Hyaluronan and its function as an unspecific regulator of cell-bound receptors.

In a former study on primary mesangial cells a regulatory function of hyaluronan (HA) was shown. HA is the backbone of a cell-bound jelly-barrier. The thickness of that cell-bound jelly-barrier regulates the access of ligands to their cellular receptors in an unspecific way. The thickness of that barrier is reduced by degradation of HA. The hypothesis was that this regulatory mechanism is not restricted to mesangial cells, but applies for other cell types as well. A selective and topic oriented review of the literature was performed to collect references, which support the impression, that this unspecific mechanism of receptor-regulation by HA is not restricted to primary mesangial cells. On the basis of the data from the review of the literature it was concluded that the regulatory mechanism of HA also applies for other than mesangial cells. On the basis of the said mechanism it was concluded that a tissue-specific regulation of HA on the cell surface might be relevant in therapy, especially in chronic diseases.

Hyaluronan is not a ligand but a regulator of toll-like receptor signaling in mesangial cells: role of extracellular matrix in innate immunity.

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 µ 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.

The danger control concept in kidney disease: mesangial cells.

Kidney remodeling is a response to intrinsic or extrinsic triggers of kidney injury. Injury initiates a set of universal response programs that were positively selected through evolution to control potentially life-threatening dangers and to regain homeostasis, including tissue repair. These danger control programs are (i) clotting, to control the risk of bleeding; (ii) inflammation, to control the risk of infection; (iii) epithelial repair; (iv) mesenchymal repair; and (v) scar resolution or minimization. In this review we focus on the role of mesangial cells in glomerular disorders and how their behaviors follow these danger control programs. We review the role of mesangial cells in glomerular coagulation and fibrinolysis, as well as their role in triggering glomerular inflammation and mesangioproliferative disorders. Furthermore, we discuss how the mesangium self-repairs, how podocyte injury triggers a "mesenchymal healing"-kind of response that leads to glomerular fibrosis and sclerosis. Thus, we can better appreciate the contribution of mesangial cells to glomerular pathology when we understand their behavior as an attempt to support the evolutionally conserved universal danger control programs. However, these mechanisms often result in maladaptive processes that destroy the complex glomerular ultrastructure rather than help to regain tissue homeostasis.