Publications

Associate Professor of Medicine (Gastroenterology and Hepatology)

Member, National Scientific Advisory Committee (Crohn's and Colitis Foundation of America, CCFA) (2015 - 2018) 


 Member, Clinical, Integrative and Molecular Gastroenterology Study Section (NIH) (2012 - 2018)

 

Publications

  • STING Signaling Promotes Inflammation in Experimental AcutePancreatitis. Gastroenterology Zhao, Q., Wei, Y., Pandol, S. J., Li, L., Habtezion, A. 2018; 154 (6): 1822

    Abstract

    BACKGROUND & AIMS: Acute pancreatitis (AP) is characterized by severe inflammation and acinar cell death. Transmembrane protein 173 (TMEM173 or STING) is a DNA sensor adaptor protein on immune cells that recognizes cytosolic nucleic acids and transmits signals that activate production of interferons and the innate immune response. We investigated whether leukocyte STING signaling mediates inflammation in mice with AP.METHODS: We induced AP in C57BL/6J mice (control) and C57BL/6J-Tmem173gt/J mice (STING-knockout mice) by injection of cerulein or placement on choline-deficient DL-ethionine supplemented diet. In some mice, STING signaling was induced by administration of a pharmacologic agonist. AP was also induced in C57BL/6J mice with bone marrow transplants from control or STING-knockout mice and in mice with disruption of the cyclic GMP-AMP synthase (Cgas) gene. Pancreata were collected, analyzed by histology, and acini were isolated and analyzed by flow cytometry, quantitative polymerase chain reaction, immunoblots, and enzyme-linked immunosorbent assay. Bone-marrow-derived macrophages were collected from mice and tested for their ability to detect DNA from dying acinar cells in the presence and absence of deoxyribonuclease (DNaseI).RESULTS: STING signaling was activated in pancreata from micewith AP but not mice without AP. STING-knockout mice developed less severe AP (less edema, inflammation, and markers of pancreatic injury) than control mice, whereas mice given a STING agonist developed more severe AP than controls. In immune cells collected from pancreata, STING was expressed predominantly in macrophages. Levels of cGAS were increased in mice with vs without AP, and cGAS-knockout mice had decreased edema, inflammation, and other markers of pancreatic injury upon induction of AP than control mice. Wild-type mice given bone marrow transplants from STING-knockout mice had less pancreatic injury and lower serum levels of lipase and pancreatic trypsin activity following induction of AP than mice given wild-type bone marrow. DNA from dying acinar cells activated STING signaling in macrophages, which was inhibited by addition of DNaseI.CONCLUSIONS: In mice with AP, STING senses acinar cell death (by detecting DNA from dying acinar cells) and activates a signaling pathway that promotes inflammation. Macrophages express STING and activate pancreatic inflammation in AP.

    View details for DOI 10.1053/j.gastro.2018.01.065

    View details for PubMedID 29425920

  • The Interface of Pancreatic Cancer With Diabetes, Obesity, and Inflammation: Research Gaps and Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop PANCREAS Abbruzzese, J. L., Andersen, D. K., Borrebaeck, C. K., Chari, S. T., Costello, E., Cruz-Monserrate, Z., Eibl, G., Engleman, E. G., Fisher, W. E., Habtezion, A., Kim, S. K., Korc, M., Logsdon, C., Lyssiotis, C. A., Pandol, S. J., Rustgi, A., Wolfe, B. M., Zheng, L., Powers, A. C. 2018; 47 (5): 516–25

    Abstract

    A workshop on "The Interface of Pancreatic Cancer with Diabetes, Obesity, and Inflammation: Research Gaps and Opportunities" was held by the National Institute of Diabetes and Digestive and Kidney Diseases on October 12, 2017. The purpose of the workshop was to explore the relationship and possible mechanisms of the increased risk of pancreatic ductal adenocarcinoma (PDAC) related to diabetes, the role of altered intracellular energy metabolism in PDAC, the mechanisms and biomarkers of diabetes caused by PDAC, the mechanisms of the increased risk of PDAC associated with obesity, and the role of inflammatory events and mediators as contributing causes of the development of PDAC. Workshop faculty reviewed the state of the current knowledge in these areas and made recommendations for future research efforts. Further knowledge is needed to elucidate the basic mechanisms contributing to the role of hyperinsulinemia, hyperglycemia, adipokines, and acute and chronic inflammatory events on the development of PDAC.

    View details for DOI 10.1097/MPA.0000000000001037

    View details for Web of Science ID 000431180300005

    View details for PubMedID 29702529

  • Diabetes Mellitus and Obesity as Risk Factors for Pancreatic Cancer JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS Eibl, G., Cruz-Monserrate, Z., Korc, M., Petrov, M. S., Goodarzi, M. O., Fisher, W. E., Habtezion, A., Lugea, A., Pandol, S. J., Hart, P. A., Andersen, D. K., Consortium Study Chronic Pancreati 2018; 118 (4): 555–67

    Abstract

    Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer. The worldwide estimates of its incidence and mortality in the general population are eight cases per 100,000 person-years and seven deaths per 100,000 person-years, and they are significantly higher in the United States than in the rest of the world. The incidence of this disease in the United States is more than 50,000 new cases in 2017. Indeed, total deaths due to PDAC are projected to increase dramatically to become the second leading cause of cancer-related deaths before 2030. Considering the failure to date to efficiently treat existing PDAC, increased effort should be undertaken to prevent this disease. A better understanding of the risk factors leading to PDAC development is of utmost importance to identify and formulate preventive strategies. Large epidemiologic and cohort studies have identified risk factors for the development of PDAC, including obesity and type 2 diabetes mellitus. This review highlights the current knowledge of obesity and type 2 diabetes as risk factors for PDAC development and progression, their interplay and underlying mechanisms, and the relation to diet. Research gaps and opportunities to address this deadly disease are also outlined.

