Low molecular weight hyaluronic acid increases the self-defense of skin epithelium by induction of beta-defensin 2 via TLR2 and TLR4.
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.
Gariboldi
Silvia
S
Mucosal Immunity Laboratory, Department of Human Morphology, Università degli Studi di Milano, Milan, Italy.
Palazzo
Marco
M
Zanobbio
Laura
L
Selleri
Silvia
S
Sommariva
Michele
M
Sfondrini
Lucia
L
Cavicchini
Stefano
S
Balsari
Andrea
A
Rumio
Cristiano
C
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001706:Biopsy; D002457:Cell Extracts / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004848:Epithelium / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008970:Molecular Weight; D010457:Peptidoglycan / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D002457:Cell Extracts; D016207:Cytokines; C106641:DEFB4A protein, human; C117047:Defb2 protein, mouse; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D016760:Proto-Oncogene Proteins c-fos; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D023083:beta-Defensins; D006820:Hyaluronic Acid; D011493:Protein Kinase C