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Low Molecular Weight Hyaluronic Acid Increases the Self-Defense of Skin Epithelium by Induction of β-Defensin 2 via TLR2 and TLR4

Silvia Gariboldi^1,*, Marco Palazzo^1,*, Laura Zanobbio^*, Silvia Selleri^*, Michele Sommariva^*, Lucia Sfondrini, Stefano Cavicchini, Andrea Balsari^, and Cristiano Rumio^2,*

^* Mucosal Immunity Laboratory, Department of Human Morphology and Institute of Pathology, Università degli Studi di Milano, Milan, Italy; Unità Operativa Dermatologia, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; and Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy

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 β-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-, IL-1β, or IL-6 was observed. Ex vivo and in vivo treatments of murine skin with LMW-HA showed a release of mouse β-defensin 2 in all layers of the epidermal compartment. Therefore, the breakdown of extracellular matrix components, for example after injury, stimulates keratinocytes to release β-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 β-defensins by keratinocytes, thus ameliorating the self-defense of the skin for the protection of cutaneous tissue from infection by microorganisms.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ S.G. and M.P. contributed equally to this work.

² Address correspondence and reprint requests to Prof. Cristiano Rumio, Faculty of Pharmacy, Department of Human Morphology, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy. E-mail address: cristiano.rumio{at}unimi.it

³ Abbreviations used in this paper: HA, hyaluronic acid; ChIP, chromatin immunoprecipitation; DEFB2, β-defensin 2; HMW, high m.w.; LEF-1, lymphoid enhancer-binding factor-1; LMW, low m.w.; NHEK, normal human epidermal keratinocyte; PGN, peptidoglycan; PKC, protein-kinase C.

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