify potentially novel therapeutic avenues for KD treatment.
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http://dx.doi.org/10.1172/jci.insight.151981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492304PMC
September 2021

The neglected brothers come of age: B cells and cancer.

Semin Immunol 2021 Feb 29;52:101479. Epub 2021 Jun 29.

Department of Pharmacology, School of Medicine, University of California San Diego, CA 92093, USA; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

The opposing roles of innate and adaptive immune cells in suppressing or supporting cancer initiation, progression, metastasis and response to therapy has been long debated. The mechanisms by which different monocyte and T cell subtypes affect and modulate cancer have been extensively studied. However, the role of B cells and their subtypes have remained elusive, perhaps partially due to their heterogeneity and range of actions. B cells can produce a variety of cytokines and present tumor-derived antigens to T cells in combination with co-stimulatory or inhibitory ligands based on their phenotype. Unlike most T cells, B cells can be activated by innate immune stimuli, such as endotoxin. Furthermore, the isotype and specificity of the antibodies produced by plasma cells regulate distinct immune responses, including opsonization, antibody-mediated cellular cytotoxicity (ADCC) and complement activation. B cells are shaped by the tumor environment (TME), with the capability to regulate the TME in return. In this review, we will describe the mechanisms of B cell action, including cytokine production, antigen presentation, ADCC, opsonization, complement activation and how they affect tumor development and response to immunotherapy. We will also discuss how B cell fate within the TME is affected by tumor stroma, microbiome and metabolism.
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http://dx.doi.org/10.1016/j.smim.2021.101479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545794PMC
February 2021

Nondegradable Collagen Increases Liver Fibrosis but Not Hepatocellular Carcinoma in Mice.

Am J Pathol 2021 09 11;191(9):1564-1579. Epub 2021 Jun 11.

Department of Medicine, University of California San Diego, San Diego, California. Electronic address:

Although hepatocellular cancer (HCC) usually occurs in the setting of liver fibrosis, the causal relationship between liver fibrosis and HCC is unclear. in vivo and in vitro models of HCC involving Col mice (that produce a collagenase-resistant type I collagen) or wild-type (WT) mice were used to assess the relationship between type I collagen, liver fibrosis, and experimental HCC. HCC was either chemically induced in WT and Col mice or Hepa 1-6 cells were engrafted into WT and Col livers. The effect of hepatic stellate cells (HSCs) from WT and Col mice on the growth of Hepa 1-6 cells was studied by using multicellular tumor spheroids and xenografts. Collagen type I deposition and fibrosis were increased in Col mice, but they developed fewer and smaller tumors. Hepa 1-6 cells had reduced tumor growth in the livers of Col mice. Although Col HSCs exhibited a more activated phenotype, Hepa 1-6 growth and malignancy were suppressed in multicellular tumor spheroids and in xenografts containing Col HSCs. Treatment with vitronectin, which mimics the presence of degraded collagen fragments, converted the Col phenotype into a WT phenotype. Although Col mice have increased liver fibrosis, they exhibited decreased HCC in several models. Thus, increased liver type I collagen does not produce increased experimental HCC.
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http://dx.doi.org/10.1016/j.ajpath.2021.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406794PMC
September 2021

Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation.

Immunity 2021 07 10;54(7):1463-1477.e11. Epub 2021 Jun 10.

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA.

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1β production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.
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http://dx.doi.org/10.1016/j.immuni.2021.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189765PMC
July 2021

Macropinocytosis: the big drinker behind cancer cell self-consumption.

Autophagy 2021 05 27;17(5):1290-1291. Epub 2021 Apr 27.

Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA.