    View details for DOI 10.1016/j.jand.2017.07.005

    View details for Web of Science ID 000428262900004

    View details for PubMedID 28919082

    View details for PubMedCentralID PMC5845842

  • A Dominant Role for Regulatory T Cells in Protecting Females Against Pulmonary Hypertension. Circulation research Tamosiuniene, R., Manouvakhova, O., Mesange, P., Saito, T., Qian, J., Sanyal, M., Lin, Y. C., Nguyen, L. P., Luria, A., Tu, A. B., Sante, J. M., Rabinovitch, M., Fitzgerald, D. J., Graham, B. B., Habtezion, A., Voelkel, N. F., Aurelian, L., Nicolls, M. R. 2018

    Abstract

    Rationale: Pulmonary arterial hypertension (PH) is a life-threatening condition associated with immune dysregulation and abnormal regulatory T cell (Treg) activity, but it is currently unknown whether and how abnormal Treg function differentially affects males and females. Objective: To evaluate whether and how Treg-deficiency differentially affects male and female rats in experimental PH. Methods and Results: Male and female athymicrnu/rnurats, lacking Tregs, were treated with the vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor SU5416 or chronic hypoxia and evaluated for PH; some animals underwent Treg immune reconstitution (IR) before SU5416 administration. Plasma prostacyclin (PGI2) levels were measured. Lung and right ventricles (RVs) were assessed for the expression of the vasoprotective proteins cyclooxygenase-2 (COX-2), prostacyclin synthase (PTGIS), programmed death ligand-1 (PDL-1), and heme oxygenase-1 (HO-1). Inhibitors of these pathways were administered to athymic rats undergoing Treg IR. Finally, human cardiac microvascular endothelial cells co-cultured with Tregs were evaluated for COX-2, PDL-1, HO-1, and estrogen receptor (ER) expression, and culture supernatants were assayed for PGI2 and IL-10. SU5416-treatment and chronic hypoxia produced more severe PH in female than male athymic rats. Females were distinguished by greater pulmonary inflammation, augmented RV fibrosis, lower plasma PGI2 levels, decreased lung COX-2, PTGIS, HO-1 and PDL-1 expression and reduced RV PDL-1 levels. In both sexes, Treg IR protected against PH development and raised levels of plasma PGI2 and cardiopulmonary COX-2, PTGIS, PDL-1, and HO-1. Inhibiting COX-2, HO-1, and programmed death-1 (PD1)/PDL1 pathways abrogated Treg protection. In vitro, human Tregs directly upregulated endothelial COX-2, PDL1, HO-1, ERs and increased supernatant levels of PGI2 and IL-10. Conclusions: In two animal models of PH based on Treg deficiency, females developed more severe PH than males. The data suggest that females are especially reliant on normal Treg function to counteract the effects of pulmonary vascular injury leading to PH.

    View details for DOI 10.1161/CIRCRESAHA.117.312058

    View details for PubMedID 29545367

  • Autophagy, Inflammation, and Immune Dysfunction in the Pathogenesis of Pancreatitis GASTROENTEROLOGY Gukovskaya, A. S., Gukovsky, I., Alguel, H., Habtezion, A. 2017; 153 (5): 1212–26

    Abstract

    Pancreatitis is a common disorder with significant morbidity and mortality, yet little is known about its pathogenesis, and there is no specific or effective treatment. Its development involves dysregulated autophagy and unresolved inflammation, demonstrated by studies in genetic and experimental mouse models. Disease severity depends on whether the inflammatory response resolves or amplifies, leading to multi-organ failure. Dysregulated autophagy might promote the inflammatory response in the pancreas. We discuss the roles of autophagy and inflammation in pancreatitis, mechanisms of deregulation, and connections among disordered pathways. We identify gaps in our knowledge and delineate perspective directions for research. Elucidation of pathogenic mechanisms could lead to new targets for treating or reducing the severity of pancreatitis.

    View details for DOI 10.1053/j.gastro.2017.08.071

    View details for Web of Science ID 000414348400022

    View details for PubMedID 28918190

  • Setting up a Lab: The Early Years CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY Habtezion, A. 2017; 4 (3): 445–46

    View details for DOI 10.1016/j.jcmgh.2017.08.003

    View details for Web of Science ID 000418402900010

    View details for PubMedID 29062880

    View details for PubMedCentralID PMC5650599

  • A Mucosal and Cutaneous Chemokine Ligand for the Lymphocyte Chemoattractant Receptor GPR15 FRONTIERS IN IMMUNOLOGY Ocon, B., Pan, J., Dinh, T., Chen, W., Ballet, R., Bscheider, M., Habtezion, A., Tu, H., Zabel, B. A., Butcher, E. C. 2017; 8: 1111

    Abstract

    Chemoattractants control lymphocyte recruitment from the blood, contributing to the systemic organization of the immune system. The G protein-linked receptor GPR15 mediates lymphocyte homing to the large intestines and skin. Here we show that the 9 kDa CC-motif containing cationic polypeptide AP57/colon-derived sushi containing domain-2 binding factor (CSBF), encoded by C10orf99 in the human and 2610528A11Rik in the mouse, functions as a chemokine ligand for GPR15 (GPR15L). GPR15L binds GPR15 and attracts GPR15-expressing T cells including lymphocytes in colon-draining lymph nodes and Vγ3+ thymic precursors of dermal epithelial T cells. Patterns of GPR15L expression by epithelial cells in adult mice and humans suggest a homeostatic role for the chemokine in lymphocyte localization to the large intestines, as well as a role in homing to the epidermis during wound healing or inflammation. GPR15L is also significantly expressed in squamous mucosa of the oral cavity and esophagus with still poorly defined regulation. Identification of the chemotactic activity of GPR15L adds to its reported antibacterial and tumor cell growth regulatory functions and suggests the potential of targeting GPR15L-GPR15 interactions for modulation of mucosal and cutaneous inflammation.

