The Role of IL-13 and IL-4 in Adipose Tissue Fibrosis

White adipose tissue (WAT) fibrosis, characterized by an excess of extracellular (ECM) matrix components, is strongly associated with WAT inflammation and dysfunction due to obesity. Interleukin (IL)-13 and IL-4 were recently identified as critical mediators in the pathogenesis of fibrotic diseases. However, their role in WAT fibrosis is still ill-defined. We therefore established an ex vivo WAT organotypic culture system and demonstrated an upregulation of fibrosis-related genes and an increase of α-smooth muscle actin (αSMA) and fibronectin abundance upon dose-dependent stimulation with IL-13/IL-4. These fibrotic effects were lost in WAT lacking il4ra, which encodes for the underlying receptor controlling this process. Adipose tissue macrophages were found to play a key role in mediating IL-13/IL-4 effects in WAT fibrosis as their depletion through clodronate dramatically decreased the fibrotic phenotype. IL-4-induced WAT fibrosis was partly confirmed in mice injected intraperitoneally with IL-4. Furthermore, gene correlation analyses of human WAT samples revealed a strong positive correlation of fibrosis markers with IL-13/IL-4 receptors, whereas IL13 and IL4 correlations failed to confirm this association. In conclusion, IL-13 and IL-4 can induce WAT fibrosis ex vivo and partly in vivo, but their role in human WAT remains to be further elucidated.

[1]  S. Antar,et al.  Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation , 2023, International journal of molecular sciences.

[2]  R. Abbott,et al.  Adipose Tissue Paracrine-, Autocrine-, and Matrix-Dependent Signaling during the Development and Progression of Obesity , 2023, Cells.

[3]  J. Macoska,et al.  The IL-4/IL-13 signaling axis promotes prostatic fibrosis , 2022, PloS one.

[4]  C. Freire-de-Lima,et al.  Expression of O-glycosylated oncofetal fibronectin in alternatively activated human macrophages , 2022, Immunologic Research.

[5]  R. Branski,et al.  Macrophages alter inflammatory and fibrotic gene expression in human vocal fold fibroblasts. , 2022, Experimental cell research.

[6]  J. Eriksson,et al.  Excess glucocorticoid exposure contributes to adipose tissue fibrosis which involves macrophage interaction with adipose precursor cells. , 2022, Biochemical pharmacology.

[7]  P. Seale,et al.  Adipose-tissue plasticity in health and disease , 2022, Cell.

[8]  M. Kirstein,et al.  Myeloid Cell–Specific IL-4 Receptor Knockout Partially Protects from Adipose Tissue Inflammation , 2021, The Journal of Immunology.

[9]  K. Clément,et al.  Adipose Tissue Fibrosis in Obesity: Etiology and Challenges. , 2021, Annual review of physiology.

[10]  K. Klingel,et al.  Elevated Fibronectin Levels in Profibrotic CD14+ Monocytes and CD14+ Macrophages in Systemic Sclerosis , 2021, Frontiers in Immunology.

[11]  J. Eilers,et al.  Adipocyte death triggers a pro-inflammatory response and induces metabolic activation of resident macrophages , 2021, Cell Death & Disease.

[12]  Indrajeet Patil,et al.  Visualizations with statistical details: The 'ggstatsplot' approach , 2021, J. Open Source Softw..

[13]  T. Adachi,et al.  Regulation of lysyl oxidase expression in THP‐1 cell‐derived M2‐like macrophages , 2021, Journal of cellular biochemistry.

[14]  I. Bechmann,et al.  CD4+ T cells regulate glucose homeostasis independent of adipose tissue dysfunction in mice , 2021, European journal of immunology.

[15]  J. Eilers,et al.  Multinucleated Giant Cells in Adipose Tissue Are Specialized in Adipocyte Degradation , 2020, Diabetes.

[16]  J. Varga,et al.  Adipocytic Progenitor Cells Give Rise to Pathogenic Myofibroblasts: Adipocyte-to-Mesenchymal Transition and Its Emerging Role in Fibrosis in Multiple Organs , 2020, Current Rheumatology Reports.

[17]  R. Abbott,et al.  Adipose Tissue Fibrosis: Mechanisms, Models, and Importance , 2020, International journal of molecular sciences.

[18]  S. Farmer,et al.  The Adipocyte Acquires a Fibroblast-Like Transcriptional Signature in Response to a High Fat Diet , 2020, Scientific Reports.

[19]  A. Mamalis,et al.  The IL-4/IL-13 axis in skin fibrosis and scarring: mechanistic concepts and therapeutic targets , 2019, Archives of Dermatological Research.

[20]  C. Ponting,et al.  Resolving the fibrotic niche of human liver cirrhosis at single cell level , 2019, Nature.

