Hyaluronan cross-linking: a protective mechanism in inflammation?

doi:10.1016/j.it.2005.09.009

Trends in Immunology

Volume 26, Issue 12, December 2005, Pages 637-643

https://doi.org/10.1016/j.it.2005.09.009 Get rights and content

Production of the glycosaminoglycan hyaluronan is increased at sites of inflammation, often correlating with the accumulation of leukocytes. Mounting evidence suggests that this polysaccharide can be organized into a wide variety of molecular architectures by its association with specific binding proteins, leading to the formation of fibrils and cable-like structures involving a large number of hyaluronan chains. We propose that hyaluronan cross-linking is part of a protective mechanism, promoting adhesion of leukocytes to the hyaluronan complexes rather than enabling contact with inflammation-promoting receptors on the underlying tissues. Leukocytes are thus maintained in a non-activated state by appropriate receptor clustering or receptor co-engagement. Additionally, hyaluronan networks might serve as scaffolds to prevent the loss of extracellular matrix components during inflammation and to sequester proinflammatory mediators.

Section snippets

Hyaluronan–protein complexes: new forms and functions

Hyaluronan (HA) is an ubiquitous polysaccharide with diverse biological roles, including acting as a crucial structural component of extracellular matrix and as an important mediator of leukocyte adhesion and migration 1, 2. Recently, the concept has emerged that the function of HA is dictated by the particular proteins associated with it (Box 1), where HA probably represents a versatile scaffold that can be used to build a variety of complex structures 3, 4. However, the full range of possible

HA cross-linking in ovulation

Much of what we know regarding the mechanisms of HA cross-linking comes from recent studies on cumulus matrix expansion, which is necessary for successful ovulation and fertilization; ovulation has many things in common with inflammation and can be described as an inflammation-like process [11]. In the pre-ovulatory follicle a large, HA-rich, viscoelastic matrix forms rapidly around the oocyte, giving it protection during ovulation and facilitating sperm capture in vivo. Four proteins, namely

Formation and structure of HA cables

HA cable-like structures were first identified emanating from cultured mucosal smooth muscle cells (M-SMCs) following stimulation with poly I:C, a viral mimic 7, 30. It is now known that they are also made by a wide variety of cells as a response to ER stress (e.g. colonic and aortic SMCs, lung mesenchymal cells and dermal fibroblasts [8]) and by proliferating renal mesangial cells exposed to high concentrations of glucose [31]. As shown in Figure 2a, an individual cable, which can be greater

Concluding remarks

Over recent years a diverse range of cross-linked HA structures have been identified that appear to have a key role in inflammation. Although it is well-established that leukocytes can bind to HA, the purpose of this interaction has been unclear. Previous literature supported a proinflammatory role for HA but here we suggest a protective or ‘counter-inflammatory’ role for the highly cross-linked HA structures. The two notions are not necessarily exclusive. We are now beginning to appreciate

Acknowledgements

We are indebted to Caroline Milner for her critical review of the manuscript and to the Arthritis Research Campaign (grants 16119 and 16539; A.J.D.) and the National Institute of Health (DK58867 and DK57756; C.d.l.M.) for their support for our research.

References (48)

M. Tammi
Hyaluronan and homeostasis: a balancing act
J. Biol. Chem.
(2002)
E. Puré et al.
A crucial role for CD44 in inflammation
Trends Mol. Med.
(2001)
A.J. Day et al.
Hyaluronan: polysaccharide chaos to protein organisation
Curr. Opin. Struct. Biol.
(2001)
C.D. Blundell
Structural and functional diversity of hyaluronan-binding proteins
L. Zhuo
Inter-α-trypsin inhibitor, a covalent protein-glycosaminoglycan-protein complex
J. Biol. Chem.
(2004)
C.A. de la Motte
Mononuclear leukocytes bind to specific hyaluronan structures on colon mucosal smooth muscle cells treated with polyinosinic acid:polycytidylic acid: Inter-α-trypsin inhibitor is crucial to structure and function
Am. J. Pathol.
(2003)
A.K. Majors
Endoplasmic reticulum stress induces hyaluronan deposition and leukocyte adhesion
J. Biol. Chem.
(2003)
V.C. Hascall
Intracellular hyaluronan: a new frontier for inflammation?
Biochim. Biophys. Acta
(2004)
J. Lesley
TSG-6 modulates the interaction between hyaluronan and cell surface CD44
J. Biol. Chem.
(2004)
L. Zhuo
Defect in SHAP-hyaluronan complex causes severe female infertility
J. Biol. Chem.
(2001)