    View details for DOI 10.3389/fimmu.2017.01111

    View details for Web of Science ID 000409477600001

    View details for PubMedID 28936214

    View details for PubMedCentralID PMC5594226

  • Immunology of pancreatitis and environmental factors CURRENT OPINION IN GASTROENTEROLOGY Lee, B., Zhao, Q., Habtezion, A. 2017; 33 (5): 383–89

    Abstract

    This report reviews recent aspects of pancreatitis immunology and environmental factors that link to development and progression of disease.Limited human and animal model studies have recently attempted to understand immune mechanisms that lead to the pathogenesis of acute and chronic pancreatitis. Based on these studies innate immune responses emerge as critical elements in disease pathogenesis and severity of inflammation. The immune basis for environmental factors such as smoking, which are highly associated with disease progression highlight novel cross talk mechanisms between immune and nonimmune pancreatic cells such as the pancreatic stellate cells.Better understanding of immune responses and signaling pathways are emerging as important contributors in pancreatitis development and progression. Such mechanisms are likely to offer future targetable therapies that can either halt or reverse disease progression.

    View details for DOI 10.1097/MOG.0000000000000387

    View details for Web of Science ID 000406956900010

    View details for PubMedID 28682796

  • Editors' Introduction to the Chronic Pancreatitis and Pancreatic Cysts Special Issue. Digestive diseases and sciences Park, W. G., Habtezion, A. 2017

    View details for DOI 10.1007/s10620-017-4613-z

    View details for PubMedID 28523572

  • Trafficking receptor signatures define blood plasmablasts responding to tissue-specific immune challenge. JCI insight Seong, Y., Lazarus, N. H., Sutherland, L., Habtezion, A., Abramson, T., He, X., Greenberg, H. B., Butcher, E. C. 2017; 2 (6)

    Abstract

    Antibody-secreting cells are generated in regional lymphoid tissues and traffic as plasmablasts (PBs) via lymph and blood to target sites for local immunity. We used multiparameter flow cytometry to define PB trafficking programs (TPs, combinations of adhesion molecules and chemoattractant receptors) and their imprinting in patients in response to localized infection or immune insults. TPs enriched after infection or autoimmune inflammation of mucosae correlate with sites of immune response or symptoms, with different TPs imprinted during small intestinal, colon, throat, and upper respiratory immune challenge. PBs induced after intramuscular or intradermal influenza vaccination, including flu-specific antibody-secreting cells, display TPs characterized by the lack of mucosal homing receptors. PBs of healthy donors display diverse mucosa-associated TPs, consistent with homeostatic immune activity. Identification of TP signatures of PBs may facilitate noninvasive monitoring of organ-specific immune responses.

    View details for DOI 10.1172/jci.insight.90233

    View details for PubMedID 28352656

  • Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system. Gut Becker, L., Nguyen, L., Gill, J., Kulkarni, S., Pasricha, P. J., Habtezion, A. 2017

    Abstract

    The enteric nervous system (ENS) undergoes neuronal loss and degenerative changes with age. The cause of this neurodegeneration is poorly understood. Muscularis macrophages residing in close proximity to enteric ganglia maintain neuromuscular function via direct crosstalk with enteric neurons and have been implicated in the pathogenesis of GI motility disorders like gastroparesis and postoperative ileus. The aim of this study was to assess whether ageing causes alterations in macrophage phenotype that contributes to age-related degeneration of the ENS.Longitudinal muscle and myenteric plexus from small intestine of young, mid-aged and old mice were dissected and prepared for whole mount immunostaining, flow cytometry, Luminex immunoassays, western blot analysis, enteric neural stem cell (ENSC) isolation or conditioned media. Bone marrow derived macrophages were prepared and polarised to classic (M1) or alternative (M2) activation states. Markers for macrophage phenotype were measured using quantitative RT-PCR.Ageing causes a shift in macrophage polarisation from anti-inflammatory 'M2' to proinflammatory 'M1' that is associated with a rise in cytokines and immune cells in the ENS. This phenotypic shift is associated with a neural response to inflammatory signals, increase in apoptosis and loss of enteric neurons and ENSCs, and delayed intestinal transit. An age-dependent decrease in expression of the transcription factor FoxO3, a known longevity gene, contributes to the loss of anti-inflammatory behaviour in macrophages of old mice, and FoxO3-deficient mice demonstrate signs of premature ageing of the ENS.A shift by macrophages towards a proinflammatory phenotype with ageing causes inflammation-mediated degeneration of the ENS.

    View details for DOI 10.1136/gutjnl-2016-312940

    View details for PubMedID 28228489

  • Regulatory T Cells And Sexual Dimorphism In Pulmonary Hypertension Tamosiuniene, R., Mesange, P., Manouvakhova, O., Saito, T., Qian, J., Sanyal, M., Lin, Y., Nguyen, L., Luria, A., Tu, A., Sante, J., Rabinovitch, M., Voelkel, N., Fitzgerald, D., Habtezion, A., Aurelian, L., Nicolls, M. R. AMER THORACIC SOC. 2017
  • Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer. The lancet. Gastroenterology & hepatology Hart, P. A., Bellin, M. D., Andersen, D. K., Bradley, D., Cruz-Monserrate, Z., Forsmark, C. E., Goodarzi, M. O., Habtezion, A., Korc, M., Kudva, Y. C., Pandol, S. J., Yadav, D., Chari, S. T. 2016; 1 (3): 226-237

    Abstract

    Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps.