[21]  I. Amit,et al.  Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner , 2019, Cell.

[22]  M. Blüher.  Obesity: global epidemiology and pathogenesis , 2019, Nature Reviews Endocrinology.

[23]  M. Fasshauer,et al.  Effects of Weight Loss on Glutathione Peroxidase 3 Serum Concentrations and Adipose Tissue Expression in Human Obesity , 2018, Obesity Facts.

[24]  Michael J. Podolsky,et al.  Fat fibrosis: friend or foe? , 2018, JCI insight.

[25]  I. Junttila.  Tuning the Cytokine Responses: An Update on Interleukin (IL)-4 and IL-13 Receptor Complexes , 2018, Front. Immunol..

[26]  Jia Gu,et al.  fastp: an ultra-fast all-in-one FASTQ preprocessor , 2018, bioRxiv.

[27]  J. Fradette,et al.  Role of the TGF‐β pathway in dedifferentiation of human mature adipocytes , 2017, FEBS open bio.

[28]  J. Mauer,et al.  IL-6 Regulates M2 Polarization and Local Proliferation of Adipose Tissue Macrophages in Obesity , 2017, The Journal of Immunology.

[29]  K. Clément,et al.  A PDGFRα-Mediated Switch toward CD9high Adipocyte Progenitors Controls Obesity-Induced Adipose Tissue Fibrosis. , 2017, Cell metabolism.

[30]  Alessandro Vullo,et al.  Ensembl 2017 , 2016, Nucleic Acids Res..

[31]  Shuqiang Li,et al.  CEL-Seq2: sensitive highly-multiplexed single-cell RNA-Seq , 2016, Genome Biology.

[32]  Lior Pachter,et al.  Near-optimal probabilistic RNA-seq quantification , 2016, Nature Biotechnology.

[33]  Jinfang Zhu.  T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production. , 2015, Cytokine.

[34]  J. Eilers,et al.  A method for long-term live imaging of tissue macrophages in adipose tissue explants. , 2015, American journal of physiology. Endocrinology and metabolism.

[35]  Tammara A. Wood,et al.  Myofibroblasts in Murine Cutaneous Fibrosis Originate From Adiponectin‐Positive Intradermal Progenitors , 2015, Arthritis & rheumatology.

[36]  Steven L Salzberg,et al.  HISAT: a fast spliced aligner with low memory requirements , 2015, Nature Methods.

[37]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[38]  H. Kwon,et al.  Adipocyte-Specific IKKβ Signaling Suppresses Adipose Tissue Inflammation through an IL-13-Dependent Paracrine Feedback Pathway , 2014, Cell reports.

[39]  Y. Inagaki,et al.  Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis , 2014, Nature Communications.

[40]  H. Collard,et al.  Endogenously Expressed IL-13Rα2 Attenuates IL-13–Mediated Responses but Does Not Activate Signaling in Human Lung Fibroblasts , 2014, The Journal of Immunology.

[41]  N. Viguerie,et al.  Immune cell Toll-like receptor 4 mediates the development of obesity- and endotoxemia-associated adipose tissue fibrosis. , 2014, Cell reports.

[42]  A. Marcus,et al.  Procaspase-3 regulates fibronectin secretion and influences adhesion, migration and survival independently of catalytic function , 2014, Journal of Cell Science.

[43]  Jaulang Hwang,et al.  Interleukin-4 regulates lipid metabolism by inhibiting adipogenesis and promoting lipolysis , 2014, Journal of Lipid Research.

[44]  R. Yu,et al.  Involvement of mast cells in adipose tissue fibrosis. , 2014, American journal of physiology. Endocrinology and metabolism.

[45]  Åsa K. Björklund,et al.  Full-length RNA-seq from single cells using Smart-seq2 , 2014, Nature Protocols.

[46]  Wei Shi,et al.  featureCounts: an efficient general purpose program for assigning sequence reads to genomic features , 2013, Bioinform..

[47]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[48]  J. Eilers,et al.  Local proliferation of macrophages in adipose tissue during obesity-induced inflammation , 2014, Diabetologia.

[49]  S. Terai,et al.  Hepatic Crown-Like Structure: A Unique Histological Feature in Non-Alcoholic Steatohepatitis in Mice and Humans , 2013, PloS one.

[50]  K. Clément,et al.  Fibrosis and adipose tissue dysfunction. , 2013, Cell metabolism.

[51]  T. Wynn,et al.  Cytokine mediated tissue fibrosis. , 2013, Biochimica et biophysica acta.

[52]  N. Hassan,et al.  Proinflammatory, anti-inflammatory cytokines and adiponkines in students with central obesity. , 2013, Cytokine.

