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. Epub 2019 Jan 31.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / immunology*
  • Acute Kidney Injury / pathology
  • Animals
  • Autophagosomes / immunology
  • Autophagosomes / metabolism
  • Autophagy / immunology
  • Biglycan / genetics
  • Biglycan / immunology
  • Biglycan / metabolism*
  • Cells, Cultured
  • Disease Models, Animal
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / immunology
  • Hyaluronan Receptors / metabolism*
  • Kidney Tubules / blood supply
  • Kidney Tubules / immunology
  • Kidney Tubules / pathology
  • Macrophage Activation
  • Macrophages / immunology*
  • Mice
  • Mice, Knockout
  • Primary Cell Culture
  • Reperfusion Injury / immunology*
  • Reperfusion Injury / pathology
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism


  • BGN protein, human
  • Bgn protein, mouse
  • Biglycan
  • CD44 protein, human
  • Cd44 protein, mouse
  • Hyaluronan Receptors
  • Toll-Like Receptor 4