Regulation of metabolic health and adipose tissue function by group 2 innate lymphoid cells

Adipose tissue (AT) is home to an abundance of immune cells. With chronic obesity, inflammatory immune cells accumulate and promote insulin resistance and the progression to type 2 diabetes mellitus. In contrast, recent studies have highlighted the regulation and function of immune cells in lean, healthy AT, including those associated with type 2 or “allergic” immunity. Although traditionally activated by infection with multicellular helminthes, AT type 2 immunity is active independently of infection, and promotes tissue homeostasis, AT “browning,” and systemic insulin sensitivity, protecting against obesity‐induced metabolic dysfunction and type 2 diabetes mellitus. In particular, group 2 innate lymphoid cells (ILC2s) are integral regulators of AT type 2 immunity, producing the cytokines interleukin‐5 and IL‐13, promoting eosinophils and alternatively activated macrophages, and cooperating with and promoting AT regulatory T (Treg) cells. In this review, we focus on the recent developments in our understanding of group 2 innate lymphoid cell cells and type 2 immunity in AT metabolism and homeostasis.

[1]  R. Medzhitov,et al.  Tissue biology perspective on macrophages , 2015, Nature Immunology.

[2]  R. Locksley,et al.  Tuft-cell-derived IL-25 regulates an intestinal ILC2–epithelial response circuit , 2015, Nature.

[3]  Irah L. King,et al.  Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells , 2015, Nature Immunology.

[4]  A. Rudensky,et al.  Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs , 2015, Science.

[5]  J. Rougemont,et al.  The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation , 2015, Immunity.

[6]  Bruce M. Spiegelman,et al.  Brown and Beige Fat: Physiological Roles beyond Heat Generation. , 2015, Cell metabolism.

[7]  B. Polić,et al.  The “Big Bang” in obese fat: Events initiating obesity‐induced adipose tissue inflammation , 2015, European journal of immunology.

[8]  B. Guigas,et al.  A worm of one's own: how helminths modulate host adipose tissue function and metabolism. , 2015, Trends in parasitology.

[9]  A. Rudensky,et al.  A Distinct Function of Regulatory T Cells in Tissue Protection , 2015, Cell.

[10]  Wei-hua Zhao,et al.  The IL‐33/ST2 axis is specifically required for development of adipose tissue‐resident regulatory T cells , 2015, Cellular and Molecular Immunology.

[11]  D. Artis,et al.  IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin–EGFR interactions , 2015, Proceedings of the National Academy of Sciences.

[12]  C. Romagnani,et al.  Group 3 innate lymphoid cells (ILC3s): Origin, differentiation, and plasticity in humans and mice , 2015, European journal of immunology.

[13]  R. Locksley,et al.  Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation. , 2015, Immunity.

[14]  D. Artis,et al.  Innate lymphoid cells in the initiation, regulation and resolution of inflammation , 2015, Nature Medicine.

[15]  R. Locksley,et al.  Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation. , 2015, Immunity.

[16]  O. Larsson,et al.  A stringent validation of mouse adipose tissue identity markers. , 2015, American journal of physiology. Endocrinology and metabolism.

[17]  M. Levings,et al.  IL-33 Reverses an Obesity-Induced Deficit in Visceral Adipose Tissue ST2+ T Regulatory Cells and Ameliorates Adipose Tissue Inflammation and Insulin Resistance , 2015, The Journal of Immunology.

[18]  Christine M. Miller,et al.  Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. , 2015, Cell metabolism.

[19]  M. Yazdanbakhsh,et al.  Chronic helminth infection and helminth‐derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese mice , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  Jonathan R. Brestoff,et al.  Immune Regulation of Metabolic Homeostasis in Health and Disease , 2015, Cell.

[21]  O. Mandelboim,et al.  NK cells link obesity-induced adipose stress to inflammation and insulin resistance , 2015, Nature Immunology.

