David Artis

Cornell University, Итак, New York, United States

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Publications (146)1961.96 Total impact

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    ABSTRACT: The barrier surfaces of the skin, lung, and intestine are constantly exposed to environmental stimuli that can result in inflammation and tissue damage. Interleukin (IL)-33-dependent group 2 innate lymphoid cells (ILC2s) are enriched at barrier surfaces and have been implicated in promoting inflammation; however, the mechanisms underlying the tissue-protective roles of IL-33 or ILC2s at surfaces such as the intestine remain poorly defined. Here we demonstrate that, following activation with IL-33, expression of the growth factor amphiregulin (AREG) is a dominant functional signature of gut-associated ILC2s. In the context of a murine model of intestinal damage and inflammation, the frequency and number of AREG-expressing ILC2s increases following intestinal injury and genetic disruption of the endogenous AREG-epidermal growth factor receptor (EGFR) pathway exacerbated disease. Administration of exogenous AREG limited intestinal inflammation and decreased disease severity in both lymphocyte-sufficient and lymphocyte-deficient mice, revealing a previously unrecognized innate immune mechanism of intestinal tissue protection. Furthermore, treatment with IL-33 or transfer of ILC2s ameliorated intestinal disease severity in an AREG-dependent manner. Collectively, these data reveal a critical feedback loop in which cytokine cues from damaged epithelia activate innate immune cells to express growth factors essential for ILC-dependent restoration of epithelial barrier function and maintenance of tissue homeostasis.
    Proceedings of the National Academy of Sciences 08/2015; DOI:10.1073/pnas.1509070112 · 9.81 Impact Factor
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    ABSTRACT: Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed ≤5 y of age, frequently presents with a different and more severe phenotype than older-onset IBD. We investigated whether patients with VEO-IBD carry rare or novel variants in genes associated with immunodeficiencies that might contribute to disease development. Patients with VEO-IBD and parents (when available) were recruited from the Children's Hospital of Philadelphia from March 2013 through July 2014. We analyzed DNA from 125 patients with VEO-IBD (ages 3 weeks to 4 y) and 19 parents, 4 of whom also had IBD. Exome capture was performed by Agilent SureSelect V4, and sequencing was performed using the Illumina HiSeq platform. Alignment to human genome GRCh37 was achieved followed by post-processing and variant calling. Following functional annotation, candidate variants were analyzed for change in protein function, minor allele frequency <0.1%, and scaled combined annotation dependent depletion scores ≤10. We focused on genes associated with primary immunodeficiencies and related pathways. An additional 210 exome samples from patients with pediatric IBD (n=45) or adult-onset Crohn's disease (n=20) and healthy individuals (controls, n=145) were obtained from the University of Kiel, Germany and used as control groups. Four-hundred genes and regions associated with primary immunodeficiency, covering approximately 6500 coding exons totaling > 1 Mbp of coding sequence, were selected from the whole exome data. Our analysis revealed novel and rare variants within these genes that could contribute to the development of VEO-IBD, including rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19. In an exome sequence analysis of patients with VEO-IBD and their parents, we identified variants in genes that regulate B- and T-cell functions and could contribute to pathogenesis. Our analysis could lead to the identification of previously unidentified IBD-associated variants. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Gastroenterology 07/2015; DOI:10.1053/j.gastro.2015.07.006 · 13.93 Impact Factor
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    ABSTRACT: Inflammatory bowel disease (IBD), comprising Crohn’s disease, ulcerative colitis, and indeterminate colitis, is a multigenetic and environmentally triggered disease resulting in a dysregulated immune response to commensal or pathogenic microbes found in the gastrointestinal tract.1, 2, 3, 4, 5, 6 and 7 Patients with IBD exhibit local and systemic immune reactivity to various microbes, have significant alterations in the composition of intestinal commensal bacteria, and can become colonized with pathogenic or opportunistic bacteria.8, 9, 10, 11, 12, 13, 14 and 15 The multifactorial nature and environmental contribution to IBD is largely responsible for its increased incidence over the last several decades.16 Added to the complex nature of the disease, host genetics may play a more prominent role in some subpopulations, particularly in very young children (younger than 6 years of age) in whom the disease is termed very early-onset IBD (VEO-IBD).17 and 18 Although this is a heterogeneous population, including some children with mild disease,19 patients with VEO-IBD can present with a different disease phenotype, including extensive colonic involvement and more severe disease than older children and adults.17, 20 and 21 In addition, due to poor response to conventional therapies, severity of inflammation, and greater duration of disease, there are higher rates of morbidity in this population.20, 22 and 23 Because of the aggressive disease phenotype, early age of onset, and strong family history of disease, some measure of VEO-IBD is thought to be a monogenic disease, often involving genes associated with primary immunodeficiencies.18, 20 and 24 This was elegantly demonstrated with the discovery that several IL10 (interleukin-10),25IL10RA (interleukin-10 receptor, α), and IL10RB (interleukin-10 receptor, β)23 gene mutations were associated with a phenotype of severe perianal disease and colitis in infants with VEO-IBD. Additional underlying immunodeficiencies or genetic disorders may also present with an intestinal phenotype in patients with VEO-IBD.20 and 24 These include, but are not limited to, common variable immunodeficiency (CVID), Wiskott-Aldrich syndrome (WAS), immunodysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome, and chronic granulomatous disease (CGD).17, 20, 22 and 26