    View details for DOI 10.1016/S2468-1253(16)30106-6

    View details for PubMedID 28404095

  • Aryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis. Gastroenterology Xue, J., Zhao, Q., Sharma, V., Nguyen, L. P., Lee, Y. N., Pham, K. L., Edderkaoui, M., Pandol, S. J., Park, W., Habtezion, A. 2016

    Abstract

    Cigarette smoke has been identified as an independent risk factor for chronic pancreatitis (CP). Little is known about the mechanisms by which smoking promotes development of CP. We assessed the effects of aryl hydrocarbon receptor (AhR) ligands found in cigarette smoke on immune cell activation in humans and pancreatic fibrosis in animal models of CP.We obtained serum samples from patients with CP treated at Stanford University hospital and healthy individuals (controls) and isolated CD4(+) T cells. Levels of interleukin-22 (IL22) were measured by enzyme-linked immunosorbent assay and smoking histories were collected. T cells from healthy nonsmokers and smokers were stimulated and incubated with AhR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin or benzo[a]pyrene) or antagonists and analyzed by flow cytometry. Mice were given intraperitoneal injections of caerulein or saline, with or without lipopolysaccharide, to induce CP. Some mice were given intraperitoneal injections of AhR agonists at the start of caerulein injection, with or without an antibody against IL22 (anti-IL22) starting 2 weeks after the first caerulein injection, or recombinant mouse IL22 or vehicle (control) intraperitoneally 4 weeks after the first caerulein injection. Mice were exposed to normal air or cigarette smoke for 6 h/d for 7 weeks and expression of AhR gene targets was measured. Pancreata were collected from all mice and analyzed by histology and quantitative reverse transcription polymerase chain reaction. Pancreatic stellate cells and T cells were isolated and studied using immunoblot, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent analyses.Mice given AhR agonists developed more severe pancreatic fibrosis (based on decreased pancreas size, histology, and increased expression of fibrosis-associated genes) than mice not given agonists after caerulein injection. In mice given saline instead of caerulein, AhR ligands did not induce fibrosis. Pancreatic T cells from mice given AhR agonists and caerulein were activated and expressed IL22, but not IL17 or interferon gamma. Human T cells exposed to AhR agonists up-regulated expression of IL22. In mice given anti-IL22, pancreatic fibrosis did not progress, whereas mice given recombinant IL22 had a smaller pancreas and increased fibrosis. Pancreatic stellate cells isolated from mouse and human pancreata expressed the IL22 receptor IL22RA1. Incubation of the pancreatic stellate cells with IL22 induced their expression of the extracellular matrix genes fibronectin 1 and collagen type I α1 chain, but not α2 smooth muscle actin or transforming growth factor-β. Serum samples from smokers had significantly higher levels of IL22 than those from nonsmokers.AhR ligands found in cigarette smoke increase the severity of pancreatic fibrosis in mouse models of pancreatitis via up-regulation of IL22. This pathway might be targeted for treatment of CP and serve as a biomarker of disease.

    View details for DOI 10.1053/j.gastro.2016.09.064

    View details for PubMedID 27769811

  • Aryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis. Gastroenterology Xue, J., Zhao, Q., Sharma, V., Nguyen, L. P., Lee, Y. N., Pham, K. L., Edderkaoui, M., Pandol, S. J., Park, W., Habtezion, A. 2016

    Abstract

    Cigarette smoke has been identified as an independent risk factor for chronic pancreatitis (CP). Little is known about the mechanisms by which smoking promotes development of CP. We assessed the effects of aryl hydrocarbon receptor (AhR) ligands found in cigarette smoke on immune cell activation in humans and pancreatic fibrosis in animal models of CP.We obtained serum samples from patients with CP treated at Stanford University hospital and healthy individuals (controls) and isolated CD4(+) T cells. Levels of interleukin-22 (IL22) were measured by enzyme-linked immunosorbent assay and smoking histories were collected. T cells from healthy nonsmokers and smokers were stimulated and incubated with AhR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin or benzo[a]pyrene) or antagonists and analyzed by flow cytometry. Mice were given intraperitoneal injections of caerulein or saline, with or without lipopolysaccharide, to induce CP. Some mice were given intraperitoneal injections of AhR agonists at the start of caerulein injection, with or without an antibody against IL22 (anti-IL22) starting 2 weeks after the first caerulein injection, or recombinant mouse IL22 or vehicle (control) intraperitoneally 4 weeks after the first caerulein injection. Mice were exposed to normal air or cigarette smoke for 6 h/d for 7 weeks and expression of AhR gene targets was measured. Pancreata were collected from all mice and analyzed by histology and quantitative reverse transcription polymerase chain reaction. Pancreatic stellate cells and T cells were isolated and studied using immunoblot, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent analyses.Mice given AhR agonists developed more severe pancreatic fibrosis (based on decreased pancreas size, histology, and increased expression of fibrosis-associated genes) than mice not given agonists after caerulein injection. In mice given saline instead of caerulein, AhR ligands did not induce fibrosis. Pancreatic T cells from mice given AhR agonists and caerulein were activated and expressed IL22, but not IL17 or interferon gamma. Human T cells exposed to AhR agonists up-regulated expression of IL22. In mice given anti-IL22, pancreatic fibrosis did not progress, whereas mice given recombinant IL22 had a smaller pancreas and increased fibrosis. Pancreatic stellate cells isolated from mouse and human pancreata expressed the IL22 receptor IL22RA1. Incubation of the pancreatic stellate cells with IL22 induced their expression of the extracellular matrix genes fibronectin 1 and collagen type I α1 chain, but not α2 smooth muscle actin or transforming growth factor-β. Serum samples from smokers had significantly higher levels of IL22 than those from nonsmokers.AhR ligands found in cigarette smoke increase the severity of pancreatic fibrosis in mouse models of pancreatitis via up-regulation of IL22. This pathway might be targeted for treatment of CP and serve as a biomarker of disease.

    View details for DOI 10.1053/j.gastro.2016.09.064

    View details for PubMedID 27769811

  • Macrophages and pancreatic ductal adenocarcinoma. Cancer letters Habtezion, A., Edderkaoui, M., Pandol, S. J. 2016; 381 (1): 211-216

    Abstract

    Monocytes and macrophages make up part of the innate immune system and provide one of the first defenses against variety of treats. Macrophages can also modulate the adaptive immune system. Efficient sensing and response to tissue environmental cues highlights the complexity and dynamic nature of macrophages and their plasticity. Macrophages may have divergent roles depending on their polarity and stimulus received. Accumulating evidence demonstrates the critical role played by macrophages in tumor initiation, development, and progression. In this review, we discuss the characteristics of tumor-associated macrophages (TAMs) and their role in pancreatic adenocarcinoma. In addition, we give an overview on recent advances related to the therapeutic implication associated with targeting TAMs in pancreas cancer.