Poorly vascularized tumors embedded within a thick desmoplastic stroma, like pancreatic ductal adenocarcinoma (PDAC), are nutritionally stressed. Such tumors are also hypoxic and rely on a number of adaptive responses, including macroautophagy/autophagy and macropinocytosis (MP), to support their bioenergetic needs. Whereas autophagy enables starved cells to recycle intracellular macromolecules via lysosomal degradation and use the liberated amino acids (AA) to fuel their metabolism, MP allows cells to take up extracellular proteins via fluid-phase endocytosis and use them as an energy source. However, how any MP-enabled organism, including the prototypical cancer cell, coordinately regulates and balances autophagy and MP is not fully understood. We recently found that inhibition of autophagy results in upregulation of MP, which enables cancer cells to overcome autophagy deficiency and continue to support their bioenergetic demands. The NFE2L2/NRF2-driven induction of MP-related genes (MRGs) is responsible for the upregulation of MP in autophagy inhibited, hypoxic, and oxidatively stressed-exposed cancer cells. Concurrent autophagy and MP blockade effectively cuts off the cancer cell's nutrient and supplies, leading to rapid tumor regression. These findings suggest MP to be an important target in cancer treatment and that shutting off the energy spigot is a promising therapeutic strategy. AA: amino acids; ADCs: autophagy deficient-cells; AI: autophagy inhibition; ALB: albumin; CHUK/IKKα: component of inhibitor of nuclear factor kappa B kinase complex; CQ: chloroquine; ECM: extracellular matrix; HCQ: hydroxychloroquine; MI: MP inhibition; MP: macropinocytosis; MRGs: MP-related genes; MRPs: MP-related proteins; PDAC: pancreatic ductal adenocarcinoma.
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http://dx.doi.org/10.1080/15548627.2021.1919969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143249PMC
May 2021

Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia.

Proc Natl Acad Sci U S A 2021 04;118(15)

Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037;

Parkinson's disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn-antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1β (IL-1β) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-β peptide (Aβ) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia.
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http://dx.doi.org/10.1073/pnas.2025847118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054017PMC
April 2021

From Liver Fat to Cancer: Perils of the Western Diet.

Cancers (Basel) 2021 Mar 4;13(5). Epub 2021 Mar 4.

Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA.

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer provides the prototypical example of an obesity-related cancer. The obesity epidemic gave rise to an enormous increase in the incidence of non-alcoholic fatty liver disease (NAFLD), a condition that affects one third of American adults. In about 20% of these individuals, simple liver steatosis (hepatosteatosis) progresses to non-alcoholic steatohepatitis (NASH) characterized by chronic liver injury, inflammation, and fibrosis. In addition to liver failure, NASH greatly increases the risk of HCC. Here we discuss the metabolic processes that control the progression from NAFLD to NASH and from NASH to HCC, with a special emphasis on the role of free-non-esterified cholesterol in the process.
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http://dx.doi.org/10.3390/cancers13051095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961422PMC
March 2021

Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor-MIG6 Axis.

Cancers (Basel) 2021 Mar 25;13(7). Epub 2021 Mar 25.

Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.

Non-alcoholic steatohepatitis (NASH) has become a serious public health problem associated with metabolic syndrome. The mechanisms by which NASH induces hepatocellular carcinoma (HCC) remain unknown. There are no approved drugs for treating NASH or preventing NASH-induced HCC. We used a genetic mouse model in which HCC was induced via high-fat diet feeding. This mouse model strongly resembles human NASH-induced HCC. The natural product honokiol (HNK) was tested for its preventative effects against NASH progression to HCC. Then, to clarify the mechanisms underlying HCC development, human HCC cells were treated with HNK. Human clinical specimens were also analyzed to explore this study's clinical relevance. We found that epidermal growth factor receptor (EGFR) signaling was hyperactivated in the livers of mice with NASH and human HCC specimens. Inhibition of EGFR signaling by HNK drastically attenuated HCC development in the mouse model. Mechanistically, HNK accelerated the nuclear translocation of glucocorticoid receptor (GR) and promoted mitogen-inducible gene 6 (MIG6)/ERBB receptor feedback inhibitor 1 (ERRFI1) expression, leading to EGFR degradation and thereby resulting in robust tumor suppression. In human samples, EGFR-positive HCC tissues and their corresponding non-tumor tissues exhibited decreased mRNA expression. Additionally, GR-positive non-tumor liver tissues displayed lower EGFR expression. Livers from patients with advanced NASH exhibited decreased expression. EGFR degradation or inactivation represents a novel approach for NASH-HCC treatment and prevention, and the GR-MIG6 axis is a newly defined target that can be activated by HNK and related compounds.
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http://dx.doi.org/10.3390/cancers13071515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037653PMC
March 2021

Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis.

Cancer Cell 2021 05 18;39(5):678-693.e11. Epub 2021 Mar 18.

Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address:

Many cancers, including pancreatic ductal adenocarcinoma (PDAC), depend on autophagy-mediated scavenging and recycling of intracellular macromolecules, suggesting that autophagy blockade should cause tumor starvation and regression. However, until now autophagy-inhibiting monotherapies have not demonstrated potent anti-cancer activity. We now show that autophagy blockade prompts established PDAC to upregulate and utilize an alternative nutrient procurement pathway: macropinocytosis (MP) that allows tumor cells to extract nutrients from extracellular sources and use them for energy generation. The autophagy to MP switch, which may be evolutionarily conserved and not cancer cell restricted, depends on activation of transcription factor NRF2 by the autophagy adaptor p62/SQSTM1. NRF2 activation by oncogenic mutations, hypoxia, and oxidative stress also results in MP upregulation. Inhibition of MP in autophagy-compromised PDAC elicits dramatic metabolic decline and regression of transplanted and autochthonous tumors, suggesting the therapeutic promise of combining autophagy and MP inhibitors in the clinic.
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http://dx.doi.org/10.1016/j.ccell.2021.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119368PMC
May 2021

Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation.

Proc Natl Acad Sci U S A 2021 02;118(8)

Division of Medical Genetics, Health Sciences, Department of Biomedical Informatics, University of California San Diego, La Jolla, CA 92093.

Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8 CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity.
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http://dx.doi.org/10.1073/pnas.2025840118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923353PMC
February 2021

Seroprevalence of antibodies to SARS-CoV-2 in healthcare workers: a cross-sectional study.

BMJ Open 2021 02 12;11(2):e043584. Epub 2021 Feb 12.

Center for Neural Science and Medicine, Department of Biomedical Sciences, Board of Governors Regenerative Medicine Institute, Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Objective: We sought to determine the extent of SARS-CoV-2 seroprevalence and the factors associated with seroprevalence across a diverse cohort of healthcare workers.

Design: Observational cohort study of healthcare workers, including SARS-CoV-2 serology testing and participant questionnaires.

Settings: A multisite healthcare delivery system located in Los Angeles County.

Participants: A diverse and unselected population of adults (n=6062) employed in a multisite healthcare delivery system located in Los Angeles County, including individuals with direct patient contact and others with non-patient-oriented work functions.

Main Outcomes: Using Bayesian and multivariate analyses, we estimated seroprevalence and factors associated with seropositivity and antibody levels, including pre-existing demographic and clinical characteristics; potential COVID-19 illness-related exposures; and symptoms consistent with COVID-19 infection.

Results: We observed a seroprevalence rate of 4.1%, with anosmia as the most prominently associated self-reported symptom (OR 11.04, p<0.001) in addition to fever (OR 2.02, p=0.002) and myalgias (OR 1.65, p=0.035). After adjusting for potential confounders, seroprevalence was also associated with Hispanic ethnicity (OR 1.98, p=0.001) and African-American race (OR 2.02, p=0.027) as well as contact with a COVID-19-diagnosed individual in the household (OR 5.73, p<0.001) or clinical work setting (OR 1.76, p=0.002). Importantly, African-American race and Hispanic ethnicity were associated with antibody positivity even after adjusting for personal COVID-19 diagnosis status, suggesting the contribution of unmeasured structural or societal factors.

Conclusion And Relevance: The demographic factors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace. The size and diversity of our study population, combined with robust survey and modelling techniques, provide a vibrant picture of the demographic factors, exposures and symptoms that can identify individuals with susceptibility as well as potential to mount an immune response to COVID-19.
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http://dx.doi.org/10.1136/bmjopen-2020-043584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883610PMC
February 2021

STARD1 promotes NASH-driven HCC by sustaining the generation of bile acids through the alternative mitochondrial pathway.

J Hepatol 2021 06 27;74(6):1429-1441. Epub 2021 Jan 27.

Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address:

Background & Aims: Besides their physiological role in bile formation and fat digestion, bile acids (BAs) synthesised from cholesterol in hepatocytes act as signalling molecules that modulate hepatocellular carcinoma (HCC). Trafficking of cholesterol to mitochondria through steroidogenic acute regulatory protein 1 (STARD1) is the rate-limiting step in the alternative pathway of BA generation, the physiological relevance of which is not well understood. Moreover, the specific contribution of the STARD1-dependent BA synthesis pathway to HCC has not been previously explored.

Methods: STARD1 expression was analyzed in a cohort of human non-alcoholic steatohepatitis (NASH)-derived HCC specimens. Experimental NASH-driven HCC models included MUP-uPA mice fed a high-fat high-cholesterol (HFHC) diet and diethylnitrosamine (DEN) treatment in wild-type (WT) mice fed a HFHC diet. Molecular species of BAs and oxysterols were analyzed by mass spectrometry. Effects of NASH-derived BA profiles were investigated in tumour-initiated stem-like cells (TICs) and primary mouse hepatocytes (PMHs).