  • Gregory F Sonnenberg · David Artis
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    ABSTRACT: A previously unappreciated cell type of the innate immune system, termed innate lymphoid cells (ILCs), has been characterized in mice and humans and found to influence the induction, regulation and resolution of inflammation. ILCs have an important role in these processes in mouse models of infection, inflammation and tissue repair. Further, disease-association studies in defined patient populations have identified significant alterations in ILC responses, suggesting a potential role for these cell populations in human health and disease. In this review we discuss the emerging family of ILCs, the role of ILCs in inflammation, and how current or novel therapeutic strategies could be used to selectively modulate ILC responses and limit chronic inflammatory diseases.
    Nature medicine 06/2015; 21(7). DOI:10.1038/nm.3892 · 28.05 Impact Factor
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    ABSTRACT: Group 2 innate lymphoid cells (ILC2s) promote type 2 cytokine-dependent immunity, inflammation, and tissue repair. Although epithelial cell-derived cytokines regulate ILC2 effector functions, the pathways that control the in vivo migration of ILC2s into inflamed tissues remain poorly understood. Here, we provide the first demonstration that expression of the prostaglandin D2 (PGD2) receptor CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) regulates the in vivo accumulation of ILC2s in the lung. Although a significant proportion of ILC2s isolated from healthy human peripheral blood expressed CRTH2, a smaller proportion of ILC2s isolated from nondiseased human lung expressed CRTH2, suggesting that dynamic regulation of CRTH2 expression might be associated with the migration of ILC2s into tissues. Consistent with this, murine ILC2s expressed CRTH2, migrated toward PGD2 in vitro, and accumulated in the lung in response to PGD2 in vivo. Furthermore, mice deficient in CRTH2 exhibited reduced ILC2 responses and inflammation in a murine model of helminth-induced pulmonary type 2 inflammation. Critically, adoptive transfer of CRTH2-sufficient ILC2s restored pulmonary inflammation in CRTH2-deficient mice. Together, these data identify a role for the PGD2-CRTH2 pathway in regulating the in vivo accumulation of ILC2s and the development of type 2 inflammation in the lung.Mucosal Immunology advance online publication, 8 April 2015; doi:10.1038/mi.2015.21.
    Mucosal Immunology 04/2015; DOI:10.1038/mi.2015.21 · 7.54 Impact Factor
  • Jonathan R Brestoff · David Artis
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    ABSTRACT: Obesity is an increasingly prevalent disease worldwide. While genetic and environmental factors are known to regulate the development of obesity and associated metabolic diseases, emerging studies indicate that innate and adaptive immune cell responses in adipose tissue have critical roles in the regulation of metabolic homeostasis. In the lean state, type 2 cytokine-associated immune cell responses predominate in white adipose tissue and protect against weight gain and insulin resistance through direct effects on adipocytes and elicitation of beige adipose. In obesity, these metabolically beneficial immune pathways become dysregulated, and adipocytes and other factors initiate metabolically deleterious type 1 inflammation that impairs glucose metabolism. This review discusses our current understanding of the functions of different types of adipose tissue and how immune cells regulate adipocyte function and metabolic homeostasis in the context of health and disease and highlights. We also highlight the potential of targeting immuno-metabolic pathways as a therapeutic strategy to treat obesity and associated diseases. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 03/2015; 161(1):146-160. DOI:10.1016/j.cell.2015.02.022 · 33.12 Impact Factor
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    ABSTRACT: Type 2 inflammatory responses can be elicited by diverse stimuli, including toxins, venoms, allergens, and infectious agents, and play critical roles in resistance and tolerance associated with infection, wound healing, tissue repair, and tumor development. Emerging data suggest that in addition to characteristic type 2-associated cytokines, the epidermal growth factor (EGF)-like molecule Amphiregulin (AREG) might be a critical component of type 2-mediated resistance and tolerance. Notably, numerous studies demonstrate that in addition to the established role of epithelial- and mesenchymal-derived AREG, multiple leukocyte populations including mast cells, basophils, group 2 innate lymphoid cells (ILC2s), and a subset of tissue-resident regulatory CD4(+) T cells can express AREG. In this review, we discuss recent advances in our understanding of the AREG-EGF receptor pathway and its involvement in infection and inflammation and propose a model for the function of this pathway in the context of resistance and tissue tolerance. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 02/2015; 42(2):216-226. DOI:10.1016/j.immuni.2015.01.020 · 19.75 Impact Factor
  • David Artis · Hergen Spits
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    ABSTRACT: The innate immune system is composed of a diverse array of evolutionarily ancient haematopoietic cell types, including dendritic cells, monocytes, macrophages and granulocytes. These cell populations collaborate with each other, with the adaptive immune system and with non-haematopoietic cells to promote immunity, inflammation and tissue repair. Innate lymphoid cells are the most recently identified constituents of the innate immune system and have been the focus of intense investigation over the past five years. We summarize the studies that formally identified innate lymphoid cells and highlight their emerging roles in controlling tissue homeostasis in the context of infection, chronic inflammation, metabolic disease and cancer.