    View details for DOI 10.1016/j.canlet.2015.11.049

    View details for PubMedID 26708507

  • Reactive Oxygen Species Imaging in a Mouse Model of Inflammatory Bowel Disease MOLECULAR IMAGING AND BIOLOGY Bronsart, L., Linh Nguyen, L., Habtezion, A., Contag, C. 2016; 18 (4): 473-478

    Abstract

    Reactive oxygen species (ROS) are important contributors to inflammatory bowel disease (IBD); however, there are insufficient tools for their in vivo evaluation.To determine if a chemiluminescent ROS reporter, coelenterazine, would be a useful tool for the detection of immune cell activation, the macrophage cell line (RAW 264.7) was treated with phorbol myristate acetate (PMA). Additionally, coelenterazine was used to monitor the changes in ROS production over time in a mouse model of IBD.In vitro, coelenterazine enabled the dynamic monitoring of the RAW 264.7 cell oxidative burst. In vivo, there were early, preclinical, changes in the localization and magnitude of coelenterazine chemiluminescent foci.Coelenterazine offers a high-throughput method for assessing immune cell activation in culture and provides a means for the in vivo detection and localization of ROS during IBD disease progression.

    View details for DOI 10.1007/s11307-016-0934-0

    View details for Web of Science ID 000379191800001

    View details for PubMedID 26873653

    View details for PubMedCentralID PMC4927601

  • HDAC3 mediates smoking-induced pancreatic cancer ONCOTARGET Edderkaoui, M., Xu, S., Chheda, C., Morvaridi, S., Hu, R. W., Grippo, P. J., Mascarinas, E., Principe, D. R., Knudsen, B., Xue, J., Habtezion, A., Uyeminami, D., Pinkerton, K. E., Pandol, S. J. 2016; 7 (7): 7747-7760

    Abstract

    Smoking is a major risk factor for developing pancreatic adenocarcinoma (PDAC); however, little is known about the mechanisms involved. Here we employed a genetic animal model of early stages of PDAC that overexpresses oncogenic Kras in the pancreas to investigate the mechanisms of smoking-induced promotion of the disease in vivo. We confirmed the regulation of the interactions between the tumor microenvironment cells using in vitro cellular systems. Aerial exposure to cigarette smoke stimulated development of pancreatic intraepithelial neaoplasia (PanIN) lesions associated with a tumor microenvironment-containing features of human PDAC including fibrosis, activated stellate cells, M2-macrophages and markers of epithelial-mesenchymal transition (EMT). The pro-cancer effects of smoking were prevented by Histone Deacetylase HDAC I/II inhibitor Saha. Smoking decreased histone acetylation associated with recruitment of and phenotypic changes in macrophages; which in turn, stimulated survival and induction of EMT of the pre-cancer and cancer cells. The interaction between the cancer cells and macrophages is mediated by IL-6 produced under the regulation of HDAC3 translocation to the nucleus in the cancer cells. Pharmacological and molecular inhibitions of HDAC3 decreased IL-6 levels in cancer cells. IL-6 stimulated the macrophage phenotype change through regulation of the IL-4 receptor level of the macrophage. This study demonstrates a novel pathway of interaction between cancer cells and tumor promoting macrophages involving HDAC3 and IL-6. It further demonstrates that targeting HDAC3 prevents progression of the disease and could provide a strategy for treating the disease considering that the HDAC inhibitor we used is FDA approved for a different disease.

    View details for Web of Science ID 000370325900030

  • Leukocyte Trafficking to the Small Intestine and Colon. Gastroenterology Habtezion, A., Nguyen, L. P., Hadeiba, H., Butcher, E. C. 2016; 150 (2): 340-354

    Abstract

    Leukocyte trafficking to the small and large intestines is tightly controlled to maintain intestinal immune homeostasis, mediate immune responses, and regulate inflammation. A wide array of chemoattractants, chemoattractant receptors, and adhesion molecules expressed by leukocytes, mucosal endothelium, epithelium, and stromal cells controls leukocyte recruitment and microenvironmental localization in intestine and in the gut-associated lymphoid tissues (GALTs). Naive lymphocytes traffic to the gut-draining mesenteric lymph nodes where they undergo antigen-induced activation and priming; these processes determine their memory/effector phenotypes and imprint them with the capacity to migrate via the lymph and blood to the intestines. Mechanisms of T-cell recruitment to GALT and of T cells and plasmablasts to the small intestine are well described. Recent advances include the discovery of an unexpected role for lectin CD22 as a B-cell homing receptor GALT, and identification of the orphan G-protein-coupled receptor 15 (GPR15) as a T-cell chemoattractant/trafficking receptor for the colon. GPR15 decorates distinct subsets of T cells in mice and humans, a difference in species that could affect translation of the results of mouse colitis models to humans. Clinical studies with antibodies to integrin α4β7 and its vascular ligand mucosal vascular addressin cell adhesion molecule 1 are proving the value of lymphocyte trafficking mechanisms as therapeutic targets for inflammatory bowel diseases. In contrast to lymphocytes, cells of the innate immune system express adhesion and chemoattractant receptors that allow them to migrate directly to effector tissue sites during inflammation. We review the mechanisms for innate and adaptive leukocyte localization to the intestinal tract and GALT, and discuss their relevance to human intestinal homeostasis and inflammation.

