2. Academic Validation
  3. Biglycan evokes autophagy in macrophages via a novel CD44/Toll-like receptor 4 signaling axis in ischemia/reperfusion injury

Biglycan evokes autophagy in macrophages via a novel CD44/Toll-like receptor 4 signaling axis in ischemia/reperfusion injury

  • Kidney Int. 2019 Mar;95(3):540-562. doi: 10.1016/j.kint.2018.10.037.
Chiara Poluzzi 1,  Madalina-Viviana Nastase 2,  Jinyang Zeng-Brouwers 1,  Heiko Roedig 1,  Louise Tzung-Harn Hsieh 1,  Jonas B Michaelis 3,  Eva Miriam Buhl 4,  Flavia Rezende 5,  Yosif Manavski 6,  André Bleich 7,  Peter Boor 8,  Ralf P Brandes 5,  Josef Pfeilschifter 1,  Ernst H K Stelzer 9,  Christian Münch 3,  Ivan Dikic 10,  Christian Brandts 11,  Renato V Iozzo 12,  Malgorzata Wygrecka 13,  Liliana Schaefer 14
Affiliations

Affiliations

  • 1 Pharmazentrum Frankfurt/ZAFES, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der JW Goethe-Universität Frankfurt am Main, Frankfurt, Germany.
  • 2 Pharmazentrum Frankfurt/ZAFES, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der JW Goethe-Universität Frankfurt am Main, Frankfurt, Germany; National Institute for Chemical-Pharmaceutical Research and Development, Bucharest, Romania.
  • 3 Institut für Biochemie II, Klinikum der JW Goethe-Universität Frankfurt am Main, Frankfurt, Germany.
  • 4 Electron Microscopy Facility, RWTH Aachen University Hospital, Aachen, Germany; Institute of Pathology & Department of Nephrology, RWTH Aachen University Hospital, Aachen, Germany.
  • 5 Institute for Cardiovascular Physiology, JW Goethe-Universität Frankfurt am Main, Frankfurt, Germany.
  • 6 Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, JW Goethe-Universität Frankfurt am Main, Frankfurt, Germany; German Centre of Cardiovascular Research (DZHK), Rhein-Main, Germany.
  • 7 Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany.
  • 8 Institute of Pathology & Department of Nephrology, RWTH Aachen University Hospital, Aachen, Germany.
  • 9 Physical Biology/Physikalische Biologie (IZN, FB 15), Buchmann Institute for Molecular Life Sciences (BMLS), Cluster of Excellence Frankfurt - Macromolecular Complexes (CEF-MC), JW Goethe-Universität Frankfurt am Main, Frankfurt, Germany.
  • 10 Institute of Biochemistry II, Goethe University Medical School, Frankfurt, Germany.
  • 11 Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany.
  • 12 Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
  • 13 Department of Biochemistry, Faculty of Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany.
  • 14 Pharmazentrum Frankfurt/ZAFES, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der JW Goethe-Universität Frankfurt am Main, Frankfurt, Germany. Electronic address: Schaefer@med.uni-frankfurt.de.
PMID: 30712922 DOI: 10.1016/j.kint.2018.10.037
Abstract

Biglycan, a small leucine-rich proteoglycan, acts as a danger signal and is classically thought to promote macrophage recruitment via Toll-like receptors (TLR) 2 and 4. We have recently shown that biglycan signaling through TLR 2/4 and the CD14 co-receptor regulates inflammation, suggesting that TLR co-receptors may determine whether biglycan-TLR signaling is pro- or anti-inflammatory. Here, we sought to identify other co-receptors and characterize their impact on biglycan-TLR signaling. We found a marked increase in the number of autophagic macrophages in mice stably overexpressing soluble biglycan. In vitro, stimulation of murine macrophages with biglycan triggered autophagosome formation and enhanced the flux of Autophagy markers. Soluble biglycan also promoted Autophagy in human peripheral blood macrophages. Using macrophages from mice lacking TLR2 and/or TLR4, CD14, or CD44, we demonstrated that the pro-autophagy signal required TLR4 interaction with CD44, a receptor involved in adhesion, migration, lymphocyte activation, and angiogenesis. In vivo, transient overexpression of circulating biglycan at the onset of renal ischemia/reperfusion injury (IRI) enhanced M1 macrophage recruitment into the kidneys of Cd44+/+ and Cd44-/- mice but not CD14-/- mice. The biglycan-CD44 interaction increased M1 Autophagy and the number of renal M2 macrophages and reduced tubular damage following IRI. Thus, CD44 is a novel signaling co-receptor for biglycan, an interaction that is required for TLR4-CD44-dependent pro-autophagic activity in macrophages. Interfering with the interaction between biglycan and specific TLR co-receptors could represent a promising therapeutic intervention to curtail kidney inflammation and damage.

Keywords

DAMP; M2 polarization; Toll-like receptor; inflammation; ischemia/reperfusion injury.

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