D. Mukhopadhyay

Specificity of the tumor necrosis factor-induced protein 6-mediated heavy chain transfer from the inter-α-inhibitor to hyaluronan. Implications for the assembly of the cumulus extracellular matrix

J. Biol. Chem.

(2004)

K.W. Sanggaard

The TSG-6 and IαI interaction promotes a transesterification cleaving the protein-glycosaminoglycan-protein (PGP) cross-link

J. Biol. Chem.

(2005)

M.S. Rugg

Characterization of complexes formed between TSG-6 and inter-α-inhibitor that act as intermediates in the covalent transfer of heavy chains onto hyaluronan

J. Biol. Chem.

(2005)

S.A. Kuznetsova

The N-terminal module of thrombospondin-1 interacts with the Link domain of TSG-6 and enhances its covalent association with the heavy chains of inter-α-trypsin inhibitor

J. Biol. Chem.

(2005)

H.G. Wisniewski et al.

Cytokine-induced gene expression at the crossroads of innate immunity, inflammation and fertility: TSG-6 and PTX3/TSG-14

Cytokine Growth Factor Rev.

(2004)

W. Yingsung

Molecular heterogeneity of the SHAP-hyaluronan complex: isolation and characterization of the complex in synovial fluid from patients with rheumatoid arthritis

J. Biol. Chem.

(2003)

M.T. Bayliss

Up-regulation and differential expression of the hyaluronan-binding protein TSG-6 in cartilage and synovium in rheumatoid arthritis and osteoarthritis

Osteoarthritis Cartilage

(2001)

D.J. Mahoney

Characterization of the interaction between tumor necrosis factor-stimulated gene-6 and heparin; implications for the inhibition of plasmin in extracelluar matrix microenvironments

J. Biol. Chem.

(2005)

C.A. de la Motte

Poly I:C induces mononuclear leukocyte-adhesive hyaluronan structures on colon smooth muscle cells: IαI and versican facilitate adhesion

A. Wang et al.

Hyaluronan structures synthesized by rat mesangial cells in response to hyperglycemia induce monocyte adhesion

J. Biol. Chem.

(2004)

X.L. Zhang

Renal proximal tubular epithelial cell transforming growth factor-β1 generation and monocyte binding

Am. J. Pathol.

(2004)

C.A. de la Motte

Mononuclear leukocytes preferentially bind via CD44 to hyaluronan on human intestinal mucosal smooth muscle cells after virus infection or treatment with poly I:C

J. Biol. Chem.

(1999)

P. Teriete

Structure of the regulatory hyaluronan-binding domain in the inflammatory leukocyte homing receptor CD44

Mol. Cell

(2004)

K.R. Taylor

Hyaluronan fragments stimulate endothelial recognition of injury through TLR4

J. Biol. Chem.

(2004)

Cited by (293)