    View details for DOI 10.1053/j.gastro.2015.10.046

    View details for PubMedID 26551552

  • Absence of keratin 8 or 18 promotes antimitochondrial autoantibody formation in aging male mice FASEB JOURNAL Toivola, D. M., Habtezion, A., Misiorek, J. O., Zhang, L., Nystrom, J. H., Sharpe, O., Robinson, W. H., Kwan, R., Omary, M. B. 2015; 29 (12): 5081-5089

    Abstract

    Human mutations in keratin 8 (K8) and keratin 18 (K18), the intermediate filament proteins of hepatocytes, predispose to several liver diseases. K8-null mice develop chronic liver injury and fragile hepatocytes, dysfunctional mitochondria, and Th2-type colitis. We tested the hypothesis that autoantibody formation accompanies the liver damage that associates with K8/K18 absence. Sera from wild-type control, K8-null, and K18-null mice were analyzed by immunoblotting and immunofluorescence staining of cell and mouse tissue homogenates. Autoantibodies to several antigens were identified in 81% of K8-null male mice 8 mo or older. Similar autoantibodies were detected in aging K18-null male mice that had a related liver phenotype but normal colon compared with K8-null mice, suggesting that the autoantibodies are linked to liver rather than colonic disease. However, these autoantibodies were not observed in nontransgenic mice subjected to 4 chronic injury models. The autoantigens are ubiquitous and partition with mitochondria. Mass spectrometry and purified protein analysis identified, mitochondrial HMG-CoA synthase, aldehyde dehydrogenase, and catalase as the primary autoantigens, and glutamate dehydrogenase and epoxide hydrolase-2 as additional autoantigens. Therefore, absence of the hepatocyte keratins results in production of anti-mitochondrial autoantibodies (AMA) that recognize proteins involved in energy metabolism and oxidative stress, raising the possibility that AMA may be found in patients with keratin mutations that associate with liver and other diseases.

    View details for DOI 10.1096/fj.14-269795

    View details for Web of Science ID 000365523600031

    View details for PubMedID 26399787

    View details for PubMedCentralID PMC4653051

  • Inflammation in acute and chronic pancreatitis. Current opinion in gastroenterology Habtezion, A. 2015; 31 (5): 395-399

    Abstract

    This report reviews recent animal model and human studies associated with inflammatory responses in acute and chronic pancreatitis.Animal model and limited human acute and chronic pancreatitis studies unravel the dynamic nature of the inflammatory processes and the ability of the immune cells to sense danger and environmental signals. In acute pancreatitis, such molecules include pathogen-associated molecular pattern recognition receptors such as toll-like receptors, and the more recently appreciated damage-associated molecular pattern molecules or 'alarmin' high mobility group box 1 and IL-33. In chronic pancreatitis, a recent understanding of a critical role for macrophage-pancreatic stellate cell interaction offers a potential targetable pathway that can alter fibrogenesis. Microbiome research in pancreatitis is a new field gaining interest but will require further investigation.Immune cell contribution to the pathogenesis of acute and chronic pancreatitis is gaining more appreciation and further understanding in immune signaling presents potential therapeutic targets that can alter disease progression.

    View details for DOI 10.1097/MOG.0000000000000195

    View details for PubMedID 26107390

  • A Thermo-Sensitive Delivery Platform for Topical Administration of Inflammatory Bowel Disease Therapies. Gastroenterology Sinha, S. R., Nguyen, L. P., Inayathullah, M., Malkovskiy, A., Habte, F., Rajadas, J., Habtezion, A. 2015; 149 (1): 52-55 e2

    Abstract

    Systemic therapies for inflammatory bowel disease are associated with increased risk of infections and malignancies. Topical therapies reduce systemic exposure, but can be difficult to retain or have limited proximal distribution. To mitigate these issues, we developed a thermo-sensitive platform, using a polymer-based system that is liquid at room temperature but turns into a viscous gel upon reaching body temperature. Following rectal administration to mice with dextran sulphate sodium-induced colitis, the platform carrying budesonide or mesalamine becomes more viscoelastic near body temperature. Mice given the drug-containing platform gained more weight and had reduced histologic and biologic features of colitis than mice given the platform alone or liquid drugs via enema. Image analysis showed that enemas delivered with and without the platform reached similar distances in the colons of mice, but greater colonic retention was achieved by using the platform.

    View details for DOI 10.1053/j.gastro.2015.04.002

    View details for PubMedID 25863215

  • Keratin 8 absence down-regulates colonocyte HMGCS2 and modulates colonic ketogenesis and energy metabolism MOLECULAR BIOLOGY OF THE CELL Helenius, T. O., Misiorek, J. O., Nystrom, J. H., Fortelius, L. E., Habtezion, A., Liao, J., Asghar, M. N., Zhang, H., Azhar, S., Omary, M. B., Toivola, D. M. 2015; 26 (12): 2298-2310

    Abstract

    Simple-type epithelial keratins are intermediate filament proteins important for mechanical stability and stress protection. Keratin mutations predispose to human liver disorders, whereas their roles in intestinal diseases are unclear. Absence of keratin 8 (K8) in mice leads to colitis, decreased Na/Cl uptake, protein mistargeting, and longer crypts, suggesting that keratins contribute to intestinal homeostasis. We describe the rate-limiting enzyme of the ketogenic energy metabolism pathway, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), as a major down-regulated protein in the K8-knockout (K8(-/-)) colon. K8 absence leads to decreased quantity and activity of HMGCS2, and the down-regulation is not dependent on the inflammatory state, since HMGCS2 is not decreased in dextran sulfate sodium-induced colitis. Peroxisome proliferator-activated receptor α, a transcriptional activator of HMGCS2, is similarly down-regulated. Ketogenic conditions-starvation or ketogenic diet-increase K8(+/+) HMGCS2, whereas this response is blunted in the K8(-/-) colon. Microbiota-produced short-chain fatty acids (SCFAs), substrates in the colonic ketone body pathway, are increased in stool, which correlates with decreased levels of their main transporter, monocarboxylate transporter 1 (MCT1). Microbial populations, including the main SCFA-butyrate producers in the colon, were not altered in the K8(-/-). In summary, the regulation of the SCFA-MCT1-HMGCS2 axis is disrupted in K8(-/-) colonocytes, suggesting a role for keratins in colonocyte energy metabolism and homeostasis.

