Showing papers by "Michael Karin published in 2016"

PI3Kγ is a molecular switch that controls immune suppression

Abstract: Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors. Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders.

Reparative inflammation takes charge of tissue regeneration

Abstract: Inflammation underlies many chronic and degenerative diseases, but it also mitigates infections, clears damaged cells and initiates tissue repair. Many of the mechanisms that link inflammation to damage repair and regeneration in mammals are conserved in lower organisms, indicating that it is an evolutionarily important process. Recent insights have shed light on the cellular and molecular processes through which conventional inflammatory cytokines and Wnt factors control mammalian tissue repair and regeneration. This is particularly important for regeneration in the gastrointestinal system, especially for intestine and liver tissues in which aberrant and deregulated repair results in severe pathologies.

Targeting Inflammation in Cancer Prevention and Therapy

Abstract: Inflammation is associated with the development and malignant progression of most cancers. As most of the cell types involved in cancer-associated inflammation are genetically stable and thus are not subjected to rapid emergence of drug resistance, the targeting of inflammation represents an attractive strategy both for cancer prevention and for cancer therapy. Tumor-extrinsic inflammation is caused by many factors, including bacterial and viral infections, autoimmune diseases, obesity, tobacco smoking, asbestos exposure, and excessive alcohol consumption, all of which increase cancer risk and stimulate malignant progression. In contrast, cancer-intrinsic or cancer-elicited inflammation can be triggered by cancer-initiating mutations and can contribute to malignant progression through the recruitment and activation of inflammatory cells. Both extrinsic and intrinsic inflammation can result in immunosuppression, thereby providing a preferred background for tumor development. In clinical trials, lifestyle modifications including healthy diet, exercise, alcohol, and smoking cessation have proven effective in ameliorating inflammation and reducing the risk of cancer-related deaths. In addition, consumption of certain anti-inflammatory drugs, including aspirin, can significantly reduce cancer risk, suggesting that common nonsteroidal anti-inflammatory drugs (NSAID) and more specific COX2 inhibitors can be used in cancer prevention. In addition to being examined for their preventative potential, both NSAIDs and more potent anti-inflammatory antibody-based drugs need to be tested for their ability to augment the efficacy of more conventional therapeutic approaches on the basis of tumor resection, radiation, and cytotoxic chemicals. Cancer Prev Res; 9(12); 895-905. ©2016 AACR.

Autophagy, NLRP3 inflammasome and auto-inflammatory/immune diseases

Abstract: Loss of homeostasis, as a result of pathogen invasion or self imbalance, causes tissue damage and inflammation. In addition to its well-established role in promoting clearance of pathogens or cell corpses, inflammation is also key to drive tissue repair and regeneration. Conserved from flies to humans, a transient, well-balanced inflammatory response is critical for restoration of tissue homeostasis after damage. The absence of such a response can result in failure of tissue repair, leading to the development of devastating immunopathologies and degenerative diseases. Studies in the past decade collectively suggest that a malfunction of NLRP3 inflammasome, a key tissue damage sensor, is a dominant driver of various autoinflammatory and autoimmune diseases, including gout, rheumatoid arthritis, and lupus. It is therefore crucial to understand the biology and regulation of NLRP3 inflammasome and determine its affect in the context of various diseases. Of note, various studies suggest that autophagy, a cellular waste removal and rejuvenation process, serves an important role as a macrophage-intrinsic negative regulator of NLRP3 inflammasome. Here, we review recent advances in understanding how autophagy regulates NLRP3 inflammasome activity and discuss the implications of this regulation on the pathogenesis of autoinflammatory and autoimmune diseases.

Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling

Abstract: The tumor microenvironment (TME) exerts critical pro-tumorigenic effects through cytokines and growth factors that support cancer cell proliferation, survival, motility and invasion. Insulin-like growth factor-1 (IGF-1) and signal transducer and activator of transcription 3 (STAT3) stimulate colorectal cancer development and progression via cell autonomous and microenvironmental effects. Using a unique inhibitor, NT157, which targets both IGF-1 receptor (IGF-1R) and STAT3, we show that these pathways regulate many TME functions associated with sporadic colonic tumorigenesis in CPC-APC mice, in which cancer development is driven by loss of the Apc tumor suppressor gene. NT157 causes a substantial reduction in tumor burden by affecting cancer cells, cancer-associated fibroblasts (CAF) and myeloid cells. Decreased cancer cell proliferation and increased apoptosis were accompanied by inhibition of CAF activation and decreased inflammation. Furthermore, NT157 inhibited expression of pro-tumorigenic cytokines, chemokines and growth factors, including IL-6, IL-11 and IL-23 as well as CCL2, CCL5, CXCL7, CXCL5, ICAM1 and TGFβ; decreased cancer cell migratory activity and reduced their proliferation in the liver. NT157 represents a new class of anti-cancer drugs that affect both the malignant cell and its supportive microenvironment.

Sestrin regulation of TORC1: Is Sestrin a leucine sensor?

Abstract: Sestrins are highly conserved, stress-inducible proteins that inhibit target of rapamycin complex 1 (TORC1) signaling. After their transcriptional induction, both vertebrate and invertebrate Sestrins turn on the adenosine monophosphate (AMP)-activated protein kinase (AMPK), which activates the tuberous sclerosis complex (TSC), a key inhibitor of TORC1 activation. However, Sestrin overexpression, on occasion, can result in TORC1 inhibition even in AMPK-deficient cells. This effect has been attributed to Sestrin's ability to bind the TORC1-regulating GATOR2 protein complex, which was postulated to control trafficking of TORC1 to lysosomes. How the binding of Sestrins to GATOR2 is regulated and how it contributes to TORC1 inhibition are unknown. New findings suggest that the amino acid leucine specifically disrupts the association of Sestrin2 with GATOR2, thus explaining how leucine and related amino acids stimulate TORC1 activity. We discuss whether and how these findings fit what has already been learned about Sestrin-mediated TORC1 inhibition from genetic studies conducted in fruit flies and mammals.

ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation.

Abstract: The ERK1/2 MAPK signalling module integrates extracellular cues that induce proliferation and differentiation of epithelial lineages, and is an established oncogenic driver, particularly in the intestine. However, the interrelation of the ERK1/2 module relative to other signalling pathways in intestinal epithelial cells and colorectal cancer (CRC) is unclear. Here we show that loss of Erk1/2 in intestinal epithelial cells results in defects in nutrient absorption, epithelial cell migration and secretory cell differentiation. However, intestinal epithelial cell proliferation is not impeded, implying compensatory mechanisms. Genetic deletion of Erk1/2 or pharmacological targeting of MEK1/2 results in supraphysiological activity of the ERK5 pathway. Furthermore, targeting both pathways causes a more effective suppression of cell proliferation in murine intestinal organoids and human CRC lines. These results suggest that ERK5 provides a common bypass route in intestinal epithelial cells, which rescues cell proliferation upon abrogation of ERK1/2 signalling, with therapeutic implications in CRC.

Liver carcinogenesis: from naughty chemicals to soothing fat and the surprising role of NRF2

Abstract: The liver is a key metabolic organ that is essential for production of blood proteins, lipid and sugar metabolism and detoxification of naturally occurring and foreign harmful chemicals. To maintain its mass and many essential functions, the liver possesses remarkable regenerative capacity, but the latter also renders it highly susceptible to carcinogenesis. In fact, liver cancer often develops in the context of chronic liver injury. Currently, primary liver cancer is the second leading cause of cancer-related deaths, and as the rates of other cancers have been declining, the incidence of liver cancer continues to rise with an alarming rate. Although much remains to be accomplished in regards to liver cancer therapy, we have learned a great deal about the molecular etiology of the most common form of primary liver cancer, hepatocellular carcinoma (HCC). Much of this knowledge has been obtained from studies of mouse models, using either toxic chemicals, a combination of fatty foods and endoplasmic reticulum stress or chronic activation of specific metabolic pathways. Surprisingly, NRF2, a transcription factor that was initially thought to protect the liver from oxidative stress, was found to play a key role in promoting HCC pathogenesis.