Berberine alleviates inflammation in polycystic ovary syndrome by inhibiting hyaluronan synthase 2 expression
2024, Phytomedicine
Polycystic ovary syndrome (PCOS) is a heterogeneous metabolic and endocrine disorder that causes anovulatory infertility and abnormal folliculogenesis in women of reproductive age. Several studies have revealed inflammation in PCOS follicles, and recent evidence suggests that Berberine (BBR) effectively reduces inflammatory responses in PCOS, however, the underlying mechanisms remain unclear.
To determine the underlying mechanisms by which BBR alleviates inflammation in PCOS.
Primary human GCs from healthy women and women with PCOS, and KGN cells were used for in vitro studies. ICR mice were used for in vivo studies.
Gene expression was measured using RT-qPCR. HAS2, inflammatory cytokines, and serum hormones were assayed by ELISA. Protein expression profiles were assayed by Western blot. Chronic low-grade inflammatory mouse models were developed by intraperitoneal injection with LPS, and PCOS mouse models were established by subcutaneous intraperitoneal injection of DHEA. BBR and 4-MU were administered by gavage. Ovarian morphologic changes were evaluated using H&E staining. HAS2 expression in the ovary was assayed using Western blot and immunohistochemistry.
Our results confirmed that HAS2 expression and hyaluronan (HA) accumulation are closely associated with inflammatory responses in PCOS. Data obtained from in vitro studies showed that HAS2 and inflammatory genes (e.g., MCP-1, IL-1β, and IL-6) are significantly upregulated in PCOS samples and LPS-induced KGN cells compared to their control groups. In addition, these effects were reversed by blocking HAS2 expression or HA synthesis using BBR or 4-MU, respectively. Furthermore, HAS2 overexpression induces the expression of inflammatory genes in PCOS. These results were further confirmed in LPS- and DHEA-induced mouse models, where inflammatory genes were reduced by BBR or 4-MU, and ovarian morphology was restored.
Our results define previously unknown links between HAS2 and chronic low-grade inflammation in the follicles of women with PCOS. BBR exerts its anti-inflammatory effects by down-regulating HAS2. This study provides a novel therapeutic target for alleviating ovarian inflammation in women with PCOS.
A highly stretchable, adhesive, anti-freezing hydrogel with prominent antibacterial property rapidly prepared by photopolymerization for wound dressing
2024, Colloids and Surfaces A: Physicochemical and Engineering Aspects
Hydrogels have been widely used in the biomedical field. Wound healing is a complex process, and improper handling can lead to inflammation, damage to health and increase pain. Moreover, wounds in joints are difficult to protect. Here, a stretchable, adhesion, anti-freezing and antibacterial hydrogel (ATSHQ) for wound healing is facilely prepared by photopolymerization under green LED irradiation, with acrylamide (AM), N-[tris(hydroxymethyl)methyl] acrylamide (THMA) and sulfobetaine methacrylate (SBMA) as the skeleton, hyaluronic acid (HA) as wound healing accelerator, and quaternized chitosan (QCS) as antibacterial component. This hydrogel design has the advantage of being cross-linked without adding specific cross-linking agents that may increase toxicity. ATSHQ hydrogels present excellent mechanical properties (the maximum stress can reach 343 kPa), strong extensibility (the maximum strain can reach 1587%), adequate tissue adhesion, rapid self-healing, tough anti-freezing, and anti-dehydration. The balanced mechanical property and adhesion of the hydrogel allow for stable joint adhesion and easy removal without damage. Furthermore, the biocompatibility and antibacterial properties of ATSHQ hydrogels were confirmed.
Fabrication and evaluation of a dual-targeting nanoparticle mediated CRISPR/Cas9 delivery to combat drug resistance in breast cancer cells
2023, Journal of Drug Delivery Science and Technology
Breast cancer treatment is hampered by drug resistance which leads to recurrence and metastasis. Alteration of specific gene expression such as ERCC1 evidently acquires drug resistance in breast cancer patients. The genome-editing technique known as the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated Cas9 system (CRISPR-Cas9) has shown promise in targeting genes. The current study aimed to design and characterize an efficient cargo through a safe and noninvasive dual-targeted polyplex for CRISPR/Cas9 delivery to downregulate the ERCC1 gene expression, which is overexpressed in MCF-7 cisplatin-resistant cells. In this manner, a carrier based on chitosan (CS) polyplex was modified with hyaluronic acid conjugated triptorelin (HA-LHRH) as dual-targeting agents and loaded with CRISPR/Cas9 plasmids. CS/HA-LHRH/pCRISPR exhibited negligible toxicity and comparable transfection efficiency with Lipofectamine™ 3000. Dual-targeted polyplexes have boosted gene transfer by nearly two times that of single-targeted polyplexes (CS/HA/pCRISPR). Also, the dual-targeted polyplexes carrying plasmids of CRISPR/Cas9 enhanced drug sensitivity and decreased ERCC1 mRNA levels in MCF-7 cisplatin-resistant cell line, significantly. Our results suggest that CS/HA-LHRH/pCRISPR-mediated targeting of ERCC1 is practicable and could be potentially adopted as a novel therapeutic tool for removing platinum drug resistance in breast cancer cells.
Monocyte adhesive hyaluronan matrix induced by hyperglycemia in diabetic lung injuries
2023, Journal of Biological Chemistry