    Nature 01/2015; 517(7534):293-301. DOI:10.1038/nature14189 · 42.35 Impact Factor
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    Brian S Kim · David Artis
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    ABSTRACT: Group 2 innate lymphoid cells (ILC2s) play critical roles in anti-helminth immunity, airway epithelial repair, and metabolic homeostasis. Recently, these cells have also emerged as key players in the development of allergic inflammation at multiple barrier surfaces. ILC2s arise from common lymphoid progenitors in the bone marrow, are dependent on the transcription factors RORα, GATA3, and TCF-1, and produce the type 2 cytokines interleukin (IL)-4, IL-5, IL-9, and/or IL-13. The epithelial cell-derived cytokines IL-25, IL-33, and TSLP regulate the activation and effector functions of ILC2s, and recent studies suggest that their responsiveness to these cytokines and other factors may depend on their tissue environment. In this review, we focus on recent advances in our understanding of the various factors that regulate ILC2 function in the context of immunity, inflammation, and tissue repair across multiple organ systems. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor perspectives in biology 01/2015; 7(5). DOI:10.1101/cshperspect.a016337 · 8.23 Impact Factor
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    ABSTRACT: Obesity is an increasingly prevalent disease regulated by genetic and environmental factors. Emerging studies indicate that immune cells, including monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are dysregulated in obesity. Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity and eosinophil and alternatively activated macrophage responses, and were recently identified in murine white adipose tissue (WAT) where they may act to limit the development of obesity. However, ILC2s have not been identified in human adipose tissue, and the mechanisms by which ILC2s regulate metabolic homeostasis remain unknown. Here we identify ILC2s in human WAT and demonstrate that decreased ILC2 responses in WAT are a conserved characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing caloric expenditure. This was associated with recruitment of uncoupling protein 1 (UCP1)(+) beige adipocytes in WAT, a process known as beiging or browning that regulates caloric expenditure. IL-33-induced beiging was dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient to drive beiging independently of the adaptive immune system, eosinophils or IL-4 receptor signalling. We found that ILC2s produce methionine-enkephalin peptides that can act directly on adipocytes to upregulate Ucp1 expression in vitro and that promote beiging in vivo. Collectively, these studies indicate that, in addition to responding to infection or tissue damage, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging.
    Nature 12/2014; 519(7542). DOI:10.1038/nature14115 · 42.35 Impact Factor
  • Theresa Alenghat · David Artis
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    ABSTRACT: The trillions of beneficial commensal microorganisms that normally reside in the gastrointestinal tract have emerged as a critical source of environmentally-derived stimuli that can impact health and disease. However, the underlying cellular and molecular mechanisms that recognize commensal bacteria-derived signals and regulate mammalian homeostasis are just beginning to be defined. Highly coordinated epigenomic modifications allow mammals to alter the transcriptional program of a cell in response to environmental cues. These modifications may play a key role in regulating the dynamic relationship between mammals and their microbiota. We review recent advances in understanding the interplay between the microbiota and mammalian epigenomic pathways, and highlight emerging findings that implicate a central role for histone deacetylases (HDACs) in orchestrating host–microbiota interactions.
