Publications by authors named "S A Winer"

63 Publications

Microbiota-Driven Activation of Intrahepatic B Cells Aggravates Nonalcoholic Steatohepatitis through Innate and Adaptive Signaling.

Hepatology 2021 Feb 20. Epub 2021 Feb 20.

Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, MN, 55455, USA.

Background And Aims: Nonalcoholic steatohepatitis (NASH) is rapidly becoming the leading cause of liver failure and indication for liver transplantation. Hepatic inflammation is a key feature of NASH but the immune pathways involved in this process are poorly understood. B lymphocytes are cells of the adaptive immune system that are critical regulators of immune responses. However, the role of B cells in the pathogenesis of NASH and the potential mechanisms leading to their activation in the liver are unclear.

Approach And Results: In this study, we report that NASH livers accumulate B cells with elevated pro-inflammatory cytokine secretion and antigen-presentation ability. Single-cell and bulk RNA sequencing of intrahepatic B cells from mice with NASH unveiled a transcriptional landscape that reflects their pro-inflammatory function. Accordingly, B cell-deficiency ameliorated NASH progression and adoptively transferring B cells from NASH livers recapitulates the disease. Mechanistically, B cell activation during NASH involves signaling through the innate adaptor myeloid differentiation primary response protein 88 (MyD88) as B cell-specific deletion of MyD88 reduced hepatic T cell-mediated inflammation and fibrosis, but not steatosis. In addition, activation of intrahepatic B cells implicates B cell receptor signaling, delineating a synergy between innate and adaptive mechanisms of antigen recognition. Furthermore, fecal microbiota transplantation of human NAFLD gut microbiotas into recipient mice promoted the progression of NASH by increasing the accumulation and activation of intrahepatic B cells, suggesting that gut microbial factors drive the pathogenic function of B cells during NASH.

Conclusion: Our findings reveal that a gut microbiota-driven activation of intrahepatic B cells leads to hepatic inflammation and fibrosis during the progression of NASH via innate and adaptive immune mechanisms.
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http://dx.doi.org/10.1002/hep.31755DOI Listing
February 2021

Nod1 promotes colorectal carcinogenesis by regulating the immunosuppressive functions of tumor-infiltrating myeloid cells.

Cell Rep 2021 Jan;34(4):108677

Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

Pioneering studies from the early 1980s suggested that bacterial peptidoglycan-derived muramyl peptides (MPs) could exert either stimulatory or immunosuppressive functions depending, in part, on chronicity of exposure. However, this Janus-faced property of MPs remains largely unexplored. Here, we demonstrate the immunosuppressive potential of Nod1, the bacterial sensor of diaminopimelic acid (DAP)-containing MPs. Using a model of self-limiting peritonitis, we show that systemic Nod1 activation promotes an autophagy-dependent reprogramming of macrophages toward an alternative phenotype. Moreover, Nod1 stimulation induces the expansion of myeloid-derived suppressor cells (MDSCs) and maintains their immunosuppressive potential via arginase-1 activity. Supporting the role of MDSCs and tumor-associated macrophages in cancer, we demonstrate that myeloid-intrinsic Nod1 expression sustains intra-tumoral arginase-1 levels to foster an immunosuppressive and tumor-permissive microenvironment during colorectal cancer (CRC) development. Our findings support the notion that bacterial products, via Nod1 detection, modulate the immunosuppressive activity of myeloid cells and fuel tumor progression in CRC.
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http://dx.doi.org/10.1016/j.celrep.2020.108677DOI Listing
January 2021

Mechanical Stiffness Controls Dendritic Cell Metabolism and Function.

Cell Rep 2021 Jan;34(2):108609

Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Pathology, University Health Network, Toronto, ON M5G 2C4, Canada; Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA. Electronic address:

Stiffness in the tissue microenvironment changes in most diseases and immunological conditions, but its direct influence on the immune system is poorly understood. Here, we show that static tension impacts immune cell function, maturation, and metabolism. Bone-marrow-derived and/or splenic dendritic cells (DCs) grown in vitro at physiological resting stiffness have reduced proliferation, activation, and cytokine production compared with cells grown under higher stiffness, mimicking fibro-inflammatory disease. Consistently, DCs grown under higher stiffness show increased activation and flux of major glucose metabolic pathways. In DC models of autoimmune diabetes and tumor immunotherapy, tension primes DCs to elicit an adaptive immune response. Mechanistic workup identifies the Hippo-signaling molecule, TAZ, as well as Ca-related ion channels, including potentially PIEZO1, as important effectors impacting DC metabolism and function under tension. Tension also directs the phenotypes of monocyte-derived DCs in humans. Thus, mechanical stiffness is a critical environmental cue of DCs and innate immunity.
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http://dx.doi.org/10.1016/j.celrep.2020.108609DOI Listing
January 2021

Bioidentical hormones.

