Contact Sensitizers Induce Skin Inflammation via ROS Production and Hyaluronic Acid Degradation

Abstract

Background Allergic contact dermatitis (ACD) represents a severe health problem with increasing worldwide prevalence. It is a T cell-mediated skin disease induced by protein-reactive organic and inorganic chemicals. A key feature of contact allergens is their ability to trigger an innate immune response that leads to skin inflammation. Previous evidence from the mouse contact hypersensitivity (CHS) model suggests a role for endogenous activators of innate immune signaling. Here, we analyzed the role of contact sensitizer induced ROS production and concomitant changes in hyaluronic acid metabolism on CHS responses. Methodology/Principal Findings We analyzed in vitro and in vivo ROS production using fluorescent ROS detection reagents. HA fragmentation was determined by gel electrophoresis. The influence of blocking ROS production and HA degradation by antioxidants, hyaluronidase-inhibitor or p38 MAPK inhibitor was analyzed in the murine CHS model. Here, we demonstrate that organic contact sensitizers induce production of reactive oxygen species (ROS) and a concomitant breakdown of the extracellular matrix (ECM) component hyaluronic acid (HA) to pro-inflammatory low molecular weight fragments in the skin. Importantly, inhibition of either ROS-mediated or enzymatic HA breakdown prevents sensitization as well as elicitation of CHS. Conclusions/Significance These data identify an indirect mechanism of contact sensitizer induced innate inflammatory signaling involving the breakdown of the ECM and generation of endogenous danger signals. Our findings suggest a beneficial role for anti-oxidants and hyaluronidase inhibitors in prevention and treatment of ACD.

Determination of the Antioxidant Status of the Skin by In Vivo-Electron Paramagnetic Resonance (EPR) Spectroscopy

“…The best effect was achieved with the antioxidant containing cream, whereas the untreated skin showed the worst results. Other studies with creams containing antioxidants also showed positive skin effects with respect to contact allergies and contact dermatitis [67][68][69][70].…”

Low Dose Ultraviolet B Irradiation Increases Hyaluronan Synthesis in Epidermal Keratinocytes via Sequential Induction of Hyaluronan Synthases Has1–3 Mediated by p38 and Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Signaling*

“…The cause of this fragmentation, whether due to the Hyal enzymes or to non-enzymatic degradation via ROS (70) generated by the irradiation (71,72), remains unsettled at the moment. ROS may also have an indirect effect by activating Hyal enzymes (73,74), adding to the complex regulatory mechanisms.…”

Rosacea – new data on pathogenesis and treatment

“…Reaktywne formy tlenu (ROS), takie jak aniony nadtlenkowe, rodniki hydroksylowe, tlen cząstecz-kowy i nadtlenek wodoru, powstają jako efekt wydzielania przez granulocyty wielojądrzaste, jak rów-nież w wyniku działania promieni słonecznych, co prowadzi do uszkodzenia tkanek [17,18].…”