    Trends in Immunology 11/2014; 35(11). DOI:10.1016/j.it.2014.09.007 · 12.03 Impact Factor
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    ABSTRACT: Isolated lymphoid follicles (ILFs) develop after birth in the small and large intestines (SI and LI) and represent a dynamic response of the gut immune system to the microbiota. Despite their similarities, ILF development in the SI and LI differs on a number of levels. We show that unlike ILF in the SI, the microbiota inhibits ILF development in the colon as conventionalization of germ-free mice reduced colonic ILFs. From this, we identified a novel mechanism regulating colonic ILF development through the action of interleukin (IL)-25 on IL-23 and its ability to modulate T regulatory cell (Treg) differentiation. Colonic ILF develop in the absence of a number of factors required for the development of their SI counterparts and can be specifically suppressed by factors other than IL-25. However, IL-23 is the only factor identified that specifically promotes colonic ILFs without affecting SI-ILF development. Both IL-23 and ILFs are associated with inflammatory bowel disease, suggesting that disruption to this pathway may have an important role in the breakdown of microbiota-immune homeostasis.
    Mucosal Immunology 09/2014; 8(3). DOI:10.1038/mi.2014.90 · 7.54 Impact Factor
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    ABSTRACT: Oropharyngeal candidiasis (OPC) is an opportunistic fungal infection caused by Candida albicans. OPC is frequent in HIV/AIDS, implicating adaptive immunity. Mice are naive to Candida, yet IL-17 is induced within 24 h of infection, and susceptibility is strongly dependent on IL-17R signaling. We sought to identify the source of IL-17 during the early innate response to candidiasis. We show that innate responses to Candida require an intact TCR, as SCID, IL-7Rα(-/-), and Rag1(-/-) mice were susceptible to OPC, and blockade of TCR signaling by cyclosporine induced susceptibility. Using fate-tracking IL-17 reporter mice, we found that IL-17 is produced within 1-2 d by tongue-resident populations of γδ T cells and CD3(+)CD4(+)CD44(hi)TCRβ(+)CCR6(+) natural Th17 (nTh17) cells, but not by TCR-deficient innate lymphoid cells (ILCs) or NK cells. These cells function redundantly, as TCR-β(-/-) and TCR-δ(-/-) mice were both resistant to OPC. Whereas γδ T cells were previously shown to produce IL-17 during dermal candidiasis and are known to mediate host defense at mucosal surfaces, nTh17 cells are poorly understood. The oral nTh17 population expanded rapidly after OPC, exhibited high TCR-β clonal diversity, and was absent in Rag1(-/-), IL-7Rα(-/-), and germ-free mice. These findings indicate that nTh17 and γδ T cells, but not ILCs, are key mucosal sentinels that control oral pathogens.
    Journal of Experimental Medicine 09/2014; 211(10). DOI:10.1084/jem.20130877 · 13.91 Impact Factor
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    Journal of Allergy and Clinical Immunology 08/2014; DOI:10.1016/j.jaci.2014.07.032 · 11.25 Impact Factor
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    ABSTRACT: Type 2 inflammation underlies allergic diseases such as atopic dermatitis, which is characterized by the accumulation of basophils and group 2 innate lymphoid cells (ILC2s) in inflamed skin lesions. Although murine studies have demonstrated that cutaneous basophil and ILC2 responses are dependent on thymic stromal lymphopoietin, whether these cell populations interact to regulate the development of cutaneous type 2 inflammation is poorly defined. In this study, we identify that basophils and ILC2s significantly accumulate in inflamed human and murine skin and form clusters not observed in control skin. We demonstrate that murine basophil responses precede ILC2 responses and that basophils are the dominant IL-4-enhanced GFP-expressing cell type in inflamed skin. Furthermore, basophils and IL-4 were necessary for the optimal accumulation of ILC2s and induction of atopic dermatitis-like disease. We show that ILC2s express IL-4Rα and proliferate in an IL-4-dependent manner. Additionally, basophil-derived IL-4 was required for cutaneous ILC2 responses in vivo and directly regulated ILC2 proliferation ex vivo. Collectively, these data reveal a previously unrecognized role for basophil-derived IL-4 in promoting ILC2 responses during cutaneous inflammation.
    The Journal of Immunology 08/2014; 193(7). DOI:10.4049/jimmunol.1401307 · 5.36 Impact Factor
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    ABSTRACT: The paradigm that macrophages that reside in steady-state tissues are derived from embryonic precursors has never been investigated in the intestine, which contains the largest pool of macrophages. Using fate-mapping models and monocytopenic mice, together with bone marrow chimera and parabiotic models, we found that embryonic precursor cells seeded the intestinal mucosa and demonstrated extensive in situ proliferation during the neonatal period. However, these cells did not persist in the intestine of adult mice. Instead, they were replaced around the time of weaning by the chemokine receptor CCR2-dependent influx of Ly6C(hi) monocytes that differentiated locally into mature, anti-inflammatory macrophages. This process was driven largely by the microbiota and had to be continued throughout adult life to maintain a normal intestinal macrophage pool.