Results: Patients with NASH-associated HCC exhibited increased hepatic expression of STARD1 and an enhanced BA pool. Using NASH-driven HCC models, STARD1 overexpression in WT mice increased liver tumour multiplicity, whereas hepatocyte-specific STARD1 deletion (Stard1) in WT or MUP-uPA mice reduced tumour burden. These findings mirrored the levels of unconjugated primary BAs, β-muricholic acid and cholic acid, and their tauroconjugates in STARD1-overexpressing and Stard1 mice. Incubation of TICs or PMHs with a mix of BAs mimicking this profile stimulated expression of genes involved in pluripotency, stemness and inflammation.

Conclusions: The study reveals a previously unrecognised role of STARD1 in HCC pathogenesis, wherein it promotes the synthesis of primary BAs through the mitochondrial pathway, the products of which act in TICs to stimulate self-renewal, stemness and inflammation.

Lay Summary: Effective therapy for hepatocellular carcinoma (HCC) is limited because of our incomplete understanding of its pathogenesis. The contribution of the alternative pathway of bile acid (BA) synthesis to HCC development is unknown. We uncover a key role for steroidogenic acute regulatory protein 1 (STARD1) in non-alcoholic steatohepatitis-driven HCC, wherein it stimulates the generation of BAs in the mitochondrial acidic pathway, the products of which stimulate hepatocyte pluripotency and self-renewal, as well as inflammation.
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http://dx.doi.org/10.1016/j.jhep.2021.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573791PMC
June 2021

Targeting cancer-promoting inflammation - have anti-inflammatory therapies come of age?

Nat Rev Clin Oncol 2021 05 19;18(5):261-279. Epub 2021 Jan 19.

Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

The immune system has crucial roles in cancer development and treatment. Whereas adaptive immunity can prevent or constrain cancer through immunosurveillance, innate immunity and inflammation often promote tumorigenesis and malignant progression of nascent cancer. The past decade has witnessed the translation of knowledge derived from preclinical studies of antitumour immunity into clinically effective, approved immunotherapies for cancer. By contrast, the successful implementation of treatments that target cancer-associated inflammation is still awaited. Anti-inflammatory agents have the potential to not only prevent or delay cancer onset but also to improve the efficacy of conventional therapeutics and next-generation immunotherapies. Herein, we review the current clinical advances and experimental findings supporting the utility of an anti-inflammatory approach to the treatment of solid malignancies. Gaining a better mechanistic understanding of the mode of action of anti-inflammatory agents and designing more effective treatment combinations would advance the clinical application of this therapeutic approach.
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http://dx.doi.org/10.1038/s41571-020-00459-9DOI Listing
May 2021

Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease.

Proc Natl Acad Sci U S A 2020 12 23;117(49):31259-31266. Epub 2020 Nov 23.

Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, CA 92093;

Triclosan (TCS), employed as an antiseptic and disinfectant, comes into direct contact with humans through a plethora of consumer products and its rising environmental release. We have demonstrated that TCS promotes liver tumorigenesis in mice, yet the biological and molecular mechanisms by which TCS exerts its toxicity, especially in early stages of liver disease, are largely unexplored. When mice were fed a high-fat diet (HFD), we found that fatty liver and dyslipidemia are prominent early signs of liver abnormality induced by TCS. The presumably protective HFD-induced hepatic expression of the metabolic regulator fibroblast growth factor 21 (FGF21) was blunted by TCS. TCS-altered expression aligned with aberrant expression of genes encoding metabolic enzymes manifested as profound systemic metabolic changes that disturb homeostasis of amino acids, fatty acids, and glucose. Using a type 1 diabetic animal model, TCS potentiates and accelerates the development of steatohepatitis and fibrosis, accompanied by increased levels of hepatic lipid droplets and oxidative stress. Analysis of fecal samples revealed that HFD-fed mice exhibited a reduction in fecal species richness, and that TCS further diminished microbial diversity and shifted the bacterial community toward lower Bacteriodetes and higher Firmicutes, resembling changes in microbiota composition in nonalcoholic steatohepatitis (NASH) patients. Using reverse-genetic approaches, we demonstrate that, along with HFD, TCS induces hepatic steatosis and steatohepatitis jointly regulated by the transcription factor ATF4 and the nuclear receptor PPARα, which participate in the transcriptional regulation of the gene. This study provides evidence linking nutritional imbalance and exposure to TCS with the progression of NASH.
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http://dx.doi.org/10.1073/pnas.2017129117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733785PMC
December 2020

Fructose stimulated de novo lipogenesis is promoted by inflammation.

