Molecular features of macrophage activation.

Cellular activation is mainly defined as the response of a cell to exogenous signals eventually leading to changes in protein expression and cellular function. Originally, macrophage activation was mainly associated with phagocytic function. Later other effector functions such as cytokine secretion, upregulation of cell surface receptors came into focus. For a while macrophage activation was classified as being either pro-inflammatory or anti-inflammatory and certain signal transduction pathways were associated with these two conditions. Most recent findings on transcriptional and epigenetic level, however, suggest that the molecular features of macrophage activation are significantly more complex. Here, we will introduce a novel and integrative model of macrophage activation. Albeit recognizing that macrophage activation cannot be reduced to nuclear processes, we will focus in this review on the most recent findings concerning transcriptional and epigenetic regulation of macrophage activation. Understanding the complexity of the central regulatory mechanisms in the nucleus will form a foundation for deciphering all the different effector functions that are associated with macrophage activation.

[1]  K. Nakai,et al.  The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection , 2010, Nature Immunology.

[2]  I. Amit,et al.  Tissue-Resident Macrophage Enhancer Landscapes Are Shaped by the Local Microenvironment , 2014, Cell.

[3]  Wolfgang Krebs,et al.  The transcriptional regulator network of human inflammatory macrophages is defined by open chromatin , 2016, Cell Research.

[4]  G. Natoli,et al.  Transcriptional regulation of macrophage polarization: enabling diversity with identity , 2011, Nature Reviews Immunology.

[5]  Allon M. Klein,et al.  Droplet Barcoding for Single-Cell Transcriptomics Applied to Embryonic Stem Cells , 2015, Cell.

[6]  J. Bernhagen,et al.  Crosstalk between Sentinel and Helper Macrophages Permits Neutrophil Migration into Infected Uroepithelium , 2014, Cell.

[7]  D. Black,et al.  Transcript Dynamics of Proinflammatory Genes Revealed by Sequence Analysis of Subcellular RNA Fractions , 2012, Cell.

[8]  Michael T. Heneka,et al.  Innate immune activation in neurodegenerative disease , 2014, Nature Reviews Immunology.

[9]  Y. Ohmori,et al.  Requirement for STAT1 in LPS‐induced gene expression in macrophages , 2001, Journal of leukocyte biology.

[10]  R. Xavier,et al.  Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity , 2014, Science.

[11]  P. Allavena,et al.  Pharmacological modulation of monocytes and macrophages. , 2014, Current opinion in pharmacology.

[12]  R. Xavier,et al.  Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. , 2012, Cell host & microbe.

[13]  M. Mittelman,et al.  Resistance of LPS-activated bone marrow derived macrophages to apoptosis mediated by dexamethasone , 2014, Scientific Reports.

[14]  Oliver Soehnlein,et al.  Atherosclerosis - A matter of unresolved inflammation. , 2015, Seminars in immunology.

[15]  J. Edwards,et al.  Exploring the full spectrum of macrophage activation , 2008, Nature Reviews Immunology.

[16]  M. Netea,et al.  BCG-induced protection: effects on innate immune memory. , 2014, Seminars in immunology.

[17]  P. Moynagh Toll-like receptor signalling pathways as key targets for mediating the anti-inflammatory and immunosuppressive effects of glucocorticoids. , 2003, The Journal of endocrinology.

[18]  C. Glass,et al.  Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription , 2013, Nature.

[19]  S. Akira,et al.  Pattern Recognition Receptors and Inflammation , 2010, Cell.

[20]  S. Gygi,et al.  Identification of a Unique TGF-β Dependent Molecular and Functional Signature in Microglia , 2013, Nature Neuroscience.

[21]  R. Medzhitov,et al.  Control of Inducible Gene Expression by Signal-Dependent Transcriptional Elongation , 2009, Cell.

[22]  R. Young,et al.  Super-Enhancers in the Control of Cell Identity and Disease , 2013, Cell.

[23]  P. Allavena,et al.  Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. , 2002, Trends in immunology.

[24]  S. Smale Selective Transcription in Response to an Inflammatory Stimulus , 2010, Cell.

[25]  Markus G. Manz,et al.  Development of Monocytes, Macrophages, and Dendritic Cells , 2010, Science.