[22]  V. Kuchroo,et al.  Cutting Edge: Maresin-1 Engages Regulatory T Cells To Limit Type 2 Innate Lymphoid Cell Activation and Promote Resolution of Lung Inflammation , 2015, The Journal of Immunology.

[23]  W. Shi,et al.  The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue–resident regulatory T cells , 2015, Nature Immunology.

[24]  R. Locksley,et al.  Activated Type 2 Innate Lymphoid Cells Regulate Beige Fat Biogenesis , 2015, Cell.

[25]  B. Spiegelman,et al.  Appearance and disappearance of the mRNA signature characteristic of Treg cells in visceral adipose tissue: Age, diet, and PPARγ effects , 2014, Proceedings of the National Academy of Sciences.

[26]  Jonathan R. Brestoff,et al.  Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity , 2014, Nature.

[27]  R. Locksley,et al.  Interleukin-5-producing group 2 innate lymphoid cells control eosinophilia induced by interleukin-2 therapy. , 2014, Blood.

[28]  G. Besra,et al.  Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of Treg cells and macrophages in adipose tissue , 2014, Nature Immunology.

[29]  R. Locksley,et al.  I-L-C-2 it: type 2 immunity and group 2 innate lymphoid cells in homeostasis. , 2014, Current opinion in immunology.

[30]  Z. Werb,et al.  Remodelling the extracellular matrix in development and disease , 2014, Nature Reviews Molecular Cell Biology.

[31]  M. Yazdanbakhsh,et al.  Helminth therapy or elimination: epidemiological, immunological, and clinical considerations. , 2014, The Lancet. Infectious diseases.

[32]  Hergen Spits,et al.  Innate lymphoid cells in inflammation and immunity. , 2014, Immunity.

[33]  M. Colonna,et al.  Development, differentiation, and diversity of innate lymphoid cells. , 2014, Immunity.

[34]  B. Cannon,et al.  The browning of white adipose tissue: some burning issues. , 2014, Cell metabolism.

[35]  Alan D. Lopez,et al.  Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013 , 2014, The Lancet.

[36]  A. Rudensky,et al.  Interactions between innate and adaptive lymphocytes , 2014, Nature Reviews Immunology.

[37]  Caroline Tao,et al.  Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. , 2014, Cell metabolism.

[38]  R. Palmiter,et al.  Eosinophils and Type 2 Cytokine Signaling in Macrophages Orchestrate Development of Functional Beige Fat , 2014, Cell.

[39]  B. Spiegelman,et al.  Meteorin-like Is a Hormone that Regulates Immune-Adipose Interactions to Increase Beige Fat Thermogenesis , 2014, Cell.

[40]  K. Mills,et al.  Induction of regulatory cells by helminth parasites: exploitation for the treatment of inflammatory diseases , 2014, Immunological reviews.

[41]  Henrique Veiga-Fernandes,et al.  Differentiation of Type 1 ILCs from a Common Progenitor to All Helper-like Innate Lymphoid Cell Lineages , 2014, Cell.

[42]  E. R. Sutherland,et al.  Linking obesity and asthma , 2014, Annals of the New York Academy of Sciences.

[43]  A. McKenzie,et al.  Faculty Opinions recommendation of Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. , 2014 .

[44]  D. Broide,et al.  Prostaglandin D2 regulates human type 2 innate lymphoid cell chemotaxis. , 2014, The Journal of allergy and clinical immunology.

[45]  K. Bae,et al.  Distinction of white, beige and brown adipocytes derived from mesenchymal stem cells. , 2014, World journal of stem cells.

[46]  Z. Ning,et al.  Adaptation of Innate Lymphoid Cells to a Micronutrient Deficiency Promotes Type 2 Barrier Immunity , 2014, Science.

[47]  R. Locksley,et al.  Cutting Edge: IL-25 Elicits Innate Lymphoid Type 2 and Type II NKT Cells That Regulate Obesity in Mice , 2013, The Journal of Immunology.

[48]  J. Graff,et al.  The developmental origins of adipose tissue , 2013, Development.

