Titanium salts tested in reconstructed human skin with integrated MUTZ‐3‐derived Langerhans cells show an irritant rather than a sensitizing potential. (6th August 2020)

• Record Type: Journal Article
• Authors: Rodrigues Neves, Charlotte T.; Spiekstra, Sander W.; de Graaf, Niels P. J.; Rustemeyer, Thomas; Feilzer, Albert J.; Kleverlaan, Cees J.; Gibbs, Susan
• Is Part Of: Contact dermatitis. Volume 83:Number 5(2020)
• Page Start: 337
• Page End: 346
• Publication Date: 2020-08-06
• Subjects: allergy -- in vitro -- irritant -- Langerhans cell -- organotypic -- reconstructed human skin -- sensitizer -- titanium; Contact dermatitis -- Periodicals; 616.51
• DOI: 10.1111/cod.13666
• Languages: English
• ISSNs: 0105-1873

Abstract

Abstract: Background: The nature of clinically related adverse reactions to titanium is still unknown. Objective: To determine whether titanium salts have irritant or sensitizing potential in a reconstructed human skin (RHS) model with integrated Langerhans cells (LCs). Methods: RHS‐LCs (ie, reconstructed epidermis) containing primary differentiated keratinocytes and CFSE + CD1a + ‐LCs generated from the MUTZ‐3 cell line on a primary fibroblast‐populated collagen hydrogel (dermis) were topically exposed to titanium(IV) bis(ammonium lactato)dihydroxide (TiALH). LC migration and plasticity were determined. Results: TiALH resulted in CFSE + CD1a + ‐LC migration out of the epidermis. Neutralizing antibodies to CCL5 and CXCL12 showed that LC migration was CCL5 and not CXCL12 mediated. LCs accumulating within the dermis after TiALH exposure were CFSE + Lang + CD68 + which is characteristic of a phenotypic switch of MUTZ‐LC to a macrophage‐like cell. Furthermore, TiALH did not result in increased interleukin (IL)‐1β or CCR7 messenger RNA (mRNA) in the dermis, but did result in increased IL‐10 mRNA. In addition, monocultures of MUTZ‐LCs failed to increase LC maturation biomarkers CD83, CD86, and CXCL‐8 when exposed to noncytotoxic concentrations of four different titanium salts. Conclusion: These results classify titanium salts as irritants rather than sensitizers and indicate that titanium implant‐related complaints could be due to localized irritant‐mediated inflammation arising from leachable agents rather than a titanium metal allergy. Abstract : Titanium scores as irritant not sensitizer. In vitro reconstructed human skin model with integrated Langerhans cells (RHS‐LCs) can be used for determining sensitizer or irritant potential of metals. Titanium(IV) bis(ammonium lactato)dihydroxide (TiALH) resulted in CFSE + CD1a + Lang + CD68 + LC migration out of the epidermis, indicating a phenotypic switch of a macrophage‐like cell. LC migration was CCL5 (irritant) and not CXCL12 (sensitizer) mediated. Results classify titanium salts as irritants rather than sensitizers and indicate that titanium implant‐related complaints could be due to localized irritant‐mediated inflammation rather than titanium metal allergy.