Infiltrated pre-inflammatory monocytes and macrophages have important roles in the induction of diabetic lung injuries, but the mechanism mediating their infiltration is still unclear. Here, we showed that airway smooth muscle cells (SMCs) activated monocyte adhesion in response to hyperglycemic glucose (25.6 mM) by significantly increasing hyaluronan (HA) in the cell matrix, with concurrent 2- to 4-fold increases in adhesion of U937 monocytic-leukemic cells. The HA-based structures were attributed directly to the high-glucose and not to increased extracellular osmolality, and they required growth stimulation of SMCs by serum. Treatment of SMCs with heparin in high-glucose induces synthesis of a much larger HA matrix, consistent with our observations in the glomerular SMCs. Further, we observed increases in tumor necrosis factor-stimulated gene-6 (TSG-6) expression in high-glucose and high-glucose plus heparin cultures, and the heavy chain (HC)-modified HA structures existed on the monocyte-adhesive cable structures in high-glucose and in high-glucose plus heparin-treated SMC cultures. Interestingly, these HC-modified HA structures were unevenly distributed along the HA cables. Further, the in vitro assay with recombinant human TSG-6 and the HA14 oligo showed that heparin has no inhibitory activity on the TSG-6-induced HC-transfer to HA, consistent with the results from SMC cultures. These results support the hypothesis that hyperglycemia in airway smooth muscle induces the synthesis of a HA matrix that recruits inflammatory cells and establishes a chronic inflammatory process and fibrosis that lead to diabetic lung injuries.
TSG6 hyaluronan matrix remodeling dampens the inflammatory response during colitis
2023, Matrix Biology
In response to tissue injury, changes in the extracellular matrix (ECM) can directly affect the inflammatory response and contribute to disease progression or resolution. During inflammation, the glycosaminoglycan hyaluronan (HA) becomes modified by tumor necrosis factor stimulated gene-6 (TSG6). TSG6 covalently transfers heavy chain (HC) proteins from inter-α-trypsin inhibitor (IαI) to HA in a transesterification reaction and is to date is the only known HC-transferase. By modifying the HA matrix, TSG6 generates HC:HA complexes that are implicated in mediating both protective and pathological responses. Inflammatory bowel disease (IBD) is a lifelong chronic disorder with well-described remodeling of the ECM and increased mononuclear leukocyte influx into the intestinal mucosa. Deposition of HC:HA matrices is an early event in inflamed gut tissue that precedes and promotes leukocyte infiltration. However, the mechanisms by which TSG6 contributes to intestinal inflammation are not well understood. The aim of our study was to understand how the TSG6 and its enzymatic activity contributes to the inflammatory response in colitis. Our findings indicate that inflamed tissues of IBD patients show an elevated level of TSG6 and increased HC deposition and that levels of HA strongly associate with TSG6 levels in patient colon tissue specimens. Additionally, we observed that mice lacking TSG6 are more vulnerable to acute colitis and exhibit an aggravated macrophage-associated mucosal immune response characterized by elevated pro-inflammatory cytokines and chemokines and diminished anti-inflammatory mediators including IL-10. Surprisingly, along with significantly increased levels of inflammation in the absence of TSG6, tissue HA levels in mice were found to be significantly reduced and disorganized, absent of typical “HA-cable” structures. Inhibition of TSG6 HC-transferase activity leads to a loss of cell surface HA and leukocyte adhesion, indicating that the enzymatic functions of TSG6 are a major contributor to stability of the HA ECM during inflammation. Finally, using biochemically generated HC:HA matrices derived by TSG6, we show that HC:HA complexes can attenuate the inflammatory response of activated monocytes. In conclusion, our data suggests that TSG6 exerts a tissue-protective, anti-inflammatory effect via the generation of HC:HA complexes that become dysregulated in IBD.
Hyaluronic acid-based multifunctional carriers for applications in regenerative medicine: A review
2023, International Journal of Biological Macromolecules
Hyaluronic acid (HA) is an important type of naturally derived carbohydrate polymer with specific polysaccharide macromolecular structures and multifaceted biological functions, including biocompatibility, low immunogenicity, biodegradability, and bioactivity. Specifically, HA hydrogels in a microscopic scale have been widely used for biomedical applications, such as drug delivery, tissue engineering, and medical cosmetology, considering their superior properties outperforming the more conventional monolithic hydrogels in network homogeneity, degradation profile, permeability, and injectability. Herein, we reviewed the recent progress in the preparation and applications of HA microgels in biomedical fields. We first summarized the fabrication of HA microgels by focusing on the different crosslinking/polymerization schemes for HA gelation and the miniaturized fabrication techniques for producing HA-based microparticles. We then highlighted the use of HA-based microgels for different applications in regenerative medicine, including cartilage repair, bioactive delivery, diagnostic imaging, modular tissue engineering. Finally, we discussed the challenges and future perspectives in bridging the translational gap in the utilization of HA-based microgels in regenerative medicine.

View all citing articles on Scopus

View full text

Trends in Immunology

Hyaluronan cross-linking: a protective mechanism in inflammation?

Section snippets

Hyaluronan–protein complexes: new forms and functions

HA cross-linking in ovulation

Formation and structure of HA cables

Concluding remarks

Acknowledgements

J. Biol. Chem.

Trends Mol. Med.

Curr. Opin. Struct. Biol.

J. Biol. Chem.

Am. J. Pathol.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cytokine Growth Factor Rev.

J. Biol. Chem.

Osteoarthritis Cartilage

J. Biol. Chem.

J. Biol. Chem.

Am. J. Pathol.

J. Biol. Chem.

Mol. Cell

J. Biol. Chem.