[26]  A. Hoffmann,et al.  A Unifying Model for the Selective Regulation of Inducible Transcription by CpG Islands and Nucleosome Remodeling , 2009, Cell.

[27]  A. Ariel,et al.  Macrophages, Meta-Inflammation, and Immuno-Metabolism , 2011, TheScientificWorldJournal.

[28]  J. O’Shea,et al.  Inducible Expression of Stat4 in Dendritic Cells and Macrophages and Its Critical Role in Innate and Adaptive Immune Responses1 , 2001, The Journal of Immunology.

[29]  F. Geissmann,et al.  Development and homeostasis of “resident” myeloid cells: The case of the microglia , 2013, Glia.

[30]  Enrico Petretto,et al.  JunD/AP1 regulatory network analysis during macrophage activation in a rat model of crescentic glomerulonephritis , 2013, BMC Systems Biology.

[31]  Liwu Li,et al.  Innate Immune Programing by Endotoxin and Its Pathological Consequences , 2015, Front. Immunol..

[32]  R. Xavier,et al.  Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes , 2012, Proceedings of the National Academy of Sciences.

[33]  I. Julkunen,et al.  Interferons up-regulate STAT1, STAT2, and IRF family transcription factor gene expression in human peripheral blood mononuclear cells and macrophages. , 1997, Journal of immunology.

[34]  H. Ziegler-Heitbrock,et al.  Tolerance to lipopolysaccharide in human blood monocytes. , 1995, Immunobiology.

[35]  A. Tall,et al.  Cholesterol, inflammation and innate immunity , 2015, Nature Reviews Immunology.

[36]  J. Pollard Trophic macrophages in development and disease , 2009, Nature Reviews Immunology.

[37]  Vidya Subramanian,et al.  Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. , 2008, Cell metabolism.

[38]  S. Akira,et al.  A variety of microbial components induce tolerance to lipopolysaccharide by differentially affecting MyD88-dependent and -independent pathways. , 2002, International immunology.

[39]  Xiaojing Ma,et al.  Interferon Regulatory Factor 1 Is an Essential and Direct Transcriptional Activator for Interferon γ-induced RANTES/CCl5 Expression in Macrophages* , 2005, Journal of Biological Chemistry.

[40]  G. Natoli,et al.  Latent Enhancers Activated by Stimulation in Differentiated Cells , 2013, Cell.

[41]  F. Geissmann,et al.  Development and homeostasis of 'resident' myeloid cells: the case of the Langerhans cell. , 2010, Trends in immunology.

[42]  G. Natoli,et al.  Chromatin contributions to the regulation of innate immunity. , 2014, Annual review of immunology.

[43]  K. Murphy,et al.  Critical role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis , 2008, Nature.

[44]  L. Joosten,et al.  The epigenetic memory of monocytes and macrophages as a novel drug target in atherosclerosis. , 2015, Clinical therapeutics.

[45]  J. Ragoussis,et al.  Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. , 2010, Immunity.

[46]  C. Glass,et al.  Epigenomics of macrophages , 2014, Immunological reviews.

[47]  Denis Gris,et al.  Fatty acid–induced NLRP3-ASC inflammasome activation interferes with insulin signaling , 2011, Nature Immunology.

[48]  K. Alitalo,et al.  Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C–dependent buffering mechanism , 2009, Nature Medicine.

[49]  G. Natoli,et al.  The genomic landscapes of inflammation. , 2011, Genes & development.

[50]  P. Reaven,et al.  Palmitic acid induces IP-10 expression in human macrophages via NF-kappaB activation. , 2007, Biochemical and biophysical research communications.

[51]  Piero Carninci,et al.  Transcription and enhancer profiling in human monocyte subsets. , 2014, Blood.

[52]  Thomas A. Wynn,et al.  Macrophage biology in development, homeostasis and disease , 2013, Nature.

[53]  B. Viollet,et al.  AMPKα1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration. , 2013, Cell metabolism.

[54]  E. J. Young,et al.  Mechanisms of endotoxin tolerance. IV. Specificity of the pyrogenic refractory state during continuous intravenous infusions of endotoxin. , 1966 .

[55]  S. Ferreira,et al.  Inflammation, Defective Insulin Signaling, and Mitochondrial Dysfunction as Common Molecular Denominators Connecting Type 2 Diabetes to Alzheimer Disease , 2014, Diabetes.

