Low molecular weight hyaluronic acid increases the self-defense of skin epithelium by induction of beta-defensin 2 via TLR2 and TLR4

• Published in: The Journal of immunology (1950) 2008-08, Vol.181 (3), p.2103-2110
• Main Authors: Gariboldi, Silvia, Palazzo, Marco, Zanobbio, Laura, Selleri, Silvia, Sommariva, Michele, Sfondrini, Lucia, Cavicchini, Stefano, Balsari, Andrea, Rumio, Cristiano
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; beta-Defensins - genetics; beta-Defensins - metabolism; Biopsy; Cell Extracts - pharmacology; Cell Line; Cytokines - biosynthesis; Epithelium - drug effects; Epithelium - immunology; Epithelium - metabolism; Escherichia coli - drug effects; Gene Expression Regulation - drug effects; Humans; Hyaluronic Acid - pharmacology; Keratinocytes - drug effects; Keratinocytes - immunology; Keratinocytes - metabolism; Lipopolysaccharides - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Weight; Peptidoglycan - pharmacology; Protein Kinase C - metabolism; Proto-Oncogene Proteins c-fos - metabolism; Signal Transduction; Skin - drug effects; Skin - immunology; Skin - metabolism; Toll-Like Receptor 2 - agonists; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - deficiency; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.181.3.2103

In sites of inflammation or tissue injury, hyaluronic acid (HA), ubiquitous in the extracellular matrix, is broken down into low m.w. HA (LMW-HA) fragments that have been reported to activate immunocompetent cells. We found that LMW-HA induces activation of keratinocytes, which respond by producing beta-defensin 2. This production is mediated by TLR2 and TLR4 activation and involves a c-Fos-mediated, protein kinase C-dependent signaling pathway. LMW-HA-induced activation of keratinocytes seems not to be accompanied by an inflammatory response, because no production of IL-8, TNF-alpha, IL-1beta, or IL-6 was observed. Ex vivo and in vivo treatments of murine skin with LMW-HA showed a release of mouse beta-defensin 2 in all layers of the epidermal compartment. Therefore, the breakdown of extracellular matrix components, for example after injury, stimulates keratinocytes to release beta-defensin 2, which protects cutaneous tissue at a time when it is particularly vulnerable to infection. In addition, our observation might be important to open new perspectives in the development of possible topical products containing LMW-HA to improve the release of beta-defensins by keratinocytes, thus ameliorating the self-defense of the skin for the protection of cutaneous tissue from infection by microorganisms.