Nat Metab 2020 10 24;2(10):1034-1045. Epub 2020 Aug 24.

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA.

Benign hepatosteatosis, affected by lipid uptake, de novo lipogenesis and fatty acid (FA) oxidation, progresses to non-alcoholic steatohepatitis (NASH) on stress and inflammation. A key macronutrient proposed to increase hepatosteatosis and NASH risk is fructose. Excessive intake of fructose causes intestinal-barrier deterioration and endotoxaemia. However, how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis remain unknown. Here we show, using mice, that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signalling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) peptide counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxaemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to FA in both mouse and human hepatocytes.
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http://dx.doi.org/10.1038/s42255-020-0261-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018782PMC
October 2020

PKCλ/ι Loss Induces Autophagy, Oxidative Phosphorylation, and NRF2 to Promote Liver Cancer Progression.

Cancer Cell 2020 08 25;38(2):247-262.e11. Epub 2020 Jun 25.

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA. Electronic address:

Oxidative stress plays a critical role in liver tissue damage and in hepatocellular carcinoma (HCC) initiation and progression. However, the mechanisms that regulate autophagy and metabolic reprogramming during reactive oxygen species (ROS) generation, and how ROS promote tumorigenesis, still need to be fully understood. We show that protein kinase C (PKC) λ/ι loss in hepatocytes promotes autophagy and oxidative phosphorylation. This results in ROS generation, which through NRF2 drives HCC through cell-autonomous and non-autonomous mechanisms. Although PKCλ/ι promotes tumorigenesis in oncogene-driven cancer models, emerging evidence demonstrate that it is a tumor suppressor in more complex carcinogenic processes. Consistently, PKCλ/ι levels negatively correlate with HCC histological tumor grade, establishing this kinase as a tumor suppressor in liver cancer.
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http://dx.doi.org/10.1016/j.ccell.2020.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423690PMC
August 2020

Neoadjuvant rituximab modulates the tumor immune environment in patients with high risk prostate cancer.

J Transl Med 2020 05 28;18(1):214. Epub 2020 May 28.

Department of Urology, UCSD Moores Cancer Center, University of California San Diego School of Medicine, 3855 Health Sciences Drive, Mail Code: 0987, La Jolla, CA, 92093-0987, USA.

Background: Immunotherapeutic regulation of the tumor microenvironment in prostate cancer patients is not understood. Most antibody immunotherapies have not succeeded in prostate cancer. We showed previously that high-risk PCa patients have a higher density of tumor infiltrating B-cells in prostatectomy specimens. In mouse models, anti-CD20 antibody ablation of B-cells delayed PCa regrowth post-treatment. We sought to determine whether neoadjuvant anti-CD20 immunotherapy with rituximab could reduce CD20+ B cell infiltration of prostate tumors in patients.

Methods: An open label, single arm clinical trial enrolled eight high-risk PCa patients to receive one cycle of neoadjuvant rituximab prior to prostatectomy. Eleven clinical specimens with similar characteristics were selected as controls. Treated and control samples were concurrently stained for CD20 and digitally scanned in a blinded fashion. A new method of digital image quantification of lymphocytes was applied to prostatectomy sections of treated and control cases. CD20 density was quantified by a deconvolution algorithm in pathologist-marked tumor and adjacent regions. Statistical significance was assessed by one sided Welch's t-test, at 0.05 level using a gatekeeper strategy. Secondary outcomes included CD3+ T-cell and PD-L1 densities.

Results: Mean CD20 density in the tumor regions of the treated group was significantly lower than the control group (p = 0.02). Mean CD3 density in the tumors was significantly decreased in the treated group (p = 0.01). CD20, CD3 and PD-L1 staining primarily occurred in tertiary lymphoid structures (TLS). Neoadjuvant rituximab was well-tolerated and decreased B-cell and T-cell density within high-risk PCa tumors compared to controls.

Conclusions: This is the first study to treat patients prior to surgical prostate removal with an immunotherapy that targets B-cells. Rituximab treatment reduced tumor infiltrating B and T-cell density especially in TLSs, thus, demonstrating inter-dependence between B- and T-cells in prostate cancer and that Rituximab can modify the immune environment in prostate tumors. Future studies will determine who may benefit from using rituximab to improve their immune response against prostate cancer. Trial registration NCT01804712, March 5th, 2013 https://clinicaltrials.gov/ct2/show/NCT01804712?cond=NCT01804712&draw=2&rank=1.
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http://dx.doi.org/10.1186/s12967-020-02370-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257145PMC
May 2020

NRF2 as a regulator of cell metabolism and inflammation in cancer.

