title: De novo expression of circulating biglycan evokes an innate inflammatory tissue response via MyD88/TRIF pathways.
abstract: Matrix-bound constituents, such as the small leucine-rich proteoglycan biglycan, can act as powerful signaling molecules when released by limited proteolysis of the extracellular matrix or de novo synthesized by macrophages in the circulation and body fluids. Specifically, biglycan acts as an endogenous ligand of innate immunity by directly engaging the Toll-like receptor (TLR)-2 and -4. In this study, we generated a transient transgenic mouse model where biglycan was de novo overproduced by hepatocytes driven by the albumin promoter. Transgenic biglycan was rapidly and abundantly synthesized by hepatocytes and released into the bloodstream. Notably, we found that circulating biglycan accumulated in the kidneys where it caused recruitment of leukocytes infiltrating the renal parenchyma concurrent with abnormal renal levels of chemoattractants CXCL1, CXCL2, CCL2 and CCL5. Using mice deficient in either TLR adapter proteins MyD88 or TRIF we discovered that MyD88 deficiency drastically reduced neutrophil and macrophage infiltration in the kidney, whereas TRIF deficiency decreased T cell infiltrates. Production of CXCL1, CXCL2 and CCL2 required MyD88, whereas the levels of T cell and macrophage attractant CCL5 required TRIF. Thus, we provide robust genetic evidence for circulating biglycan as a powerful pro-inflammatory mediator targeting the renal parenchyma. Furthermore, our results provide the first evidence that biglycan differentially triggers chemoattraction of leukocytes via two independent pathways, both under the control of TLR2/4, utilizing either MyD88 or TRIF adaptor proteins. As aberrant expression of biglycan occurs in several inflammatory diseases, this transient transgenic mouse model could serve as a valuable research tool in investigating the effects of increased biglycan expression in vivo and for the development of therapeutic strategies in the treatment of inflammatory diseases.
authors.affiliation: Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Jinyang
authors.initials: J
authors.lastname: Zeng-Brouwers
authors.affiliation: Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Janet
authors.initials: J
authors.lastname: Beckmann
authors.affiliation: Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Madalina-Viviana
authors.initials: MV
authors.lastname: Nastase
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.affiliation: Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der Goethe-Universität, Frankfurt am Main, Germany. Electronic address: schaefer@med.uni-frankfurt.de.
authors.forename: Liliana
authors.initials: L
authors.lastname: Schaefer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D058578:Biglycan / Q000096:biosynthesis* / Q000097:blood* / Q000235:genetics; D015153:Blotting, Western; D002630:Chemotactic Factors / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D022781:Hepatocytes / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D007668:Kidney / Q000276:immunology / Q000378:metabolism*; D007962:Leukocytes / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism; D012150:Polymorphism, Restriction Fragment Length; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D058578:Biglycan; D002630:Chemotactic Factors; D017931:DNA Primers; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse
keywords: Chemoattractants; Danger signal; Extracellular matrix; Innate immunity; Macrophage; Toll-like receptors