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Transcriptional Profile of Human Anti-Inflamatory Macrophages Under Homeostatic, Activating and Pathological Conditions

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UNIVERSIDAD COMPLUTENSE DE MADRID FACULTAD DE CIENCIAS QUÍMICAS Departamento de Bioquímica y Biología Molecular I TESIS DOCTORAL Transcriptional profile of human anti-inflamatory macrophages under homeostatic, activating and pathological conditions Perfil transcripcional de macrófagos antiinflamatorios humanos en condiciones de homeostasis, activación y patológicas MEMORIA PARA OPTAR AL GRADO DE DOCTOR PRESENTADA POR Víctor Delgado Cuevas Directores María Marta Escribese Alonso Ángel Luís Corbí López Madrid, 2017 © Víctor Delgado Cuevas, 2016 Universidad Complutense de Madrid Facultad de Ciencias Químicas Dpto. de Bioquímica y Biología Molecular I TRANSCRIPTIONAL PROFILE OF HUMAN ANTI-INFLAMMATORY MACROPHAGES UNDER HOMEOSTATIC, ACTIVATING AND PATHOLOGICAL CONDITIONS Perfil transcripcional de macrófagos antiinflamatorios humanos en condiciones de homeostasis, activación y patológicas. Víctor Delgado Cuevas Tesis Doctoral Madrid 2016 Universidad Complutense de Madrid Facultad de Ciencias Químicas Dpto. de Bioquímica y Biología Molecular I TRANSCRIPTIONAL PROFILE OF HUMAN ANTI-INFLAMMATORY MACROPHAGES UNDER HOMEOSTATIC, ACTIVATING AND PATHOLOGICAL CONDITIONS Perfil transcripcional de macrófagos antiinflamatorios humanos en condiciones de homeostasis, activación y patológicas. Este trabajo ha sido realizado por Víctor Delgado Cuevas para optar al grado de Doctor en el Centro de Investigaciones Biológicas de Madrid (CSIC), bajo la dirección de la Dra. María Marta Escribese Alonso y el Dr. Ángel Luís Corbí López Fdo. Dra. María Marta Escribese Alonso Fdo. Dr. Ángel Luís Corbí López Gracias a los que me enseñan, me pagan, me ayudan, me prestan, me acompañan, me soportan, me quieren, me dan de comer, me invitan a beber y me llevan a bailar. Esto no ha hecho más que empezar. INDEX ABBREVIATIONS 9 ABSTRACT 13 RESUMEN 15 INTRODUCTION 19 MACROPHAGE ONTOGENY 21 MACROPHAGES IN INFLAMMATION 21 TISSUE-RESIDENT MACROPHAGES 23 MACROPHAGE ACTIVATION 26 Toll-like receptors 28 MAFB 31 Structural features and expression 31 MAFB functions 32 MAFB-related pathologies 34 Multicentric carpotarsal osteolysis (MCTO) 35 OBJECTIVES 37 RESULTS 39 CHAPTER ONE: A novel set of genes that define the activation state of human anti-inflammatory macrophages 39 Differential cytokine LPS responsiveness of GM-MØ and M-MØ 41 Differential LPS-initiated intracellular signaling pathways in GM-MØ and M-MØ 45 Definition of the LPS-regulated transcriptional signature of GM-MØ and M-MØ 47 Biological function of the genes upregulated by LPS exclusively in anti-inflammatory M-MØ 50 Contribution of ERK, JNK and p38 activation to the M-MØ-specific LPS-dependent transcriptional profile 50 Physiologic and pathologic relevance of the M-MØ-specific LPS-induced transcriptional profile 54 Table III. LPS-activated GM-MØ and M-MØ: microarray results. Digital format. See attached CD on the reverse of the back cover. Table IV. Genes regulated by LPS exclusively in GM-MØ or M-MØ 56 Table V. Genes regulated by LPS in both GM-MØ and M-MØ 60 Table VI. Effect of MAPK inhibitors on the LPS-induced transcriptional profile of M-MØ 63 CHAPTER TWO: MAFB determines human macrophage anti-inflammatory polarization: pathological relevance for Multicentric carpotarsal osteolysis 65 MAFB expression in human macrophages under homeostatic and anti-inflammatory conditions. 67 MAFB controls the acquisition of the anti-inflammatory transcriptional profile of M-MØ. 67 The M-MØ-specific macrophage transcriptome is altered in macrophages derived from Multicentric carpotarsal osteolysis monocytes. 74 MAFB also influences the LPS responsiveness of human macrophages. 78 Co-expression of MAFB and MAFB-regulated genes in human macrophages in vivo. 80 Table VII. Probes and annotated genes with altered expression in siMAFB M-MØ. 82 Table VIII. Probes and annotated genes with altered expression in MCTO#1 M-MØ 89 DISCUSSION 99 Human M-MØ activation 101 MAFB-directed human macrophage anti-inflammatory polarization 105 Pathological relevance of MAFB-driven macrophage polarization 108 CONCLUSSIONS 113 EXPERIMENTAL PROCEDURES 117 REFERENCES 125 ABBREVIATIONS AHR: aryl hydrocarbon receptor DMSO: dimethyl sulfoxide ARNT: aryl hydrocarbon receptor nuclear EGF: epidermal growth factor translocator ELISA: enzyme-linked immunosorbent assay bHLH-PAS: basic helix-loop-helix-PER-ARNT- SIM Enrichr: interactive and collaborative HTML5 gene list enrichment tool BMP: bone morphogenic protein ERK: extracellular signal-regulated kinase CCL: C-C motif chemokine ligand FDR: false discovery rate CCR: C-C chemokyne receptor FOS: Fos proto-oncogene, AP-1 transcription CD: cluster of differentiation factor subunit ChIP-seq: chromatin immunoprecipitation