The role of IL-17 signaling in regulation of the liver-brain axis and intestinal permeability in Alcoholic Liver Disease.

Abstract: Alcoholic liver disease (ALD) progresses from a normal liver, to steatosis, steatohepatitis, fibrosis and hepatocellular carcinoma (HCC). Despite intensive studies, the pathogenesis of ALD is poorly understood, in part due to a lack of suitable animal models which mimic the stages of ALD progression. Furthermore, the role of IL-17 in ALD has not been evaluated. We and others have recently demonstrated that IL-17 signaling plays a critical role in development of liver fibrosis and cancer. Here we summarize the most recent evidence supporting the role of IL-17 in ALD. As a result of a collaborative effort of Drs. Karin, Gao, Tsukamoto and Kisseleva, we developed several improved models of ALD in mice: 1) chronic-plus-binge model that mimics early stages of steatohepatitis, 2) intragastric ethanol feeding model that mimics alcoholic steatohepatitis and fibrosis, and 3) diethylnitrosamine (DEN)+alcohol model that mimics alcoholic liver cancer. These models might provide new insights into the mechanism of IL-17 signaling in ALD and help identify novel therapeutic targets.

Signaling cascades and inflammasome activationin microbial infections

Abstract: transcriptional program via several pathways including NF-κB, MAPK and AKT. “Signal 2” is generated by microbial virulence factors including Bacillus anthracis lethal toxin, Shigella toxin, Staphylococcus aureus alpha hemolysin, group A streptococcal (GAS) streptolysin O (SLO) andflagellin, or by danger associated molecular patterns (DAMPs) including ATP, uric acid, alums and silica [1-4] “Signal 2” activates inflammasome formation for proteolytic cleavage of caspase-1, which controls the processing and secretion of IL-1β and IL-18 and induction of a “proinflammatory niche” [4,5]. Pathogen-induced NLR activation may also lead to host pyroptosis, which is marked by increases in cell membrane porosity, cell death and release of DAMPs [1-4]. Inflammasome complexes contain a unique sensor protein belonging to either the NLR (Nucleotide-binding domain and Leucine-rich repeat-containing receptors) or the PYHIN (pyrin and HIN domain-containing proteins) family [5]. More than 22 inflammasome sensors are known and their structure and activation have been reviewed elsewhere [1-5]. These sensors respond to specific ligands; for instance NALP1 is activated by B. anthracis lethal toxin, NALP3 responds to GAS SLO and Staphylococcus aureus alpha-hemolysin, NLRC4 is induced by Salmonella typhimurium flagellin and NLRP12 is stimulated by the plague Yersinia pestis [1,6-8]. Most “Signal 2” agonists do not directly associate with NLRs to activate inflammasomes. NLR inducers such as bacterial pore-forming toxins induce lysosomal destabilization, plasma membrane disruption, K+ efflux and generation of DAMPs, Shigella toxin triggers mitochondrial reactive oxygen species (ROS) production, and anthrax lethal toxin induces ATP and K+ efflux [1,6,9]. Events such as ROS induction, mitochondrial membrane permeabilization, or K+ efflux play important roles in inflammasome activation [1,6,9]. However, the exact sequence of events leading to caspase-1 activation remains largely unknown and the exact functions of individual inflammasome sensor proteins are still nebulous. Emerging data suggest that several signaling pathways may also participate in transmitting effects of the “Signal 2” Abstract: Recognition of extracellular pathogenassociated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) results in activation of host defense signaling pathways. Some virulent microbes can attenuate and escape antimicrobial immunity by manipulating these signaling pathways. However, impairment of the primary innate response may potentiate the activation of secondary defense program, centered around Nucleotide-binding domain and Leucine-rich repeat containing Receptor (NLRs) for inflammasome formation and IL-1β production. This review analyzes the current knowledge regarding association of innate immune signaling pathways with inflammasome activation in response to bacterial infection.

