Hyaluronan is not a ligand but a regulator of toll-like receptor signaling in
mesangial cells: role of extracellular matrix in innate immunity
#MMPMID24967246
Ebid R
; Lichtnekert J
; Anders HJ
ISRN Nephrol
2014[]; 2014
(?): 714081
PMID24967246
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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? ? g/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.
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