Climacteric 2021 Feb 6;24(1):38-45. Epub 2021 Jan 6.

Departments of Obstetrics and Gynecology.

After the results of the Women's Health Initiative trials were published, patient and clinician interest in potential alternatives to conventional hormone therapy (HT) has grown. A commonly used alternative therapy involves custom-compounded steroid hormone preparations, formulated by compounding pharmacies. Many postmenopausal women consider the hormones as natural or bioidentical, in contrast to hormones used in conventional HT, which they consider synthetic. In actuality, the chemical structures of many of the hormones used in bioidentical HT (BHT) are the same as those used in conventional HT. To customize formulations, compounding pharmacies frequently use saliva testing to measure hormones. However, there is a misconception that salivary hormone levels are equivalent to non-protein-bound (free) hormones in blood. Because hormonal custom-compounded formulations are not approved by the Food and Drug Administration (FDA), there are concerns regarding their purity, potency, and quality. Evolving regulatory guidelines by the FDA on oversight of these products should lessen the concerns regarding their safety and efficacy. This review addresses important misconceptions and uncertainties pertaining to BHT, the relationship between salivary and serum/plasma steroid hormone concentrations, the effect of topical progesterone creams on the endometrium, the variability in custom-compounded steroid preparations, and FDA oversight of custom-compounded products.
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http://dx.doi.org/10.1080/13697137.2020.1862079DOI Listing
February 2021

Gut-associated IgA immune cells regulate obesity-related insulin resistance.

Nat Commun 2019 08 13;10(1):3650. Epub 2019 Aug 13.

Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON, M5G 2C4, Canada.

The intestinal immune system is emerging as an important contributor to obesity-related insulin resistance, but the role of intestinal B cells in this context is unclear. Here, we show that high fat diet (HFD) feeding alters intestinal IgA immune cells and that IgA is a critical immune regulator of glucose homeostasis. Obese mice have fewer IgA immune cells and less secretory IgA and IgA-promoting immune mediators. HFD-fed IgA-deficient mice have dysfunctional glucose metabolism, a phenotype that can be recapitulated by adoptive transfer of intestinal-associated pan-B cells. Mechanistically, IgA is a crucial link that controls intestinal and adipose tissue inflammation, intestinal permeability, microbial encroachment and the composition of the intestinal microbiome during HFD. Current glucose-lowering therapies, including metformin, affect intestinal-related IgA B cell populations in mice, while bariatric surgery regimen alters the level of fecal secretory IgA in humans. These findings identify intestinal IgA immune cells as mucosal mediators of whole-body glucose regulation in diet-induced metabolic disease.
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http://dx.doi.org/10.1038/s41467-019-11370-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692361PMC
August 2019

Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity.

Int J Obes (Lond) 2019 12 3;43(12):2407-2421. Epub 2019 Apr 3.

Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON, M5G 1L7, Canada.

Background/objectives: Low-grade chronic inflammation in visceral adipose tissue and the intestines are important drivers of obesity associated insulin resistance. Bioactive compounds derived from plants are an important source of potential novel therapies for the treatment of chronic diseases. In search for new immune based treatments of obesity associated insulin resistance, we screened for tissue relevant anti-inflammatory properties in 20 plant-based extracts.

Methods: We screened 20 plant-based extracts to assess for preferential production of IL-10 compared to TNFα, specifically targetting metabolic tissues, including the visceral adipose tissue. We assessed the therapeutic potential of the strongest anti-inflammatory compound, indigo, in the C57BL/6J diet-induced obesity mouse model with supplementation for up to 16 weeks by measuring changes in body weight, glucose and insulin tolerance, and gut barrier function. We also utilized flow cytometry, quantitative PCR, enzyme-linked immunosorbent assay (ELISA), and histology to measure changes to immune cells populations and cytokine profiles in the intestine, visceral adipose tissue (VAT), and liver. 16SrRNA sequencing was performed to examine gut microbial differences induced by indigo supplementation.