[53]  B. Hinz,et al.  The myofibroblast matrix: implications for tissue repair and fibrosis , 2013, The Journal of pathology.

[54]  M. Shiau,et al.  Regulation of glucose/lipid metabolism and insulin sensitivity by interleukin-4 , 2012, International Journal of Obesity.

[55]  N. Frangogiannis,et al.  TGF-β signaling in fibrosis , 2011, Growth factors.

[56]  Marcel Martin.  Cutadapt removes adapter sequences from high-throughput sequencing reads , 2011 .

[57]  Y. Kamei,et al.  Increased Expression of Macrophage-Inducible C-type Lectin in Adipose Tissue of Obese Mice and Humans , 2011, Diabetes.

[58]  C. Peterson,et al.  Adipose tissue macrophages in insulin resistant subjects are 1 associated with collagen VI, fibrosis and demonstrate 2 alternative activation , 2010 .

[59]  M. Fasshauer,et al.  Insulin-sensitive obesity. , 2010, American journal of physiology. Endocrinology and metabolism.

[60]  V. Borges,et al.  Epithelial and Mesenchymal Cell Biology Alternatively Activated Macrophages and Collagen Remodeling Characterize the Postpartum Involuting Mammary Gland across Species , 2010 .

[61]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[62]  M. Robinson,et al.  A scaling normalization method for differential expression analysis of RNA-seq data , 2010, Genome Biology.

[63]  Eric Ravussin,et al.  Adipose tissue collagen VI in obesity. , 2009, The Journal of clinical endocrinology and metabolism.

[64]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[65]  K. Clément,et al.  Macrophage-secreted factors promote a profibrotic phenotype in human preadipocytes. , 2009, Molecular endocrinology.

[66]  Philipp E. Scherer,et al.  Metabolic Dysregulation and Adipose Tissue Fibrosis: Role of Collagen VI , 2008, Molecular and Cellular Biology.

[67]  S. Chouzenoux,et al.  Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway , 2008, Laboratory Investigation.

[68]  S. McGarvey,et al.  Th2 cytokines are associated with persistent hepatic fibrosis in human Schistosoma japonicum infection. , 2007, The Journal of infectious diseases.

[69]  R. Puri,et al.  IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. , 2006, Nature medicine.

[70]  R. Puri,et al.  IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis , 2006, Nature Medicine.

[71]  Shupei Wang,et al.  Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500294-JLR200 , 2005, Journal of Lipid Research.

[72]  M. Jinnin,et al.  Interleukin-13 Stimulates the Transcription of the Human α2(I) Collagen Gene in Human Dermal Fibroblasts* , 2004, Journal of Biological Chemistry.

[73]  L. Wakefield,et al.  IL-13 Activates a Mechanism of Tissue Fibrosis That Is Completely TGF-β Independent , 2004, The Journal of Immunology.

[74]  N. Rooijen,et al.  Elimination of phagocytic cells in the spleen after intravenous injection of liposome-encapsulated dichloromethylene diphosphonate , 1984, Cell and Tissue Research.

[75]  D. Lindemann,et al.  Glucocorticoid inhibition of interleukin-4 (IL-4) and interleukin-13 (IL-13) induced up-regulation of arginase in rat airway fibroblasts , 2003, Naunyn-Schmiedeberg's Archives of Pharmacology.

[76]  Michael J. Grusby,et al.  Enhanced Interleukin (IL)-13 Responses in Mice Lacking IL-13 Receptor α 2 , 2003, The Journal of experimental medicine.

[77]  R. Homer,et al.  Interleukin-13 Induces Tissue Fibrosis by Selectively Stimulating and Activating Transforming Growth Factor β1 , 2001, The Journal of experimental medicine.

[78]  K Eichmann,et al.  Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells. , 1999, Journal of immunology.

[79]  J. Banchereau,et al.  Interleukin-4 and interleukin-13: their similarities and discrepancies. , 1998, International reviews of immunology.

[80]  T. K. van den Berg,et al.  Apoptosis of macrophages induced by liposome-mediated intracellular delivery of clodronate and propamidine. , 1996, Journal of immunological methods.

[81]  G. Zurawski,et al.  Receptors for interleukin‐13 and interleukin‐4 are complex and share a novel component that functions in signal transduction. , 1993, The EMBO journal.

[82]  N. Rooijen,et al.  Elimination of phagocytic cells in the spleen after intravenous injection of liposomeencapsulated dichloromethylene diphosphonate , 1985 .

[83]  N. Van Rooijen,et al.  Elimination of phagocytic cells in the spleen after intravenous injection of liposome-encapsulated dichloromethylene diphosphonate. An enzyme-histochemical study. , 1984, Cell and tissue research.