[49]  P. Seale,et al.  Brown and beige fat: development, function and therapeutic potential , 2013, Nature Medicine.

[50]  C. Benoist,et al.  Regulatory T cells in nonlymphoid tissues , 2013, Nature Immunology.

[51]  R. Locksley,et al.  Type 2 innate lymphoid cells control eosinophil homeostasis , 2013, Nature.

[52]  J. Granneman,et al.  Identification of an adipogenic niche for adipose tissue remodeling and restoration. , 2013, Cell metabolism.

[53]  D. Voehringer,et al.  Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. , 2013, Immunity.

[54]  V. Tergaonkar,et al.  Chronic adipose tissue inflammation: all immune cells on the stage. , 2013, Trends in molecular medicine.

[55]  T. Wynn,et al.  Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths , 2013, Nature Reviews Immunology.

[56]  M. Croft,et al.  Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production. , 2013, The Journal of allergy and clinical immunology.

[57]  D. Mathis Immunological goings-on in visceral adipose tissue. , 2013, Cell metabolism.

[58]  Yuejin Liang,et al.  IL-33 Induces Nuocytes and Modulates Liver Injury in Viral Hepatitis , 2013, The Journal of Immunology.

[59]  W. Paul,et al.  Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells , 2013, Nature Immunology.

[60]  F. Bosch,et al.  New insights into adipose tissue VEGF-A actions in the control of obesity and insulin resistance , 2013, Adipocyte.

[61]  R. Locksley,et al.  Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. , 2013, Annual review of immunology.

[62]  J. Urban,et al.  Parasitic Nematode-Induced Modulation of Body Weight and Associated Metabolic Dysfunction in Mouse Models of Obesity , 2013, Infection and Immunity.

[63]  R. Locksley,et al.  Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages , 2013, The Journal of experimental medicine.

[64]  B. Spiegelman,et al.  Adaptive thermogenesis in adipocytes: is beige the new brown? , 2013, Genes & development.

[65]  O. Dekkers,et al.  Relationship between Carotid Intima Media Thickness and Helminth Infections on Flores Island, Indonesia , 2013, PloS one.

[66]  A. McKenzie,et al.  Innate lymphoid cells — how did we miss them? , 2013, Nature Reviews Immunology.

[67]  M. Yacoub,et al.  Adipose tissue: friend or foe? , 2012, Nature Reviews Cardiology.

[68]  S. Kajimura,et al.  Human BAT Possesses Molecular Signatures That Resemble Beige/Brite Cells , 2012, PloS one.

[69]  Y. Djuardi,et al.  Helminth infection in populations undergoing epidemiological transition: a friend or foe? , 2012, Seminars in Immunopathology.

[70]  S. Balk,et al.  Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. , 2012, Immunity.

[71]  B. Spiegelman,et al.  Beige Adipocytes Are a Distinct Type of Thermogenic Fat Cell in Mouse and Human , 2012, Cell.

[72]  Y. Deshaies,et al.  Thymic stromal lymphopoietin: an immune cytokine gene associated with the metabolic syndrome and blood pressure in severe obesity. , 2012, Clinical science.

[73]  P. Froguel,et al.  Interleukin-7 Regulates Adipose Tissue Mass and Insulin Sensitivity in High-Fat Diet-Fed Mice through Lymphocyte-Dependent and Independent Mechanisms , 2012, PloS one.

[74]  H. Spits,et al.  Type 2 innate lymphoid cells–new members of the “type 2 franchise” that mediate allergic airway inflammation , 2012, European journal of immunology.

[75]  C. Benoist,et al.  PPARγ is a major driver of the accumulation and phenotype of adipose-tissue Treg cells , 2012, Nature.

[76]  Fumio Takei,et al.  Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. , 2012, Immunity.

[77]  J. Olefsky,et al.  The cellular and signaling networks linking the immune system and metabolism in disease , 2012, Nature Medicine.

[78]  C. Benoist,et al.  Tissular T(regs): a unique population of adipose-tissue-resident Foxp3+CD4+ T cells that impacts organismal metabolism. , 2011, Seminars in immunology.

