CCL2-CCR2 Signaling in the Skin Drives Surfactant-Induced Irritant Contact Dermatitis through IL-1β-Mediated Neutrophil Accumulation

Surfactant-induced cumulative irritant contact dermatitis (ICD) is a common and clinically important skin disorder. CCL2 is known to mediate inflammation after tissue damage in various organs. Thus, we investigated whether and how CCL2 contributes to the development of murine cumulative ICD induced by a common surfactant, SDS. Wild-type mice treated topically with SDS for 6 consecutive days developed skin inflammation that recapitulated the features of human cumulative ICD, including barrier disruption, epidermal thickening, and neutrophil accumulation. CCL2 was upregulated in SDS-treated skin, and local CCL2 blockade attenuated SDS-induced ICD. SDS-induced ICD and neutrophil accumulation were also attenuated in mice deficient in CCR2, the receptor for CCL2. Neutrophil depletion alleviated SDS-induced ICD, suggesting that impaired neutrophil accumulation was responsible for the amelioration of ICD in CCR2-deficient mice. In RNA-sequencing analyses of SDS-treated skin, the expression levels of Il1 beta in Ccr2-deficient mice were highly downregulated compared with those in wild-type mice. Furthermore, the intradermal administration of IL-1 beta in the SDS-treated skin of CCR2-deficient mice restored the local accumulation of neutrophils and the development of ICD. Collectively, our results suggest that CCL2-CCR2 signaling in the skin critically promotes the development of SDS-induced ICD by inducing IL-1b expression for neutrophil accumulation.

Automated summary

The CCL2-CCR2 signaling pathway plays a critical role in the development of SDS-induced cumulative irritant contact dermatitis (ICD). Treatment with SDS upregulates CCL2, and mice deficient in CCR2 show reduced neutrophil accumulation and alleviated ICD. Neutrophil depletion can alleviate SDS-induced ICD, and intradermal administration of IL-1 beta restores neutrophil accumulation and the development of ICD in CCR2-deficient mice.