[56]  Ansuman T. Satpathy,et al.  Heme-Mediated SPI-C Induction Promotes Monocyte Differentiation into Iron-Recycling Macrophages , 2014, Cell.

[57]  L. Joosten,et al.  Trained innate immunity and atherosclerosis , 2013, Current opinion in lipidology.

[58]  B. Chazaud Macrophages: supportive cells for tissue repair and regeneration. , 2014, Immunobiology.

[59]  D. Mosser,et al.  The many faces of macrophage activation , 2003, Journal of leukocyte biology.

[60]  A. Sica,et al.  Macrophage plasticity and polarization in tissue repair and remodelling , 2013, The Journal of pathology.

[61]  Simmie L. Foster,et al.  Gene-specific control of inflammation by TLR-induced chromatin modifications , 2007, Nature.

[62]  Michael Rehli,et al.  Dynamic epigenetic enhancer signatures reveal key transcription factors associated with monocytic differentiation states. , 2012, Blood.

[63]  R. Medzhitov,et al.  Tissue-Specific Signals Control Reversible Program of Localization and Functional Polarization of Macrophages , 2014, Cell.

[64]  Adwitia Dey,et al.  Ontogeny and Polarization of Macrophages in Inflammation: Blood Monocytes Versus Tissue Macrophages , 2015, Front. Immunol..

[65]  M. Feldmann,et al.  Distinct pathways of LPS-induced NF-kappa B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP. , 2004, Blood.

[66]  Tom C. Freeman,et al.  Transcriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation , 2014, Immunity.

[67]  J. Stender,et al.  Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. , 2013, Molecular cell.

[68]  R. Evans,et al.  STAT6 Transcription Factor Is a Facilitator of the Nuclear Receptor PPARγ-Regulated Gene Expression in Macrophages and Dendritic Cells , 2010, Immunity.

[69]  L. Hui,et al.  High salt primes a specific activation state of macrophages, M(Na) , 2015, Cell Research.

[70]  G. Cline,et al.  Functional polarization of tumour-associated macrophages by tumour-derived lactic acid , 2014, Nature.

[71]  M. Lazar,et al.  Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome , 2012, Proceedings of the National Academy of Sciences.

[72]  M. Brčić,et al.  poly(I:C) and LPS induce distinct IRF3 and NF‐κB signaling during type‐I IFN and TNF responses in human macrophages , 2008, Journal of leukocyte biology.

[73]  C. Glass,et al.  Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. , 2010, Molecular cell.

[74]  T. Wynn,et al.  Protective and pathogenic functions of macrophage subsets , 2011, Nature Reviews Immunology.

[75]  G. Natoli Maintaining cell identity through global control of genomic organization. , 2010, Immunity.

[76]  R. Xavier,et al.  mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity , 2014, Science.

[77]  Vladimir B. Bajic,et al.  Redefining the transcriptional regulatory dynamics of classically and alternatively activated macrophages by deepCAGE transcriptomics , 2015, Nucleic acids research.

[78]  David A. Orlando,et al.  Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes , 2013, Cell.

[79]  Bing Li,et al.  The Role of Chromatin during Transcription , 2007, Cell.

[80]  Alberto Mantovani,et al.  Macrophage plasticity and polarization: in vivo veritas. , 2012, The Journal of clinical investigation.

[81]  I. Amit,et al.  Massively Parallel Single-Cell RNA-Seq for Marker-Free Decomposition of Tissues into Cell Types , 2014, Science.

[82]  Howard Y. Chang,et al.  Single-cell chromatin accessibility reveals principles of regulatory variation , 2015, Nature.

[83]  D. Gilroy,et al.  Resolution-phase macrophages possess a unique inflammatory phenotype that is controlled by cAMP , 2008, Blood.

[84]  N. Perkins,et al.  Transcriptional profiling of the LPS induced NF-κB response in macrophages , 2007, BMC Immunology.

[85]  Steffen Jung,et al.  TGF‐β signaling through SMAD2/3 induces the quiescent microglial phenotype within the CNS environment , 2012, Glia.

[86]  Jeffrey W. Pollard,et al.  Macrophage Diversity Enhances Tumor Progression and Metastasis , 2010, Cell.

[87]  F. Ginhoux,et al.  Monocytes and macrophages: developmental pathways and tissue homeostasis , 2014, Nature Reviews Immunology.