Epithelial Control of Gut-Associated Lymphoid Tissue Formation through p38α-Dependent Restraint of NF-κB Signaling.

Abstract: The protein kinase p38α mediates cellular responses to environmental and endogenous cues that direct tissue homeostasis and immune responses. Studies of mice lacking p38α in several different cell types have demonstrated that p38α signaling is essential to maintaining the proliferation-differentiation balance in developing and steady-state tissues. The mechanisms underlying these roles involve cell-autonomous control of signaling and gene expression by p38α. In this study, we show that p38α regulates gut-associated lymphoid tissue (GALT) formation in a noncell-autonomous manner. From an investigation of mice with intestinal epithelial cell-specific deletion of the p38α gene, we find that p38α serves to limit NF-κB signaling and thereby attenuate GALT-promoting chemokine expression in the intestinal epithelium. Loss of this regulation results in GALT hyperplasia and, in some animals, mucosa-associated B cell lymphoma. These anomalies occur independently of luminal microbial stimuli and are most likely driven by direct epithelial-lymphoid interactions. Our study illustrates a novel p38α-dependent mechanism preventing excessive generation of epithelial-derived signals that drive lymphoid tissue overgrowth and malignancy.

NF-κB restricts NLRP3 inflammasome activation via p62-dependent mitophagy which eliminates mitochondrial signals

Abstract: NF-κB, a key activator of inflammation primes the NLRP3-inflammasome for activation by inducing pro-IL-1β and NLRP3 expression. NF-κB, however, also prevents excessive inflammation and restrains NLRP3-inflammasome activation through a poorly defined mechanism. We now show that NF-κB exerts its anti-inflammatory activity by inducing delayed accumulation of the autophagy receptor p62/SQSTM1. External NLRP3-activating stimuli trigger a form of mitochondrial (mt) damage that is caspase-1- and NLRP3-independent and causes release of direct NLRP3-inflammasome activators, including mtDNA and mtROS. Damaged mitochondria undergo Parkin-dependent ubiquitin conjugation and are specifically recognized by p62, which induces their mitophagic clearance. Macrophage-specific p62 ablation causes pronounced accumulation of damaged mitochondria and excessive IL-1β-dependent inflammation and enhances macrophage death. Therefore, the “NF-κB-p62-mitophagy” pathway is a macrophage-intrinsic regulatory loop through which NF-κB restrains its own inflammation-promoting activity and orchestrates a self-limiting host response that maintains homeostasis and favors tissue repair. This pathway, however, is bypassed when NLRP3 is genetically activated.

Animal model of nash-induced hepatocellular carcinoma and methods for developing specific therapeutics

Abstract: The invention provides a non-human animal model for non-alcoholic steatohepatitis (NASH)-induced heptocellular carcinoma, methods of screening for agents for treating heptocellular carcinoma, methods of screening for targets useful in suppressing NASH progression to heptocellular carcinoma, methods of treating heptocellular carcinoma, and compositions for treating the same.

Hepatocytes with high regenerative capacity for liver repair

Abstract: The invention provides purified mammalian hybrid hepatocyte (HybHP) cells, compositions comprising HybHP cells, methods for purifying HybHP cells, methods for in vitro culture of HybHP cells, and methods for using HybHP cells to repopulate and/or treat the liver of a subject in need thereof.

Novel chemoimmunotherapy for epithelial cancer

Abstract: The invention provides a method for treating cancer in a subject in need thereof, wherein said subject comprises cancer tissue that 'contains epithelial cancer cells and immunosuppressive 8 cells, and wherein said method comprises administering to said subject a therapeutically effective amount of a) one or more first composition that pauses- immunogenic eel' death and/or of said epithelial cancer cells, and b) one or more second composition that reduces one or both of the number and function of said immunosuppressive B cells in said cancer.