The High and Low Molecular Weight Forms of Hyaluronan Have Distinct Effects on CD44 Clustering

Yang, Chao; Cao, Manlin; Liu, Hua; He, Yiqing; Xu, Jing; Du, Yan; Liu, Yiwen; Wang, Wenjuan; Cui, Lian; Hu, Jiajie; Gao, Feng

doi:10.1074/jbc.m112.349209

Cited by 256 publications

(180 citation statements)

References 63 publications

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“…Clinically, we suggest using HA as a topical vaginal treatment rather than a bladder treatment, hence we predict that any flushing effects would be reduced. One method by which UPEC has been reported to infect the murine urinary tract is through attaching to CD44 receptors44 that also bind HA 45. Although receptor masking by HMW HA may have functioned in reducing UPEC infection in vivo , specific localisation of UPEC to the epithelial tight junctions was less supportive of such a mechanism operating in the human urothelial cell model.…”

Section: Discussionmentioning

confidence: 99%

“…It cannot be excluded, however, that these data were prejudiced by the signalling activities of receptors persisting following incomplete gene knockdown. HMW HA treatment is not only associated with receptor binding but also receptor clustering that functions, potentially, to stabilise cell membrane transporters and/or receptors 45. Hence, if activated urothelial TLR5 and CD44 receptors cluster similarly in response to flagellin and HA, then the outcome supports signal amplification through either better retention of their respective ligands or increased rebinding.…”

Section: Discussionmentioning

confidence: 99%

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High molecular weight hyaluronic acid: a two‐pronged protectant against infection of the urogenital tract?

et al. 2018

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ObjectivesRecurrent urinary tract infections are associated with uropathogenic Escherichia coli (UPEC) ascending and infecting the urinary tract. Antibiotics provide only symptomatic relief, not prevent recurrence. Clinical evidence suggests that intravesical glycosaminoglycan therapy, such as hyaluronic acid (HA), helps reduce UTI recurrence. This has been investigated here using in vitro systems modelling the urogenital tract tissues.Methods RT4 bladder cells were preconditioned with high molecular weight HA (> 1500 kDa) at 2 mg mL−1 and challenged with UPEC to analyse barrier protection and bacterial adherence. Untreated and HA‐preconditioned VK2 E6/E7 vaginal cells were challenged with E. coli flagellin (50 ng mL−1) to mimic bacterial challenge, and media analysed for lipocalin‐2, human β‐defensin 2 and interleukin‐8 by ELISA. Experiments were repeated after siRNA knockdown of Toll‐like receptors 2, 4 and 5, and CD44 to investigate signalling.ResultsMicroscopic analyses showed reduced bacterial adherence and urothelial disruption with HA, suggesting that HA functions as a barrier protecting the epithelium from bacterial infection. Cells treated with HA and flagellin simultaneously produced more of the host antimicrobial peptide LCN2 and pro‐inflammatory IL‐8 (P < 0.05) compared to the no HA/flagellin challenges. Increased gene expression of DEFB4 (P < 0.05), but not the hBD2 peptide, was observed in the HA/flagellin‐challenged cells.ConclusionThese data suggest that exogenous HA has potential to protect the urogenital epithelia from UPEC infection via a two‐pronged approach that involves the physical enhancement of the epithelial barrier and augmentation of its innate immune response.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

High molecular weight hyaluronic acid: a two‐pronged protectant against infection of the urogenital tract?

et al. 2018

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“…Under conditions of inflammation, HMM HA is broken down into LMM HA, which exhibits multiple pro-inflammatory effects on cells and tissues [13, 18, 26]. HMM HA is broken down into LMM HA by the combined actions of hyaluronidases and reactive oxygen species (ROS) that are produced by inflammatory cells [35].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that LMM HA exhibits pronounced biological effects on cells and in tissues [13, 18]. Most importantly, LMM HA has multiple pro-inflammatory effects not observed for HMM HA [15, 26]. In fact, HMM HA can block the pro-inflammatory effects of LMM HA and help support tissue integrity [13, 26].…”

Section: Introductionmentioning

confidence: 99%

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Hyaluronan deposition and co-localization with inflammatory cells and collagen in a murine model of fungal allergic asthma

et al. 2014

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Objective Allergic asthma is a chronic inflammatory disease of the airways characterized by excessive inflammation and remodeling of the extracellular matrix (ECM) and associated cells of the airway wall. Under inflammatory conditions, hyaluronan (HA), a major component of the ECM, undergoes dynamic changes, which may in turn affect the recruitment and activation of inflammatory cells leading to acute and chronic immunopathology of allergic asthma. Methods In the present study, we measured the changes in HA levels generated at sites of inflammation and examined its effect on inflammatory responses and collagen deposition in an Aspergillus fumigatus murine inhalational model of allergic asthma. Results We found that HA levels are elevated in allergic animals and that the increase correlated with the influx of inflammatory cells 5 days after the second allergen challenge. This increase in HA levels appeared largely due to up regulation of hyaluronidase-1 (HYAL1) and hyaluronidase-2 (HYAL2). Furthermore, HA co-localizes with areas of new collagen synthesis and deposition. Conclusions Overall our findings contribute to the growing literature that focuses on the components of ECM as inflammatory mediators rather than mere structural support products. The evidence of HA localization in fungal allergic asthma provides the impetus to study HA more closely with allergic leukocytes in murine models. Further studies examining HA’s role in mediating cellular responses may help to develop targets for treatment in patients with severe asthma due to fungal sensitization.

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Hyaluronic acid metabolism and chemotherapy resistance: recent advances and therapeutic potential

Liu,

Hou,

Fang

et al. 2024

Molecular Oncology

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Hyaluronic acid (HA) is a major component of the extracellular matrix, providing essential mechanical scaffolding for cells and, at the same time, mediating essential biochemical signals required for tissue homeostasis. Many solid tumors are characterized by dysregulated HA metabolism, resulting in increased HA levels in cancer tissue. HA interacts with several cell surface receptors, such as CD44 and RHAMM, thus co‐regulating important signaling pathways in cancer development and progression. In this review, we describe the enzymes controlling HA metabolism and its intracellular effectors emphasizing their impact in cancer chemotherapy resistance. We will also explore the current and future prospects of HA‐based therapy, highlighting the opportunities and challenges in the field.

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The High and Low Molecular Weight Forms of Hyaluronan Have Distinct Effects on CD44 Clustering

Cited by 256 publications

References 63 publications

High molecular weight hyaluronic acid: a two‐pronged protectant against infection of the urogenital tract?

High molecular weight hyaluronic acid: a two‐pronged protectant against infection of the urogenital tract?

Hyaluronan deposition and co-localization with inflammatory cells and collagen in a murine model of fungal allergic asthma

Hyaluronic acid metabolism and chemotherapy resistance: recent advances and therapeutic potential

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