Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011 Jan;91(1):221-64.
doi: 10.1152/physrev.00052.2009.

Hyaluronan as an immune regulator in human diseases

Dianhua Jiang  1 , Jiurong Liang, Paul W Noble
Affiliations
Review

Hyaluronan as an immune regulator in human diseases

Dianhua Jiang et al. Physiol Rev. 2011 Jan.

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.

PubMed Disclaimer

Figures

Figure 1
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
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
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
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
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
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
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
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
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
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
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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Acharya PS, Majumdar S, Jacob M, Hayden J, Mrass P, Weninger W, Assoian RK, Pure E. Fibroblast migration is mediated by CD44-dependent TGF beta activation. J Cell Sci. 2008;121:1393–1402. - PubMed
    1. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature. 2000;406:782–787. - PubMed
    1. Agren UM, Tammi RH, Tammi MI. Reactive oxygen species contribute to epidermal hyaluronan catabolism in human skin organ culture. Free Radic Biol Med. 1997;23:996–1001. - PubMed
    1. Akishima Y, Ito K, Zhang L, Ishikawa Y, Orikasa H, Kiguchi H, Akasaka Y, Komiyama K, Ishii T. Immunohistochemical detection of human small lymphatic vessels under normal and pathological conditions using the LYVE-1 antibody. Virchows Arch. 2004;444:153–157. - PubMed
    1. Al Qteishat A, Gaffney JJ, Krupinski J, Slevin M. Hyaluronan expression following middle cerebral artery occlusion in the rat. Neuroreport. 2006;17:1111–1114. - PubMed

Publication types

-