Biglycan, a novel trigger of Th1 and Th17 cell recruitment into the kidney.

Autor: Nastase MV; Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; National Institute for Chemical-Pharmaceutical Research and Development, 112 Vitan Avenue, 031287 Bucharest, Romania., Zeng-Brouwers J; Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany., Beckmann J; Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany., Tredup C; Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany., Christen U; Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany., Radeke HH; Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany., Wygrecka M; Department of Biochemistry, Faculty of Medicine, Universities of Giessen and Marburg Lung Center, Friedrichstrasse 24, 35392 Giessen, Germany., Schaefer L; Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Electronic address: Schaefer@med.uni-frankfurt.de.
Jazyk: angličtina
Zdroj: Matrix biology : journal of the International Society for Matrix Biology [Matrix Biol] 2018 Aug; Vol. 68-69, pp. 293-317. Date of Electronic Publication: 2017 Dec 15.
DOI: 10.1016/j.matbio.2017.12.002
Abstrakt: Th1 and Th17 cells, T helper (Th) subtypes, are key inducers of renal fibrosis. The molecular mechanisms of their recruitment into the kidney, however, are not well understood. Here, we show that biglycan, a proteoglycan of the extracellular matrix, acting in its soluble form as a danger signal, stimulates autonomously the production of Th1 and Th17 chemoattractants CXCL10 and CCL20 in macrophages. In the presence of IFNγ, biglycan synergistically stimulates CXCL9. In macrophages deficient for TLR2, TLR4, and their adaptor molecules MyD88 or TRIF, we identified highly selective mechanisms of biglycan-dependent Th1/17 chemoattraction. Thus, the expression of CXCL9 and CXCL10, common chemoattractants for CXCR3-positive Th1 and Th17 cells, is triggered in a biglycan-TLR4/TRIF-dependent manner. By contrast, biglycan induces CCL20 chemokine production, responsible for CCR6-positive Th17 cell recruitment, in a TLR2/4/MyD88-dependent manner. Importantly, at the onset of diabetes mellitus and lupus nephritis we provide evidence for biglycan-dependent recruitment of Th1 and Th17 cells, IFNγ and IL-17 production, and development of albuminuria in mice lacking or overexpressing soluble biglycan. Furthermore, by genetic ablation of Cxcl10 we showed in vivo involvement of this chemokine in biglycan-dependent recruitment of Th1 and Th17 cells into the kidney. Finally, a positive correlation of biglycan and CXCL10/CXCL9 levels was detected in plasma from patients with diabetic nephropathy and lupus nephritis. Taken together, we identified biglycan as a novel trigger of Th1 and Th17 cell recruitment into the kidney and we postulate that interfering with biglycan/TLR/TRIF/MyD88-signaling might provide novel therapeutic avenues for renal fibrosis.
(Copyright © 2017 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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