GATA6: GATA binding protein 6 sequencing GM-CSF: granulocyte macrophage-colony ChIP: chromatin immunoprecipitation assay stimulating factor CLEC: C-type lectin GM-MØ: GM-CSF-polarized macrophage CRE: cAMP-responsive element GSEA: gene set enrichment analysis CREB: cAMP response element binding protein GSK3: glycogen synthase kinase 3 CSF1R: colony-stimulating factor 1 receptor HIF: hypoxia-inducible factor CXCL: C-X-C motif ligand HMGB1: high mobility group box 1 protein DAMP: damage-associated molecular pattern HTR: 5-hydroxytryptamine receptor 11 IFN: interferon pMAFB: MAFB pCDNA3.1(+) expression vector IL: interleukin PPAR: peroxisome proliferator activated receptor IL-34-MØ: IL-34-polarized macrophage PRR: pattern recognition receptor IRAK: interleukin-1 receptor-associated kinase qRT-PCR: quantitative real-time polymerase chain reaction IRF: interferon-regulatory transcription factor RANKL: receptor activator of nuclear factor- JNK: JUN N-terminal kinase kappaB ligand LPS: lipopolysaccharide RPMI: Roswell Park Memorial Institute medium LRR: leucine-rich repeat SARM: sterile alpha and TIR motif-containing protein LXR: liver X receptor SIM: single-minded family bHLH transcription M-CSF: macrophage-colony stimulating factor factor 1 M-MØ: M-CSF-polarized macrophage siRNA: small interfering RNA MAF: v-Maf avian musculoaponeurotic SLC40A1: solute carrier family 40 member 1 fibrosarcoma oncogene homolog SOCS: suppressor of cytokine signaling MAL: MYD88-adapter like SPIC: Spi-C transcription factor MAPK: mitogen-activated protein kinase STAT: signal transducer and activator of MARE: Maf-recognition element transcription MCTO: multicentric carpotarsal osteolysis TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin MEK: MAPK/ERK kinase TGF: transforming growth factor MHC: major histocompatibility complex TIR: Toll/interleukin-1 receptor MITF: melanogenesis associated transcription TLR: toll-like receptor factor TNF: tumor necrosis factor MMP: matrix metalloproteinase TRAF: TNF receptor-associated factor MONA: multicentric osteolysis, nodulosis and arthropathy TRAM: TRIF-related adaptor molecule MYD88: myeloid differentiation primary response TRAP: tartrate-resistant acid phosphatase 88 TRE: 12-O-tetradecanoyl phorbol 13-acetate NFATc1: nuclear factor of activated T cell 1 (TPA)-responsive element k NF B: nuclear factor-kappa B TRIF: TIR domain-containing adaptor protein inducing interferon beta NPAS4: neuronal PAS domain protein 4 VEGF: vascular endothelial growth factor NRL: neural retina leucine zipper protein WT: wild type p38: p38 mitogen activated protein kinase ZXDC: ZXD family zinc finger C protein PAM3CSK4: N-palmitoyl-S-[2,3-bis (palmitoyloxy)-(2RS)-propyl]-[R]-cysteinyl-[S]- seryl-[S]-lysyl-[S]-lysyl-[S]-lysyl-[S]-lysine PAMP: pathogen-associated molecular pattern PBMC: peripheral blood mononuclear cells PDGF: platelet-derived growth factor 12 ABSTRACT Macrophages are cells of the innate immune system that exhibit a huge phenotypic and functional heterogeneity, what gives macrophages the ability to sense and respond accurately to the needs of their microenvironment. Thus, macrophage differentiation and functions are dependent on the integration of cues provided by their ontogeny, surrounding tissue, microbiota, metabolism and pathogens. In line with their functional plasticity, macrophages are able to both initiate and resolve inflammation. Besides, macrophages have essential roles in development, homeostasis and inflammation and, consequently, deregulation of macrophage functions leads to the onset and maintenance of numerous chronic inflammatory pathologies. Therefore, determination of the molecular basis of the macrophage functional heterogeneity should pave the way for the development of tissue-specific anti-inflammatory therapies. Macrophage activation relies on the recognition of pathogen- and danger-associated molecular patterns from exogenous and endogenous factors by a variety of receptors, like TLRs. Depending on the nature of previous cues received by macrophages, the response to activating stimuli may be pro- or anti- inflammatory. The former is characteristic of macrophages exposed to GM-CSF or IFNγ and results in the production of TNF-α, IL-12, IL-6 and IL-23. The latter is specific for macrophages exposed to M-CSF, IL-4 or glucocorticoids and leads to the secretion of IL-10. Unlike the macrophage pro-inflammatory response, which has been extensively studied, scarce knowledge is currently available on the activation of anti-inflammatory macrophages, especially in humans. To address this issue, we have thoroughly analyzed the transcriptome of TLR-activated, human M-CSF-polarized anti-inflammatory macrophages (M-MØ). Microarray analysis of M-MØ after a short exposure to LPS revealed the existence of a gene set that includes chemokines (e.g., CCL19), signaling molecules (e.g., SOCS2)
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