    View details for DOI 10.1091/mbc.E14-02-0736

    View details for Web of Science ID 000357037300013

    View details for PubMedID 25904331

  • Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis NATURE COMMUNICATIONS Xue, J., Sharma, V., Hsieh, M. H., Chawla, A., Murali, R., Pandol, S. J., Habtezion, A. 2015; 6

    Abstract

    Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis (AP), we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on interleukin (IL)-4 and IL-13 signalling, and we show that mice lacking IL-4Rα, myeloid-specific IL-4Rα and IL-4/IL-13 were less susceptible to pancreatic fibrosis. Furthermore, we demonstrate that mouse and human pancreatic stellate cells (PSCs) are a source of IL-4/IL-13. Notably, we show that pharmacologic inhibition of IL-4/IL-13 in human ex vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis. We identify a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage-alternative activation. Our study challenges and identifies pathways involved in crosstalk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression.

    View details for DOI 10.1038/ncomms8158

    View details for Web of Science ID 000355534000005

    View details for PubMedID 25981357

  • Protective role of hemeoxygenase-1 in gastrointestinal diseases. Cellular and molecular life sciences Chang, M., Xue, J., Sharma, V., Habtezion, A. 2015; 72 (6): 1161-1173

    Abstract

    Disorders and diseases of the gastrointestinal system encompass a wide array of pathogenic mechanisms as a result of genetic, infectious, neoplastic, and inflammatory conditions. Inflammatory diseases in general are rising in incidence and are emerging clinical problems in gastroenterology and hepatology. Hemeoxygenase-1 (HO-1) is a stress-inducible enzyme that has been shown to confer protection in various organ-system models. Its downstream effectors, carbon monoxide and biliverdin have also been shown to offer these beneficial effects. Many studies suggest that induction of HO-1 expression in gastrointestinal tissues and cells plays a critical role in cytoprotection and resolving inflammation as well as tissue injury. In this review, we examine the protective role of HO-1 and its downstream effectors in modulating inflammatory diseases of the upper (esophagus and stomach) and lower (small and large intestine) gastrointestinal tract, the liver, and the pancreas. Cytoprotective, anti-inflammatory, anti-proliferative, antioxidant, and anti-apoptotic activities of HO-1 make it a promising if not ideal therapeutic target for inflammatory diseases of the gastrointestinal system.

    View details for DOI 10.1007/s00018-014-1790-1

    View details for PubMedID 25428780

  • Role and species-specific expression of colon T cell homing receptor GPR15 in colitis. Nature immunology Nguyen, L. P., Pan, J., Dinh, T. T., Hadeiba, H., O'Hara, E., Ebtikar, A., Hertweck, A., Gökmen, M. R., Lord, G. M., Jenner, R. G., Butcher, E. C., Habtezion, A. 2015; 16 (2): 207-213

    Abstract

    Lymphocyte recruitment maintains intestinal immune homeostasis but also contributes to inflammation. The orphan chemoattractant receptor GPR15 mediates regulatory T cell homing and immunosuppression in the mouse colon. We show that GPR15 is also expressed by mouse TH17 and TH1 effector cells and is required for colitis in a model that depends on the trafficking of these cells to the colon. In humans GPR15 is expressed by effector cells, including pathogenic TH2 cells in ulcerative colitis, but is expressed poorly or not at all by colon regulatory T (Treg) cells. The TH2 transcriptional activator GATA-3 and the Treg-associated transcriptional repressor FOXP3 robustly bind human, but not mouse, GPR15 enhancer sequences, correlating with receptor expression. Our results highlight species differences in GPR15 regulation and suggest it as a potential therapeutic target for colitis.

    View details for DOI 10.1038/ni.3079

    View details for PubMedID 25531831

  • Detection of intestinal cancer by local, topical application of a quenched fluorescence probe for cysteine cathepsins. Chemistry & biology Segal, E., Prestwood, T. R., van der Linden, W. A., Carmi, Y., Bhattacharya, N., Withana, N., Verdoes, M., Habtezion, A., Engleman, E. G., Bogyo, M. 2015; 22 (1): 148-158

    Abstract

    Early detection of colonic polyps can prevent up to 90% of colorectal cancer deaths. Conventional colonoscopy readily detects the majority of premalignant lesions, which exhibit raised morphology. However, lesions that are flat and depressed are often undetected using this method. Therefore, there is a need for molecular-based contrast agents to improve detection rates over conventional colonoscopy. We evaluated a quenched fluorescent activity-based probe (qABP; BMV109) that targets multiple cysteine cathepsins that are overexpressed in intestinal dysplasia in a genetic model of spontaneous intestinal polyp formation and in a chemically induced model of colorectal carcinoma. We found that the qABP selectively targets cysteine cathepsins, resulting in high sensitivity and specificity for intestinal tumors in mice and humans. Additionally, the qABP can be administered by either intravenous injection or by local delivery to the colon, making it a highly valuable tool for improved detection of colorectal lesions using fluorescence-guided colonoscopy.

    View details for DOI 10.1016/j.chembiol.2014.11.008

    View details for PubMedID 25579207

    View details for PubMedCentralID PMC4353655

  • Immunodeficiency Mediate The Gender Dimorphism In Pulmonary Hypertension Tamosiuniene, R., Nguyen, L. P., Saito, T., Luria, A., Sante, J., Sung, Y., Rabinovitch, M., Habtezion, A., Nicolls, M. R. AMER THORACIC SOC. 2015
  • Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis. Nature communications Xue, J., Sharma, V., Hsieh, M. H., Chawla, A., Murali, R., Pandol, S. J., Habtezion, A. 2015; 6: 7158-?