Results: We identifed indigo, an aryl hydrocarbon receptor (AhR) ligand agonist, as a potent inducer of IL-10 and IL-22, which protects against high-fat diet (HFD)-induced insulin resistance and fatty liver disease in the diet-induced obesity model. Therapeutic actions were mechanistically linked to decreased inflammatory immune cell tone in the intestine, VAT and liver. Specifically, indigo increased Lactobacillus bacteria and elicited IL-22 production in the gut, which improved intestinal barrier permeability and reduced endotoxemia. These changes were associated with increased IL-10 production by immune cells residing in liver and VAT.

Conclusions: Indigo is a naturally occurring AhR ligand with anti-inflammatory properties that effectively protects against HFD-induced glucose dysregulation. Compounds derived from indigo or those with similar properties could represent novel therapies for diseases associated with obesity-related metabolic tissue inflammation.
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http://dx.doi.org/10.1038/s41366-019-0340-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892742PMC
December 2019

Gut T Cells Feast on GLP-1 to Modulate Cardiometabolic Disease.

Cell Metab 2019 04;29(4):787-789

Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Pathology, University Health Network, Toronto, ON M5G 2C4, Canada; Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA. Electronic address:

Glucagon-like peptide-1 (GLP-1) is an enteroendocrine hormone that controls insulin secretion, intestinal function, and food intake. Recently in Nature, He et al. (2019) reported that gut intraepithelial T cells regulate GLP-1 bioavailability by capturing it on GLP-1 receptors and impacting L-cell numbers. This study delineates a novel endocrine-immune axis through which intestinal immune cells regulate whole-body metabolism.
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http://dx.doi.org/10.1016/j.cmet.2019.03.002DOI Listing
April 2019

Insulin Receptor-Mediated Stimulation Boosts T Cell Immunity during Inflammation and Infection.

Cell Metab 2018 12 30;28(6):922-934.e4. Epub 2018 Aug 30.

Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Pathology, University Health Network, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Toronto General Research Institute (TGRI), Toronto, ON M5G 2C4, Canada. Electronic address:

T cells represent a critical effector of cell-mediated immunity. Activated T cells engage in metabolic reprogramming during effector differentiation to accommodate dynamic changes in energy demands. Here, we show that the hormone, insulin, and downstream signaling through its insulin receptor shape adaptive immune function through modulating T cell metabolism. T cells lacking insulin receptor expression (LckCre+ Insr) show reduced antigen-specific proliferation and compromised production of pro-inflammatory cytokines. In vivo, T cell-specific insulin receptor deficiency reduces T cell-driven colonic inflammation. In a model of severe influenza infection with A/PR8 (H1N1), lack of insulin receptor on T cells curtails antigen-specific immunity to influenza viral antigens. Mechanistically, insulin receptor signaling reinforces a metabolic program that supports T cell nutrient uptake and associated glycolytic and respiratory capacities. These data highlight insulin receptor signaling as an important node integrating immunometabolic pathways to drive optimal T cell effector function in health and disease.
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http://dx.doi.org/10.1016/j.cmet.2018.08.003DOI Listing
December 2018

Pseudomelanosis Duodeni and Duodenal Polyp.

Intern Med 2018 04 8;57(7):1049-1050. Epub 2017 Dec 8.

Division of Gastroenterology, The Centre of Advanced Therapeutic Endoscopy and Endoscopic Oncology, St. Michael's Hospital, University of Toronto, Canada.

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http://dx.doi.org/10.2169/internalmedicine.9733-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919870PMC
April 2018

Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome.

Sci Immunol 2017 Apr;2(10)

Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, 101 College Street, Toronto, Ontario M5G 1L7, Canada.