Carcinogenesis 2020 06;41(4):405-416

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, San Diego, La Jolla, CA, USA.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of genes whose products defend our cells for toxic and oxidative insults. Although NRF2 activation may reduce cancer risk by suppressing oxidative stress and tumor-promoting inflammation, many cancers exhibit elevated NRF2 activity either due to mutations that disrupt the negative control of NRF2 activity or other factors. Importantly, NRF2 activation is associated with poor prognosis and NRF2 has turned out to be a key activator of cancer-supportive anabolic metabolism. In this review, we summarize the diverse roles played by NRF2 in cancer focusing on metabolic reprogramming and tumor-promoting inflammation.
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http://dx.doi.org/10.1093/carcin/bgaa039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298623PMC
June 2020

Consensus guidelines for the definition, detection and interpretation of immunogenic cell death.

J Immunother Cancer 2020 03;8(1)

Program of Immunology and Immunotherapy, Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain.

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
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http://dx.doi.org/10.1136/jitc-2019-000337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064135PMC
March 2020

Immunotherapy, Inflammation and Colorectal Cancer.

Cells 2020 03 4;9(3). Epub 2020 Mar 4.

Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

Colorectal cancer (CRC) is the third most common cancer type, and third highest in mortality rates among cancer-related deaths in the United States. Originating from intestinal epithelial cells in the colon and rectum, that are impacted by numerous factors including genetics, environment and chronic, lingering inflammation, CRC can be a problematic malignancy to treat when detected at advanced stages. Chemotherapeutic agents serve as the historical first line of defense in the treatment of metastatic CRC. In recent years, however, combinational treatment with targeted therapies, such as vascular endothelial growth factor, or epidermal growth factor receptor inhibitors, has proven to be quite effective in patients with specific CRC subtypes. While scientific and clinical advances have uncovered promising new treatment options, the five-year survival rate for metastatic CRC is still low at about 14%. Current research into the efficacy of immunotherapy, particularly immune checkpoint inhibitor therapy (ICI) in mismatch repair deficient and microsatellite instability high (dMMR-MSI-H) CRC tumors have shown promising results, but its use in other CRC subtypes has been either unsuccessful, or not extensively explored. This Review will focus on the current status of immunotherapies, including ICI, vaccination and adoptive T cell therapy (ATC) in the treatment of CRC and its potential use, not only in dMMR-MSI-H CRC, but also in mismatch repair proficient and microsatellite instability low (pMMR-MSI-L).
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http://dx.doi.org/10.3390/cells9030618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140520PMC
March 2020

NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly.

J Hepatol 2020 06 24;72(6):1182-1195. Epub 2020 Feb 24.

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address:

Background & Aims: Hepatomegaly can be triggered by insulin and insulin-unrelated etiologies. Insulin acts via AKT, but how other challenges cause hepatomegaly is unknown.

Methods: Since many hepatomegaly-inducing toxicants and stressors activate NRF2, we examined the effect of NRF2 activation on liver size and metabolism using a conditional allele encoding a constitutively active NRF2 variant to generate Nrf2 mice in which NRF2 is selectively activated in hepatocytes. We also used adenoviruses encoding variants of the autophagy adaptor p62/SQSTM1, which activates liver NRF2, as well as liver-specific ATG7-deficient mice (Atg7) and liver specimens from patients with hepatic sinusoidal obstruction syndrome (HSOS) and autoimmune hepatitis (AIH). RNA sequencing and cell signaling analyses were used to determine cellular consequences of NRF2 activation and diverse histological analyses were used to study effects of the different manipulations on liver and systemic pathophysiology.

Results: Hepatocyte-specific NRF2 activation, due to p62 accumulation or inhibition of KEAP1 binding, led to hepatomegaly associated with enhanced glycogenosis, steatosis and G2/M cell cycle arrest, fostering hyperplasia without cell division. Surprisingly, all manipulations that led to NRF2 activation also activated AKT, whose inhibition blocked NRF2-induced hepatomegaly and glycogenosis, but not NRF2-dependent antioxidant gene induction. AKT activation was linked to NRF2-mediated transcriptional induction of PDGF and EGF receptor ligands that signaled through their cognate receptors in an autocrine manner. Insulin and insulin-like growth factors were not involved. The NRF2-AKT signaling axis was also activated in human HSOS- and AIH-related hepatomegaly.

