Essential role of CCL2-CCR2 axis in the pathogenesis of chronic irritant contact dermatitis

Abstract

Abstract Chronic irritant contact dermatitis (ICD) including hand eczema is a common skin disorder caused by the repetitive exposure to irritants such as chemical detergents and organic solvents. Products including sodium dodecyl sulfate (SDS), such as soap or shampoo, are the leading cause of occupational ICD. Previous studies have shown that irritants cause epidermal damage which induce the production of proinflammatory mediators, followed by a dermal influx of inflammatory cells. However, the detailed immunological cascades occurring in the chronic ICD remains unclear. Repeated application of SDS, onto murine ear skin induced ear swelling, accompanied by epidermal hyperplasia and barrier dysfunction. Dermal infiltration of neutrophils, eosinophils and monocytes were remarkable in the SDS-applied skin. Our observation described above was consistent with the features of human chronic ICD. Here, we found that CCR2 deficiency or blockade of CCL2, a major ligand for CCR2, significantly attenuated SDS-induced ear swelling as well as inflammatory cell accumulation. Among the differentially expressed genes, which were up-regulated by SDS application, genes related to cell interaction at the vascular wall were significantly affected by CCR2 deficiency. Further, we investigated whether CCR2 on radiosensitive cells or radioresistant cells is critical. Lethally irradiated CCR2−/− mice transplanted with CCR2+/+ bone marrow cells (BMC) exhibited impaired SDS-induced ICD, while CCR2+/+ mice transplanted with CCR2−/− did not. Collectively, our data suggest that CCR2 expression by radioresistant cells plays an essential role in the pathogenesis of chronic ICD.