Obesity-related insulin resistance is driven by low-grade chronic inflammation of metabolic tissues. In the liver, non-alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance and systemic glucose dysregulation. However, the immunological factors supporting these processes are poorly understood. We found that the liver accumulates pathogenic CD8+ T cell subsets which control hepatic insulin sensitivity and gluconeogenesis during diet-induced obesity in mice. In a cohort of human patients, CD8+ T cells represent a dominant intrahepatic immune cell population which links to glucose dysregulation. Accumulation and activation of these cells are largely supported by type I interferon (IFN-I) responses in the liver. Livers from obese mice upregulate critical interferon regulatory factors (IRFs), interferon stimulatory genes (ISGs), and IFNα protein, while IFNαR1 mice, or CD8-specific IFNαR1 chimeric mice are protected from disease. IFNαR1 inhibitors improve metabolic parameters in mice, while CD8+ T cells and IFN-I responses correlate with NAFLD activity in human patients. Thus, IFN-I responses represent a central immunological axis that governs intrahepatic T cell pathogenicity during metabolic disease.
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http://dx.doi.org/10.1126/sciimmunol.aai7616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447456PMC
April 2017

Immunologic impact of the intestine in metabolic disease.

J Clin Invest 2017 01 3;127(1):33-42. Epub 2017 Jan 3.

Obesity and diabetes are associated with increased chronic low-grade inflammation and elevated plasma glucose levels. Although inflammation in the fat and liver are established features of obesity-associated insulin resistance, the intestine is emerging as a new site for immunologic changes that affect whole-body metabolism. Specifically, microbial and dietary factors incurred by diet-induced obesity influence underlying innate and adaptive responses of the intestinal immune system. These responses affect the maintenance of the intestinal barrier, systemic inflammation, and glucose metabolism. In this Review we propose that an understanding of the changes to the intestinal immune system, and how these changes influence systemic immunity and glucose metabolism in a whole-body integrative and a neuronal-dependent network, will unveil novel intestinal pathologic and therapeutic targets for diabetes and obesity.
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http://dx.doi.org/10.1172/JCI88879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199708PMC
January 2017

A Schwannoma of the Distal Esophagus.

Clin Gastroenterol Hepatol 2016 11 27;14(11):A19-A20. Epub 2016 Jul 27.

Division of Gastroenterology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1016/j.cgh.2016.07.023DOI Listing
November 2016

A Giant Circumferential Inlet Patch With Acid Secretion Causing Stricture.

Clin Gastroenterol Hepatol 2017 04 8;15(4):A22-A23. Epub 2016 Oct 8.

Division of Gastroenterology, Department of Medicine, The Centre of Advanced Therapeutic Endoscopy and Endoscopic Oncology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1016/j.cgh.2016.10.004DOI Listing
April 2017

Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance.

Cell Rep 2016 07 30;16(3):717-30. Epub 2016 Jun 30.

Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada; Department of Pathology, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

Obesity-related inflammation of metabolic tissues, including visceral adipose tissue (VAT) and liver, are key factors in the development of insulin resistance (IR), though many of the contributing mechanisms remain unclear. We show that nucleic-acid-targeting pathways downstream of extracellular trap (ET) formation, unmethylated CpG DNA, or ribonucleic acids drive inflammation in IR. High-fat diet (HFD)-fed mice show increased release of ETs in VAT, decreased systemic clearance of ETs, and increased autoantibodies against conserved nuclear antigens. In HFD-fed mice, this excess of nucleic acids and related protein antigens worsens metabolic parameters through a number of mechanisms, including activation of VAT macrophages and expansion of plasmacytoid dendritic cells (pDCs) in the liver. Consistently, HFD-fed mice lacking critical responders of nucleic acid pathways, Toll-like receptors (TLR)7 and TLR9, show reduced metabolic inflammation and improved glucose homeostasis. Treatment of HFD-fed mice with inhibitors of ET formation or a TLR7/9 antagonist improves metabolic disease. These findings reveal a pathogenic role for nucleic acid targeting as a driver of metabolic inflammation in IR.
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http://dx.doi.org/10.1016/j.celrep.2016.06.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354586PMC
July 2016

Starving Intestinal Inflammation with the Amino Acid Sensor GCN2.

Cell Metab 2016 May;23(5):763-5

Diabetes Research Group, Division of Cellular & Molecular Biology, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 1L7, Canada; Department of Pathology, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

Metabolic stressors are emerging as important controls over immune system function. In a recent paper, Ravindran et al. (2016) uncovered a novel mechanism by which an amino acid sensing pathway controls inflammation in the gut.
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http://dx.doi.org/10.1016/j.cmet.2016.04.020DOI Listing
May 2016

NLRX1 Acts as an Epithelial-Intrinsic Tumor Suppressor through the Modulation of TNF-Mediated Proliferation.