Conclusions: NRF2, a transcription factor readily activated by xenobiotics, oxidative stress and autophagy disruptors, may be a common mediator of hepatomegaly; its effects on hepatic metabolism can be reversed by AKT/tyrosine kinase inhibitors.

Lay Summary: Hepatomegaly can be triggered by numerous etiological factors, including infections, liver cancer, metabolic disturbances, toxicant exposure, as well as alcohol abuse or drug-induced hepatitis. This study identified the oxidative stress response transcription factor NRF2 as a common mediator of hepatomegaly. NRF2 activation results in elevated expression of several growth factors. These growth factors are made by hepatocytes and activate their receptors in an autocrine fashion to stimulate the accumulation of glycogen and lipids that lead to hepatocyte and liver enlargement. The protein kinase AKT plays a key role in this process and its inhibition leads to reversal of hepatomegaly.
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http://dx.doi.org/10.1016/j.jhep.2020.01.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054878PMC
June 2020

Blockade of IL-17 signaling reverses alcohol-induced liver injury and excessive alcohol drinking in mice.

JCI Insight 2020 02 13;5(3). Epub 2020 Feb 13.

Department of Surgery, and.

Chronic alcohol abuse has a detrimental effect on the brain and liver. There is no effective treatment for these patients, and the mechanism underlying alcohol addiction and consequent alcohol-induced damage of the liver/brain axis remains unresolved. We compared experimental models of alcoholic liver disease (ALD) and alcohol dependence in mice and demonstrated that genetic ablation of IL-17 receptor A (IL-17ra-/-) or pharmacological blockade of IL-17 signaling effectively suppressed the increased voluntary alcohol drinking in alcohol-dependent mice and blocked alcohol-induced hepatocellular and neurological damage. The level of circulating IL-17A positively correlated with the alcohol use in excessive drinkers and was further increased in patients with ALD as compared with healthy individuals. Our data suggest that IL-17A is a common mediator of excessive alcohol consumption and alcohol-induced liver/brain injury, and targeting IL-17A may provide a novel strategy for treatment of alcohol-induced pathology.
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http://dx.doi.org/10.1172/jci.insight.131277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098802PMC
February 2020

Cruel to Be Kind: Epithelial, Microbial, and Immune Cell Interactions in Gastrointestinal Cancers.

Annu Rev Immunol 2020 04 10;38:649-671. Epub 2020 Feb 10.

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA; email:

A plethora of experimental and epidemiological evidence supports a critical role for inflammation and adaptive immunity in the onset of cancer and in shaping its response to therapy. These data are particularly robust for gastrointestinal (GI) cancers, such as those affecting the GI tract, liver, and pancreas, on which this review is focused. We propose a unifying hypothesis according to which intestinal barrier disruption is the origin of tumor-promoting inflammation that acts in conjunction with tissue-specific cancer-initiating mutations. The gut microbiota and its products impact tissue-resident and recruited myeloid cells that promote tumorigenesis through secretion of growth- and survival-promoting cytokines that act on epithelial cells, as well as fibrogenic and immunosuppressive cytokines that interfere with the proper function of adaptive antitumor immunity. Understanding these relationships should improve our ability to prevent cancer development and stimulate the immune system to eliminate existing malignancies.
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http://dx.doi.org/10.1146/annurev-immunol-082019-081656DOI Listing
April 2020

An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis.

Science 2020 02;367(6478):652-660

Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

Liver cell death has an essential role in nonalcoholic steatohepatitis (NASH). The activity of the energy sensor adenosine monophosphate (AMP)-activated protein kinase (AMPK) is repressed in NASH. Liver-specific AMPK knockout aggravated liver damage in mouse NASH models. AMPK phosphorylated proapoptotic caspase-6 protein to inhibit its activation, keeping hepatocyte apoptosis in check. Suppression of AMPK activity relieved this inhibition, rendering caspase-6 activated in human and mouse NASH. AMPK activation or caspase-6 inhibition, even after the onset of NASH, improved liver damage and fibrosis. Once phosphorylation was decreased, caspase-6 was activated by caspase-3 or -7. Active caspase-6 cleaved Bid to induce cytochrome c release, generating a feedforward loop that leads to hepatocyte death. Thus, the AMPK-caspase-6 axis regulates liver damage in NASH, implicating AMPK and caspase-6 as therapeutic targets.
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http://dx.doi.org/10.1126/science.aay0542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012106PMC
February 2020

NF-κB-p62-NRF2 survival signaling is associated with high ROR1 expression in chronic lymphocytic leukemia.