[79]  Hergen Spits,et al.  Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161 , 2011, Nature Immunology.

[80]  David Artis,et al.  Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus , 2011, Nature Immunology.

[81]  R. Locksley,et al.  Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis , 2011, Nature.

[82]  P. Scherer,et al.  Adipose tissue remodeling and obesity. , 2011, The Journal of clinical investigation.

[83]  R. Locksley,et al.  Eosinophils Sustain Adipose Alternatively Activated Macrophages Associated with Glucose Homeostasis , 2011, Science.

[84]  K. Walsh,et al.  Adipokines in inflammation and metabolic disease , 2011, Nature Reviews Immunology.

[85]  S. Shoelson,et al.  Type 2 diabetes as an inflammatory disease , 2011, Nature Reviews Immunology.

[86]  A. Chawla,et al.  Alternative macrophage activation and metabolism. , 2011, Annual review of pathology.

[87]  Ashley M. Miller,et al.  Interleukin-33 Induces Protective Effects in Adipose Tissue Inflammation During Obesity in Mice , 2010, Circulation research.

[88]  Yuanyuan Wu,et al.  Adipose tissue remodeling in pathophysiology of obesity , 2010, Current opinion in clinical nutrition and metabolic care.

[89]  David J. Erle,et al.  Systemically dispersed innate IL-13–expressing cells in type 2 immunity , 2010, Proceedings of the National Academy of Sciences.

[90]  W. Wahli,et al.  Cyclooxygenase-2 Controls Energy Homeostasis in Mice by de Novo Recruitment of Brown Adipocytes , 2010, Science.

[91]  S. Cinti,et al.  Distribution and development of brown adipocytes in the murine and human adipose organ. , 2010, Cell metabolism.

[92]  L. Orci,et al.  Lipid homeostasis, lipotoxicity and the metabolic syndrome. , 2010, Biochimica et biophysica acta.

[93]  A. McKenzie,et al.  Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity , 2010, Nature.

[94]  Christophe Benoist,et al.  Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters , 2009, Nature Medicine.

[95]  E. Palmer,et al.  Identification and importance of brown adipose tissue in adult humans. , 2009, The New England journal of medicine.

[96]  A. Saltiel,et al.  Phenotypic Switching of Adipose Tissue Macrophages With Obesity Is Generated by Spatiotemporal Differences in Macrophage Subtypes , 2008, Diabetes.

[97]  R. Seeley,et al.  The integrative role of CNS fuel-sensing mechanisms in energy balance and glucose regulation. , 2008, Annual review of physiology.

[98]  Frank Brombacher,et al.  Macrophage-specific PPARγ controls alternative activation and improves insulin resistance , 2007, Nature.

[99]  A. Saltiel,et al.  Obesity induces a phenotypic switch in adipose tissue macrophage polarization. , 2007, The Journal of clinical investigation.

[100]  J Fernando Bazan,et al.  IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. , 2005, Immunity.

[101]  M. Leach,et al.  IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. , 2001, Immunity.

[102]  J. Bishop,et al.  Macrophages are required for cell death and tissue remodeling in the developing mouse eye , 1993, Cell.

[103]  S Gordon,et al.  Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation , 1992, The Journal of experimental medicine.

[104]  Jerrold M. Olefsky,et al.  Regulation of metabolism by the innate immune system , 2016, Nature Reviews Endocrinology.

[105]  J. Heeren,et al.  Adipose tissue browning and metabolic health , 2014, Nature Reviews Endocrinology.

[106]  茂呂 和世 Innate production of T[H]2 cytokines by adipose tissue-associated c-Kit[+]Sca-1[+] lymphoid cells , 2010 .

[107]  P. Scherer From Lipid Storage Compartment to Endocrine Organ , 2006 .

[108]  Jan Nedergaard,et al.  Brown adipose tissue: function and physiological significance. , 2004, Physiological reviews.

[109]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.