Cell Rep 2016 Mar 10;14(11):2576-86. Epub 2016 Mar 10.

Department of Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A8 Toronto, Canada. Electronic address:

The mitochondrial Nod-like receptor protein NLRX1 protects against colorectal tumorigenesis through mechanisms that remain unclear. Using mice with an intestinal epithelial cells (IEC)-specific deletion of Nlrx1, we find that NLRX1 provides an IEC-intrinsic protection against colitis-associated carcinogenesis in the colon. These Nlrx1 mutant mice have increased expression of Tnf, Egf, and Tgfb1, three factors essential for wound healing, as well as increased epithelial proliferation during the epithelial regeneration phase following injury triggered by dextran sodium sulfate. In primary intestinal organoids lacking Nlrx1, stimulation with TNF resulted in exacerbated proliferation and expression of the intestinal stem cell markers Olfm4 and Myb. This hyper-proliferation response was associated with increased activation of Akt and NF-κB pathways in response to TNF stimulation. Together, these results identify NLRX1 as a suppressor of colonic tumorigenesis that acts by controlling epithelial proliferation in the intestine during the regeneration phase following mucosal injury.
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http://dx.doi.org/10.1016/j.celrep.2016.02.065DOI Listing
March 2016

The Intestinal Immune System in Obesity and Insulin Resistance.

Cell Metab 2016 Mar 4;23(3):413-26. Epub 2016 Feb 4.

Diabetes Research Group, Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine, St. Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada. Electronic address:

Obesity and insulin resistance are associated with chronic inflammation in metabolic tissues such as adipose tissue and the liver. Recently, growing evidence has implicated the intestinal immune system as an important contributor to metabolic disease. Obesity predisposes to altered intestinal immunity and is associated with changes to the gut microbiota, intestinal barrier function, gut-residing innate and adaptive immune cells, and oral tolerance to luminal antigens. Accordingly, the gut immune system may represent a novel therapeutic target for systemic inflammation in insulin resistance. This review discusses the emerging field of intestinal immunity in obesity-related insulin resistance and how it affects metabolic disease.
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http://dx.doi.org/10.1016/j.cmet.2016.01.003DOI Listing
March 2016

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

Am J Gastroenterol 2015 Sep 25;110(9):1324-38. Epub 2015 Aug 25.

Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Objectives: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-to-target" clinical management strategy using an evidence-based expert consensus process.

Methods: A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely).

Results: The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target.

Conclusions: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.
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http://dx.doi.org/10.1038/ajg.2015.233DOI Listing
September 2015

Immunopathology of Adipose Tissue during Metabolic Syndrome.

Turk Patoloji Derg 2015 ;31 Suppl 1:172-80

Department of Immunology, University of Toronto, ON, Canada.

Excess energy intake and a sedentary lifestyle have led to increasing incidence of obesity which is a major risk factor for the development of insulin resistance. Research in the last two decades has revealed that chronic-low grade inflammation in adipose tissue is a key link between obesity and insulin resistance. As a result, adipose tissue is now considered an active immune organ with a key role in metabolic homeostasis. In the course of obesity, cells of the immune system infiltrate visceral adipose tissue (VAT) in an active process that promotes local and systemic inflammation. This inflammatory process in VAT is driven by various subsets of immune cells and is a central mechanism connecting obesity with its metabolic complications. One key event of adipose tissue inflammation is the switching of macrophages towards a pro-inflammatory phenotype. In addition, recent research has discovered an expanding list of immune cells contributing to this inflammatory process. Pro-inflammatory immune cells are crucial to obese VAT inflammation because of their production of cytokines, which can interfere with insulin signaling in peripheral tissues. This review summarizes our current knowledge of the pathology of innate and adaptive immune cells in obese adipose tissue, with emphasis in the immunological mechanisms mediating obesity-associated insulin resistance.
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http://dx.doi.org/10.5146/tjpath.2015.01323DOI Listing
March 2016

Are obesity-related insulin resistance and type 2 diabetes autoimmune diseases?