Cell Death Differ 2020 07 28;27(7):2206-2216. Epub 2020 Jan 28.

Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.

Progression of chronic lymphocytic leukemia (CLL) and resistance to therapy are affected by tumor microenvironmental factors. One such factor is B-cell activating factor (BAFF), a cytokine that is produced mainly by nurse-like cells (NLC) and enhances CLL cells survival and modulates response to therapy. In CLL cells, BAFF activates NF-κB signaling, but how NF-κB supports CLL survival is not entirely clear. In this study we show that BAFF induces accumulation of the signaling and autophagy adaptor p62/SQSTM1 in a manner dependent on NF-κB activation. p62 potentiates mTORC1 signaling and activates NRF2, the master regulator of the anti-oxidant response. We found that expression of NRF2 target genes, such as NAD(P)H quinone oxidoreductase 1 (NQO1), is particularly enriched in CLL cells with high ROR1 surface expression (ROR1). ROR1 CLL cells with elevated NQO1 expression exhibit resistance to drugs that induce ROS accumulation, such venetoclax. However, such cells are more sensitive to compound 29h, a pro-drug that only becomes active after being metabolized by NQO1. Accordingly, 29h sensitizes high NQO1 CLL cells to venetoclax. Collectively, our study unravels a previously unknown signaling network through which the NF-κB-p62-NRF2 axis protects ROR1-high CLL cells from ROS-inducing therapeutics.
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http://dx.doi.org/10.1038/s41418-020-0496-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308363PMC
July 2020

A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control.

J Hepatol 2020 05 15;72(5):960-975. Epub 2020 Jan 15.

Institute of Experimental Immunology, Bonn, Germany.

Background & Aims: Hepatic innate immune control of viral infections has largely been attributed to Kupffer cells, the liver-resident macrophages. However, hepatocytes, the parenchymal cells of the liver, also possess potent immunological functions in addition to their known metabolic functions. Owing to their abundance in the liver and known immunological functions, we aimed to investigate the direct antiviral mechanisms employed by hepatocytes.

Methods: Using lymphocytic choriomeningitis virus (LCMV) as a model of liver infection, we first assessed the role of myeloid cells by depletion prior to infection. We investigated the role of hepatocyte-intrinsic innate immune signaling by infecting mice lacking canonical NF-κB signaling (Ikkβ) specifically in hepatocytes. In addition, mice lacking hepatocyte-specific interferon-α/β signaling-(Ifnar), or interferon-α/β signaling in myeloid cells-(Ifnar) were infected.

Results: Here, we demonstrate that LCMV activates NF-κB signaling in hepatocytes. LCMV-triggered NF-κB activation in hepatocytes did not depend on Kupffer cells or TNFR1 signaling but rather on Toll-like receptor signaling. LCMV-infected Ikkβ livers displayed strongly elevated viral titers due to LCMV accumulation within hepatocytes, reduced interferon-stimulated gene (ISG) expression, delayed intrahepatic immune cell influx and delayed intrahepatic LCMV-specific CD8 T cell responses. Notably, viral clearance and ISG expression were also reduced in LCMV-infected primary hepatocytes lacking IKKβ, demonstrating a hepatocyte-intrinsic effect. Similar to livers of Ikkβ mice, enhanced hepatocytic LCMV accumulation was observed in livers of Ifnar mice, whereas Ifnar mice were able to control LCMV infection. Hepatocytic NF-κB signaling was also required for efficient ISG induction in HDV-infected dHepaRG cells and interferon-α/β-mediated inhibition of HBV replication in vitro.

Conclusions: Together, these data show that hepatocyte-intrinsic NF-κB is a vital amplifier of interferon-α/β signaling, which is pivotal for strong early ISG responses, immune cell infiltration and hepatic viral clearance.

Lay Summary: Innate immune cells have been ascribed a primary role in controlling viral clearance upon hepatic infections. We identified a novel dual role for NF-κB signaling in infected hepatocytes which was crucial for maximizing interferon responses and initiating adaptive immunity, thereby efficiently controlling hepatic virus replication.
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http://dx.doi.org/10.1016/j.jhep.2019.12.019DOI Listing
May 2020
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