Table of Contents
ISRN Nephrology
Volume 2014, Article ID 714081, 11 pages
Research Article

Hyaluronan Is Not a Ligand but a Regulator of Toll-Like Receptor Signaling in Mesangial Cells: Role of Extracellular Matrix in Innate Immunity

Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV der LMU, Pettenkoferstr. 8a, 80336 Munich, Germany

Received 28 September 2013; Accepted 30 October 2013; Published 21 January 2014

Academic Editors: T. Doi, T. D. Hewitson, and M. Merta

Copyright © 2014 Rainer Ebid et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Glomerular mesangial cells (MC), like most cell types secrete hyaluronan (HA), which attached to the cell surface via CD44, is the backbone of a hydrophilic gel matrix around these cells. Reduced extracellular matrix thickness and viscosity result from HA cleavage during inflammation. HA fragments were reported to trigger innate immunity via Toll-like receptor-(TLR-) 2 and/or TLR4 in immune cells. We questioned whether HA fragments also regulate the immunostimulatory capacity of smooth muscle cell-like MC. LPS (TLR4-ligand) and PAM3CysSK4 (TLR2-ligand) induced IL-6 secretion in MC; highly purified endotoxin-free HA 3000 Da up to 50 μg/mL did not. Bovine-testis-hyaluronidase from was used to digest MC-HA into HA fragments of different size directly in the cell culture. Resultant HA fragments did not activate TLR4-deficient MC, while TLR2-deficient MC responded to LPS-contamination of hyaluronidase, not to produced HA fragments. Hyaluronidase increased the stimulatory effect of TLR2-/-3/-5 ligands on their TLR-receptors in TLR4-deficient MC, excluding any effect by LPS-contamination. Supplemented heparin suppressed every stimulatory effect in a dose-dependent manner. We conclude that the glycosaminoglycan HA creates a pericellular jelly barrier, which covers surface receptors like the TLRs. Barrier-thickness and viscosity balanced by HA-synthesis and degradation and the amount of HA-receptors on the cell surface regulate innate immunity via the accessibility of the receptors.