Diabetes 2015 Jun;64(6):1886-97

Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada Department of Pathology, University Health Network, Toronto, Ontario, Canada Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, Toronto, Ontario, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada Department of Immunology, University of Toronto, Toronto, Ontario, Canada

Obesity and associated insulin resistance predispose individuals to develop chronic metabolic diseases, such as type 2 diabetes and cardiovascular disease. Although these disorders affect a significant proportion of the global population, the underlying mechanisms of disease remain poorly understood. The discovery of elevated tumor necrosis factor-α in adipose tissue as an inducer of obesity-associated insulin resistance marked a new era of understanding that a subclinical inflammatory process underlies the insulin resistance and metabolic dysfunction that precedes type 2 diabetes. Advances in the field identified components of both the innate and adaptive immune response as key players in regulating such inflammatory processes. As antigen specificity is a hallmark of an adaptive immune response, its role in modulating the chronic inflammation that accompanies obesity and type 2 diabetes begs the question of whether insulin resistance and type 2 diabetes can have autoimmune components. In this Perspective, we summarize current data that pertain to the activation and perpetuation of adaptive immune responses during obesity and discuss key missing links and potential mechanisms for obesity-related insulin resistance and type 2 diabetes to be considered as potential autoimmune diseases.
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http://dx.doi.org/10.2337/db14-1488DOI Listing
June 2015

Regulation of obesity-related insulin resistance with gut anti-inflammatory agents.

Cell Metab 2015 Apr;21(4):527-42

Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Pathology, University Health Network, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada. Electronic address:

Obesity has reached epidemic proportions, but little is known about its influence on the intestinal immune system. Here we show that the gut immune system is altered during high-fat diet (HFD) feeding and is a functional regulator of obesity-related insulin resistance (IR) that can be exploited therapeutically. Obesity induces a chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations. Reduction of the gut immune system, using beta7 integrin-deficient mice (Beta7(null)), decreases HFD-induced IR. Treatment of wild-type HFD C57BL/6 mice with the local gut anti-inflammatory, 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters. These beneficial effects are dependent on adaptive and gut immunity and are associated with reduced gut permeability and endotoxemia, decreased visceral adipose tissue inflammation, and improved antigen-specific tolerance to luminal antigens. Thus, the mucosal immune system affects multiple pathways associated with systemic IR and represents a novel therapeutic target in this disease.
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http://dx.doi.org/10.1016/j.cmet.2015.03.001DOI Listing
April 2015

Response to Villanacci et. al.

J Crohns Colitis 2015 May 11;9(5):429. Epub 2015 Mar 11.

Department of Pathology and Laboratory Medicine, Mt Sinai Hospital, Toronto, ON, Canada

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http://dx.doi.org/10.1093/ecco-jcc/jjv046DOI Listing
May 2015

Systematic review: histological remission in inflammatory bowel disease. Is 'complete' remission the new treatment paradigm? An IOIBD initiative.

J Crohns Colitis 2014 Dec 27;8(12):1582-97. Epub 2014 Sep 27.

Department of Pathology and Laboratory Medicine, Mt Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada. Electronic address:

Background And Aims: Advances in the medical management of inflammatory bowel disease (IBD) have altered treatment targets. Endoscopic mucosal healing is associated with better outcomes in IBD, though less is known about the significance of achieving histological remission. Our aim was to perform a systematic review to investigate whether histological or 'complete' remission constitutes a further therapeutic target in IBD.

Methods: A bibliographic search was performed on the 1st of October 2013 and subsequently on the 1st of March 2014 of online databases (OVID SP MEDLINE, OVID EMBASE, National Pubmed Central Medline, Cochrane Library, ISI, conference abstracts), using MeSH terms and key words: ("inflammatory bowel diseases" OR "crohn disease" OR "ulcerative colitis" OR "colitis") AND ("mucosal healing" OR "histological healing" OR "pathological healing" OR "histological scoring" OR "pathological scoring").

Results: The search returned 2951 articles. 120 articles were cited in the final analysis. There is no validated definition of histological remission in IBD. There are 22 different histological scoring systems for IBD, none of which are fully validated. Microscopic inflammation persists in 16-100% of cases of endoscopically quiescent disease. There is evidence that histological remission may predict risk of complications in ulcerative colitis beyond endoscopic mucosal healing, though data are scarce in Crohn's disease.

