Low molecular weight hyaluronan mediated CD44 dependent induction of IL-6 and chemokines in human dermal fibroblasts potentiates innate immune response

Vištějnová, Lucie; Šafránková, Barbora; Nešporová, Kristina; Slavkovský, Rastislav; Hermannová, Martina; Hošek, Petr; Velebný, Vladimı́r; Kubala, Lukáš

doi:10.1016/j.cyto.2014.07.006

Cited by 58 publications

(38 citation statements)

References 23 publications

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“…Qualitatively, Western blotting confirmed these findings (see Sections S2.3 and S2.5, and Figure S1, Supporting Information): predominant expression of the CD44 standard isoform (CD44s; CD44pan bands at 85–90 kDa) in HDF, HUVEC, and THP‐1,36a,39 and that of high MW isoforms (CD44pan bands at 140–200 kDa) for HT‐29 and HCT‐116, with essentially the same order in CD44v6 expression (HCT‐116 ≫ HT‐29>PANC‐1; compare Figure B with Figure A left). Of note, the prevalent expression of CD44s in AsPC‐1 and PANC‐1, with small amounts of variants, is also confirmed by higher molecular weight/low intensity bands at longer exposure times (see Figure S1, Supporting Information).…”

Section: Resultssupporting

confidence: 62%

Binding and Internalization in Receptor‐Targeted Carriers: The Complex Role of CD44 in the Uptake of Hyaluronic Acid‐Based Nanoparticles (siRNA Delivery)

rosa

Pingrajai

Pelliccia

et al. 2019

Adv Healthcare Materials

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often, while we may have some mechanistic knowledge of how a delivery vehicle initially binds to such a group, we hardly know what happens during later phases. These phases, however, are equally critical for the efficacy of the treatment: for example, whether a nucleic acid-loaded particle remains on a cell surface or is transported intracellularly can make the difference between therapeutic success and failure. In short, the rational development of a targeted delivery approach should require the understanding of both surface binding and internalization processes, and the interplay between them.Here, we have focused on these points, using nanoparticles where hyaluronic acid (HA) acts as a targeting element and siRNA is the payload (i.e., the drug). Rather than for cell targeting, HA is better known as a major component of extracellular matrices, [1] and for its use as a matrix component in regenerative medicine, [2] as a dermal filler, [3] or a viscosupplementation agent. [4] However, besides its physical properties, HA is also capable of interacting with a number of biomolecules. [5] Most, but not all HA-binding proteins (also referred to as hyaladherins) share a homologous, HA-binding Link domain, whose CD44 is an endocytic hyaluronic acid (HA) receptor, and is overexpressed in many carcinomas. This has encouraged the use of HA to design CD44targeting carriers. This paper is about dissecting the mechanistic role of CD44. Here, HA-decorated nanoparticles are used to deliver siRNA to both tumoral (AsPC-1, PANC-1, HT-29, HCT-116) and non-tumoral (fibroblasts, differently polarized THP-1 macrophages, HUVEC) human cell lines, evaluating the initial binding of the nanoparticles, their internalization rate, and the silencing efficiency (cyclophilin B (PPIB) gene). Tumoral cells internalize faster and experience higher silencing than non-tumoral cells. This is promising as it suggests that, in a tumor, HA nanocarriers may have limited off-target effects. More far-reaching is the inter-relation between the four parameters of the study: CD44 expression, HA binding on cell surfaces, internalization rate, and silencing efficiency. No correlation is found between binding (an early event) and any of the other parameters, whereas silencing correlates both with speed of the internalization process and CD44 expression. This study confirms on one hand that HA-based carriers can perform a targeted action, but on the other it suggests that this may not be due to a selective binding event, but rather to a later recognition leading to selective internalization.

