Hyaluronan as an immune regulator in human diseases

Abstract

Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on various cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage from the environment by interacting with TLR2 and TLR4. Hyaluronan and hyaluronan-binding proteins regulate inflammation, tissue injury, and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration. This review focuses on the role of hyaluronan as an immune regulator in human diseases.

Figure 1. Hyaluronan structure

Hyaluronan is composed of repeating polymeric disaccharides D-glucuronic acid (GlcA) and N-acetyl-D-glucosamine (GlcNAc) linked by a glucuronidic β(1→3) bond. Three disaccharide GlcA-GlcNAc are shown.

Figure 2. HA synthase reaction

Hyaluronan synthase catalyzes the reaction by adding N-acetyl-D-glucosamine (GlcNAc) and D-glucuronic acid (GlcA) alternatively to expand HA chain.

Figure 3. HAS2-deficient mice

Disruption of hyaluronan synthase 2 resulted in the defect in heart formation. Representative wild-type (A) and Has2^−/− (B) embryos at E9.5. Note the diminished size, the bloodless heart, and distorted somites of the Has2^−/− embryo. E9.5 wild-type (C) and Has2^−/− (D) embryos stained for the endothelial marker PECAM. Note the absence of an organized vascular network expressing PECAM in the Has2^−/− embryo. P, pericardium; E, endoderm; M, mesoderm; OpP, optic placode; OtP, otic placode; first and secondpharyngeal pouches are numbered. From Camenisch et al., J. Clin. Invest. 106:349–360 (2000), with permission.

FIGURE 4. HA FRAGMENT

Purified HA fragments but not HMW-HAinduced NF-KB DNA binding activity in MH-S cells. (A) Densitometric scanning demonstrating the molecular weights of HMW-HA (top), and purified HA fragments (bottom). (B) Electrophoretic mobility shift assay of nuclear extracts prepared from MH-S cell stimulated for 2 h with either serum-free media (unstim), HMW-HA, HA-fragment, or LPS. HA fragments induced NF-KB DNA binding activity. From Noble et al., J. Exp. Med. 183:2373–2378 (1996), with permission.

FIGURE 5. CD44 NULL HA STAINING

Accumulation of HA after bleomycin treatment. Lung tissue stained for HA at day10 through 14. Wild-type (A) and CD44-deficient mice (B). From Teder et al., Science 296, 155 (2002), with permission.

FIGURE 6. HA FRAGMENT ACCUMULATION IN CD44 MICE

Accumulation of HA after bleomycin treatment. (A) HA content was measured by an HA-specific enzyme-linked immunosorbent assay in lungs of wild-type (open square) and CD44-deficient mice (closed square). (B) HA MW at day 7 in lungs of saline-treatedwild-type mouse (top panel, MWaverage 1.443106), bleomycin-treated wild-type mouse (middle panel, MW average 0.54 3 106), and bleomycin-treatedCD44-de?cient mouse (bottom panel, MW averagesfrom left to right 2.10 3 106, 1.41 3 106, 0.16 3 106, and,0.02 3 106). From Teder et al., Science 296, 155 (2002), with permission.

FIGURE 7. CD44 AND HA SIGNALING

HA signaling is independent on the presence of CD44. Chemokine CXCL2 expression by peritoneal macrophages was not affected by the deficiency of CD44. From Jiang et al., Nat Med, 11:1173 (2005), with permission.

FIGURE 8. TLR AND HA SIGNALING

HA signaling is independent on the presence of CD44. Chemokine CXCL2 expression by peritoneal macrophages was not affected by the deficiency of CD44. From Jiang et al., Nat Med, 11:1173 (2005), with permission.

Figure 9. TLR and lung injury

TLR2 and TLR4 double deficient mice were more susceptible (A), while mice overexpressing HAS2 on epithelial cells were more resistant, to bleomycin induced lung injury (B).

Figure 10. TLR, HA, and NF-kB

TLR2 and TLR4 double deficient mice displayed lower basal NK-kB activity (A). The epithelial cells from TLR2−/− TLR4−/− mice expressed reduced cell surface HA (B).

Figure 11. Analogous signaling of HA and LPS

Analogous signaling of HA and LPS. LPS uses TLR4, CD14 and MD2 to transduce its signal, while HA interacts with TLR4, CD44 and MD2 to elicit its signaling.