Conclusions: Histological remission in IBD represents a target distinct from endoscopic mucosal healing, not yet routinely sought in clinical trials or practice. There remains a need for a standardized and validated histological scoring system and to confirm the prognostic value of histological remission as a treatment target in IBD.
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http://dx.doi.org/10.1016/j.crohns.2014.08.011DOI Listing
December 2014

Perforin is a novel immune regulator of obesity-related insulin resistance.

Diabetes 2015 Jan 21;64(1):90-103. Epub 2014 Jul 21.

Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada Department of Pathology, University Health Network, Toronto, Ontario, Canada

Obesity-related insulin resistance is associated with an influx of pathogenic T cells into visceral adipose tissue (VAT), but the mechanisms regulating lymphocyte balance in such tissues are unknown. Here we describe an important role for the immune cytotoxic effector molecule perforin in regulating this process. Perforin-deficient mice (Prf1(null)) show early increased body weight and adiposity, glucose intolerance, and insulin resistance when placed on high-fat diet (HFD). Regulatory effects of perforin on glucose tolerance are mechanistically linked to the control of T-cell proliferation and cytokine production in inflamed VAT. HFD-fed Prf1(null) mice have increased accumulation of proinflammatory IFN-γ-producing CD4(+) and CD8(+) T cells and M1-polarized macrophages in VAT. CD8(+) T cells from the VAT of Prf1(null) mice have increased proliferation and impaired early apoptosis, suggesting a role for perforin in the regulation of T-cell turnover during HFD feeding. Transfer of CD8(+) T cells from Prf1(null) mice into CD8-deficient mice (CD8(null)) resulted in worsening of metabolic parameters compared with wild-type donors. Improved metabolic parameters in HFD natural killer (NK) cell-deficient mice (NK(null)) ruled out a role for NK cells as a single source of perforin in regulating glucose homeostasis. The findings support the importance of T-cell function in insulin resistance and suggest that modulation of lymphocyte homeostasis in inflamed VAT is one possible avenue for therapeutic intervention.
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http://dx.doi.org/10.2337/db13-1524DOI Listing
January 2015

The mitochondrial protein NLRX1 controls the balance between extrinsic and intrinsic apoptosis.

J Biol Chem 2014 Jul 27;289(28):19317-30. Epub 2014 May 27.

From the Departments of Laboratory Medicine and Pathobiology and

NLRX1 is a mitochondrial Nod-like receptor (NLR) protein whose function remains enigmatic. Here, we observed that NLRX1 expression was glucose-regulated and blunted by SV40 transformation. In transformed but not primary murine embryonic fibroblasts, NLRX1 expression mediated resistance to an extrinsic apoptotic signal, whereas conferring susceptibility to intrinsic apoptotic signals, such as glycolysis inhibition, increased cytosolic calcium and endoplasmic reticulum stress. In a murine model of colorectal cancer induced by azoxymethane, NLRX1-/- mice developed fewer tumors than wild type mice. In contrast, in a colitis-associated cancer model combining azoxymethane and dextran sulfate sodium, NLRX1-/- mice developed a more severe pathology likely due to the increased sensitivity to dextran sulfate sodium colitis. Together, these results identify NLRX1 as a critical mitochondrial protein implicated in the regulation of apoptosis in cancer cells. The unique capacity of NLRX1 to regulate the cellular sensitivity toward intrinsic versus extrinsic apoptotic signals suggests a critical role for this protein in numerous physiological processes and pathological conditions.
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http://dx.doi.org/10.1074/jbc.M114.550111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094044PMC
July 2014

Morphological and inflammatory changes in visceral adipose tissue during obesity.

Endocr Pathol 2014 Mar;25(1):93-101

Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON, Canada.

Obesity is a major health burden worldwide and is a major factor in the development of insulin resistance and metabolic complications such as type II diabetes. Chronic nutrient excess leads to visceral adipose tissue (VAT) expansion and dysfunction in an active process that involves the adipocytes, their supporting matrix, and immune cell infiltrates. These changes contribute to adipose tissue hypoxia, adipocyte cell stress, and ultimately cell death. Accumulation of lymphocytes, macrophages, and other immune cells around dying adipocytes forms the so-called "crown-like structure", a histological hallmark of VAT in obesity. Cross talk between immune cells in adipose tissue dictates the overall inflammatory response, ultimately leading to the production of pro-inflammatory mediators which directly induce insulin resistance in VAT. In this review, we summarize recent studies demonstrating the dramatic changes that occur in visceral adipose tissue during obesity leading to low-grade chronic inflammation and metabolic disease.
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http://dx.doi.org/10.1007/s12022-013-9288-1DOI Listing
March 2014

B Lymphocytes in obesity-related adipose tissue inflammation and insulin resistance.