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Section: Resultssupporting

confidence: 62%

Binding and Internalization in Receptor‐Targeted Carriers: The Complex Role of CD44 in the Uptake of Hyaluronic Acid‐Based Nanoparticles (siRNA Delivery)

rosa

Pingrajai

Pelliccia

et al. 2019

Adv Healthcare Materials

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“…Nevertheless, low molecular weight HA seems to be involved in the inflammation process, inducing the production of cytokines and contributing to macrophage activation as well as angiogenesis [20], [21], [22]. Furthermore, high molecular weight HA was synthesized by HAS1 and HAS2, while HAS3 is involved in the synthesis of low molecular weight HA, and HA was degraded essentially by Hyl1 and Hyal2 [23], [24].…”

Section: Discussionmentioning

confidence: 99%

Extracellular matrix alterations in the Peyronie’s disease

Watanabe

Theodoro

Coelho

et al. 2017

Journal of Advanced Research

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“…However, as studies demonstrating a direct effect of HA on inflammation have relied on stimulating cells or animals with exogenous HA29303743454647, caution is needed, and efforts should be made to ensure that the effects are not due to picogram levels of endotoxin contamination, from either the HA source or from the HA’se used to generate the fragments. Endotoxin contaminated Huc HA tested in this study activated macrophages and DCs regardless of the HA binding ability of CD44 or CD44 expression, consistent with the ability of LPS to induce pro-inflammatory effects through Toll-like receptor 4 (TLR-4), which was also reported to be necessary for HA induced inflammation4348.…”

Section: Discussionmentioning

confidence: 99%

Endotoxin free hyaluronan and hyaluronan fragments do not stimulate TNF-α, interleukin-12 or upregulate co-stimulatory molecules in dendritic cells or macrophages

Dong

Arif

Olsson

et al. 2016

Sci Rep

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The extracellular matrix glycosaminoglycan, hyaluronan, has been described as a regulator of tissue inflammation, with hyaluronan fragments reported to stimulate innate immune cells. High molecular mass hyaluronan is normally present in tissues, but upon inflammation lower molecular mass fragments are generated. It is unclear if these hyaluronan fragments induce an inflammatory response or are a consequence of inflammation. In this study, mouse bone marrow derived macrophages and dendritic cells (DCs) were stimulated with various sizes of hyaluronan from different sources, fragmented hyaluronan, hyaluronidases and heavy chain modified-hyaluronan (HA-HC). Key pro-inflammatory molecules, tumour necrosis factor alpha, interleukin-1 beta, interleukin-12, CCL3, and the co-stimulatory molecules, CD40 and CD86 were measured. Only human umbilical cord hyaluronan, bovine testes and Streptomyces hyaluronlyticus hyaluronidase stimulated macrophages and DCs, however, these reagents were found to be contaminated with endotoxin, which was not fully removed by polymyxin B treatment. In contrast, pharmaceutical grade hyaluronan and hyaluronan fragments failed to stimulate in vitro-derived or ex vivo macrophages and DCs, and did not induce leukocyte recruitment after intratracheal instillation into mouse lungs. Hence, endotoxin-free pharmaceutical grade hyaluronan does not stimulate macrophages and DCs in our inflammatory models. These results emphasize the importance of ensuring hyaluronan preparations are endotoxin free.

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Low molecular weight hyaluronan mediated CD44 dependent induction of IL-6 and chemokines in human dermal fibroblasts potentiates innate immune response

Cited by 58 publications

References 23 publications

Binding and Internalization in Receptor‐Targeted Carriers: The Complex Role of CD44 in the Uptake of Hyaluronic Acid‐Based Nanoparticles (siRNA Delivery)

Binding and Internalization in Receptor‐Targeted Carriers: The Complex Role of CD44 in the Uptake of Hyaluronic Acid‐Based Nanoparticles (siRNA Delivery)

Extracellular matrix alterations in the Peyronie’s disease

Endotoxin free hyaluronan and hyaluronan fragments do not stimulate TNF-α, interleukin-12 or upregulate co-stimulatory molecules in dendritic cells or macrophages

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