    Abstract

    Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis (AP), we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on interleukin (IL)-4 and IL-13 signalling, and we show that mice lacking IL-4Rα, myeloid-specific IL-4Rα and IL-4/IL-13 were less susceptible to pancreatic fibrosis. Furthermore, we demonstrate that mouse and human pancreatic stellate cells (PSCs) are a source of IL-4/IL-13. Notably, we show that pharmacologic inhibition of IL-4/IL-13 in human ex vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis. We identify a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage-alternative activation. Our study challenges and identifies pathways involved in crosstalk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression.

    View details for DOI 10.1038/ncomms8158

    View details for PubMedID 25981357

  • Pharmacologic therapy for acute pancreatitis WORLD JOURNAL OF GASTROENTEROLOGY Kambhampati, S., Park, W., Habtezion, A. 2014; 20 (45): 16868-16880

    Abstract

    While conservative management such as fluid, bowel rest, and antibiotics is the mainstay of current acute pancreatitis management, there is a lot of promise in pharmacologic therapies that target various aspects of the pathogenesis of pancreatitis. Extensive review of preclinical studies, which include assessment of therapies such as anti-secretory agents, protease inhibitors, anti-inflammatory agents, and anti-oxidants are discussed. Many of these studies have shown therapeutic benefit and improved survival in experimental models. Based on available preclinical studies, we discuss potential novel targeted pharmacologic approaches that may offer promise in the treatment of acute pancreatitis. To date a variety of clinical studies have assessed the translational potential of animal model effective experimental therapies and have shown either failure or mixed results in human studies. Despite these discouraging clinical studies, there is a great clinical need and there exist several preclinical effective therapies that await investigation in patients. Better understanding of acute pancreatitis pathophysiology and lessons learned from past clinical studies are likely to offer a great foundation upon which to expand future therapies in acute pancreatitis.

    View details for DOI 10.3748/wjg.v20.i45.16868

    View details for Web of Science ID 000346050700007

    View details for PubMedCentralID PMC4258556

  • Combination of HDAC1 and GSK-3 beta Inhibition as a Treatment Strategy for Pancreatic Cancer Edderkaoui, M., Chheda, C., Xu, S., Principe, D., Grippo, P., Benhaddou, H., Bourhim, M., Habtezion, A., Dale, Y., Pinkerton, K., Pandol, S. LIPPINCOTT WILLIAMS & WILKINS. 2014: 1355
  • Targeting Macrophage IL-4R alpha Signaling: a Novel Immune Therapy for Chronic Pancreatitis Xue, J., Sharma, V., Murali, R., Pandol, S. J., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2014: 1424
  • Alcoholic chronic pancreatitis increases tissue transformed macrophages (M2) which promote pancreatic cancer lesions in a Kras mouse model Edderkaoui, M., Grippo, P., Benhaddou, H., Ouhaddi, Y., Tsukamoto, H., Swartwood, S., Knudsen, B., Goodridge, H. S., Habtezion, A., Go, V., Pandol, S. J. AMER ASSOC CANCER RESEARCH. 2014
  • Immune cells and immune-based therapy in pancreatitis. Immunologic research Xue, J., Sharma, V., Habtezion, A. 2014; 58 (2-3): 378-386

    Abstract

    Alcohol and gallstones are the most common etiologic factors in acute pancreatitis (AP). Recurrent AP can lead to chronic pancreatitis (CP). Although the underlying pathophysiology of the disease is complex, immune cells are critical in the pathogenesis of pancreatitis and determining disease severity. In this review, we discuss the role of innate and adaptive immune cells in both AP and CP, potential immune-based therapeutic targets, and animal models used to understand our knowledge of the disease. The relative difficulty of obtaining human pancreatic tissue during pancreatitis makes animal models necessary. Animal models of pancreatitis have been generated to understand disease pathogenesis, test therapeutic interventions, and investigate immune responses. Although current animal models do not recapitulate all aspects of human disease, until better models can be developed available models are useful in addressing key research questions. Differences between experimental and clinical pancreatitis need consideration, and when therapies are tested, models with established disease ought to be included.

    View details for DOI 10.1007/s12026-014-8504-5

    View details for PubMedID 24710635

  • Carbon monoxide-based therapy ameliorates acute pancreatitis via TLR4 inhibition JOURNAL OF CLINICAL INVESTIGATION Xue, J., Habtezion, A. 2014; 124 (1): 437-447

    Abstract

    The protective role of hemeoxygenase-1 (HO-1) in various inflammatory conditions is mediated in part by its products, carbon monoxide (CO) and biliverdin. Here we investigated a therapeutic role for CO and CO-primed cells in acute pancreatitis (AP). In a mouse model of AP, treatment with CO-releasing molecule-2 (CORM-2) decreased mortality, pancreatic damage, and lung injury. CORM-2 decreased systemic inflammatory cytokines, suppressed systemic and pancreatic macrophage TNF-α secretion, and inhibited macrophage TLR4 receptor complex expression. In both human and mouse cells, CORM-2 inhibited endogenous and exogenous ligand-dependent TLR4 activation, which indicates that CORM-2 could be therapeutic for both early and late stages of AP, which involve sterile- and endotoxin-mediated inflammation, respectively. Mice engrafted with TLR4-deficient hematopoietic cells were protected against caerulein-induced AP. In the absence of leukocyte TLR4 expression, CORM-2 did not confer additional protection, which indicates that CORM-2-dependent effects are mediated via suppression of macrophage TLR4 activation. We determined that CO was directly responsible for the protective effects of CORM-2 in AP, as inactive forms of CORM-2 were ineffective. Importantly, adoptive transfer of CORM-2-primed cells reduced AP. Such a therapeutic approach would translate the beneficial effects of CO-based therapies, avoiding CO- or CO-RM-mediated toxicities in AP and a wide range of diseases.

    View details for DOI 10.1172/JCI71362

    View details for Web of Science ID 000329333500048

    View details for PubMedID 24334457

    View details for PubMedCentralID PMC3871246