Cell Mol Life Sci 2014 Mar 15;71(6):1033-43. Epub 2013 Oct 15.

Department of Pathology, Toronto General Hospital, University Health Network, University of Toronto, Eaton Wing, 11E - 424A, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada.

Obesity-related insulin resistance is a chronic inflammatory condition that often gives rise to type 2 diabetes (T2D). Much evidence supports a role for pro-inflammatory T cells and macrophages in promoting local inflammation in tissues such as visceral adipose tissue (VAT) leading to insulin resistance. More recently, B cells have emerged as an additional critical player in orchestrating these processes. B cells infiltrate VAT and display functional and phenotypic changes in response to diet-induced obesity. B cells contribute to insulin resistance by presenting antigens to T cells, secreting inflammatory cytokines, and producing pathogenic antibodies. B cell manipulation represents a novel approach to the treatment of obesity-related insulin resistance and potentially to the prevention of T2D. This review summarizes the roles of B cells in governing VAT inflammation and the mechanisms by which these cells contribute to altered glucose homeostasis in insulin resistance.
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http://dx.doi.org/10.1007/s00018-013-1486-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954849PMC
March 2014

TRPV1 gates tissue access and sustains pathogenicity in autoimmune encephalitis.

Mol Med 2013 Jul 24;19:149-59. Epub 2013 Jul 24.

Neuroscience and Mental Health Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.

Multiple sclerosis (MS) is a chronic progressive, demyelinating condition whose therapeutic needs are unmet, and whose pathoetiology is elusive. We report that transient receptor potential vanilloid-1 (TRPV1) expressed in a major sensory neuron subset, controls severity and progression of experimental autoimmune encephalomyelitis (EAE) in mice and likely in primary progressive MS. TRPV1-/- B6 congenics are protected from EAE. Increased survival reflects reduced central nervous systems (CNS) infiltration, despite indistinguishable T cell autoreactivity and pathogenicity in the periphery of TRPV1-sufficient and -deficient mice. The TRPV1+ neurovascular complex defining the blood-CNS barriers promoted invasion of pathogenic lymphocytes without the contribution of TRPV1-dependent neuropeptides such as substance P. In MS patients, we found a selective risk-association of the missense rs877610 TRPV1 single nucleotide polymorphism (SNP) in primary progressive disease. Our findings indicate that TRPV1 is a critical disease modifier in EAE, and we identify a predictor of severe disease course and a novel target for MS therapy.
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http://dx.doi.org/10.2119/molmed.2012.00329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3745593PMC
July 2013

Interleukin-17 in post-stroke neurodegeneration.

Neurosci Biobehav Rev 2013 Mar 28;37(3):436-47. Epub 2013 Jan 28.

Neuropsychopharmacology Research Group, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario M4N 3M5, Canada.

Stroke is a leading cause of physical disability with neurodegenerative sequelae such as dementia and depression causing significant excess morbidity. Stroke severity can be exacerbated by apoptotic cell death in ischemic tissue, of which inflammatory activity is a key determinant. Studies have identified harmful and beneficial sets of T lymphocytes that infiltrate the brain post-stroke and their activation signals, suggesting that they might be targeted for therapeutic benefit. Animal models and human studies implicate interleukin(IL)-17 and its congeners (e.g. IL-23, IL-21) as mediators of tissue damage in the delayed phase of the inflammatory cascade and the involvement of T lymphocytes in propagating IL-17 release. In this review, we highlight the current understanding of IL-17 secreting cells, including sets of CD4(+) αβ and CD4(-) γδ T lymphocytes, as potentially important mediators of brain pathology post-stroke. Interactions between the IL-17 axis and innate pathways, positive feedback mechanisms that prolong or amplify IL-17, and IL-17 regulatory pathways may offer intervention targets to enhance recovery, prevent long-term decline, and improve quality of life.
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http://dx.doi.org/10.1016/j.neubiorev.2013.01.021DOI Listing
March 2013