    Nature Immunology 08/2014; 15(10). DOI:10.1038/ni.2967 · 24.97 Impact Factor
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    ABSTRACT: The mammalian intestine is colonized by beneficial commensal bacteria and is a site of infection by pathogens, including helminth parasites. Helminths induce potent immunomodulatory effects, but whether these effects are mediated by direct regulation of host immunity or indirectly through eliciting changes in the microbiota is unknown. We tested this in the context of virus-helminth coinfection. Helminth coinfection resulted in impaired antiviral immunity and was associated with changes in the microbiota and STAT6-dependent helminth-induced alternative activation of macrophages. Notably, helminth-induced impairment of antiviral immunity was evident in germ-free mice, but neutralization of Ym1, a chitinase-like molecule that is associated with alternatively activated macrophages, could partially restore antiviral immunity. These data indicate that helminth-induced immunomodulation occurs independently of changes in the microbiota but is dependent on Ym1.
    Science 07/2014; 345(6196-6196):578-82. DOI:10.1126/science.1256942 · 31.48 Impact Factor
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    ABSTRACT: The response to influenza virus (IAV) infection and severity of disease is highly variable in humans. We hypothesized that one factor contributing to this variability is the presence of specific respiratory tract (RT) microbes. One such microbe is Streptococcus pneumoniae (Sp) that is carried asymptomatically in the RT of many humans. In a mouse co-infection model we found that in contrast to secondary bacterial infection that exacerbates disease, Sp colonization 10 days prior to IAV protects from virus-induced morbidity and lung pathology. Using mutant Sp strains, we identified a critical role for the bacterial virulence factor pneumolysin (PLY) in mediating this protection. Colonization with the PLY-sufficient Sp strain induces expression of the immune-suppressive enzyme arginase 1 in alveolar macrophages (aMø) and correlates with attenuated recruitment and function of pulmonary inflammatory cells. Our study demonstrates a novel role for PLY in Sp-mediated protection by maintaining aMø as "gatekeepers" against virus-induced immunopathology.
    Virology 07/2014; 462-463C:254-265. DOI:10.1016/j.virol.2014.06.019 · 3.28 Impact Factor
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    ABSTRACT: The mammalian gastrointestinal (GI) tract is colonized by trillions of beneficial commensal bacteria that are essential for promoting normal intestinal physiology. While the majority of commensal bacteria are found in the intestinal lumen, many species have also adapted to colonize different anatomical locations in the intestine, including the surface of intestinal epithelial cells (IECs) and the interior of gut-associated lymphoid tissues. These distinct tissue localization patterns permit unique interactions with the mammalian immune system and collectively influence intestinal immune cell homeostasis. Conversely, dysregulated localization of commensal bacteria can lead to inappropriate activation of the immune system and is associated with numerous chronic infectious, inflammatory, and metabolic diseases. Therefore, regulatory mechanisms that control proper anatomical containment of commensal bacteria are essential to maintain tissue homeostasis and limit pathology. In this review, we propose that commensal bacteria associated with the mammalian GI tract can be anatomically defined as (i) luminal, (ii) epithelial-associated, or (iii) lymphoid tissue-resident, and we discuss the role and regulation of these microbial populations in health and disease.
    Immunological Reviews 07/2014; 260(1):35-49. DOI:10.1111/imr.12186 · 12.91 Impact Factor
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    ABSTRACT: The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα) as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon γ (IFNγ)-expressing M1-like myeloid cells. In IKKα mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKα mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKα as a promising target for colorectal cancer (CRC) therapy.
    Cell Reports 05/2014; 7(6). DOI:10.1016/j.celrep.2014.05.006 · 8.36 Impact Factor

Publication Stats

9k Citations
1,961.96 Total Impact Points

Institutions

  • 2014–2015
    • Cornell University
      Итак, New York, United States
    • Weill Cornell Medical College
      • Department of Microbiology and Immunology
      New York, New York, United States
  • 2008–2014
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2000–2014
    • University of Pennsylvania
      • • Institute for Immunology
      • • Department of Pathobiology
      • • School of Veterinary Medicine
      Philadelphia, Pennsylvania, United States
  • 2009
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
    • The University of Edinburgh
      • Institute of Immunology and Infection Research
      Edinburgh, SCT, United Kingdom
  • 1999
    • The University of Manchester
      • Manchester Immunology Group
      Manchester, ENG, United Kingdom