Opsin 3 in keratinocytes mediates the light-induced exaggeration of atopic dermatitis

Atopic dermatitis (AD) is a common chronic inflammatory skin disease often exaggerated by sun exposure, whereas sun-exposed regions are usually spared from psoriasis. Opsin 3 (OPN3), a photoreceptor, has been implicated in nonvisual functions of the skin including skin pigmentation and barrier restoration. However, whether OPN3 engages in light-induced inflammation of AD remains unclear.

We sought to explore the role and mechanism of OPN3 in light-induced exaggeration of AD.

The expression of OPN3 was assessed by reverse transcription quantitative PCR, western blotting, immunohistochemistry, and immunofluorescence. The roles of light and OPN3 in type 2 inflammation were evaluated in mouse models and cultured keratinocytes (KCs). The mechanisms by which OPN3 regulates light-induced inflammation in KCs were examined by bulk RNA-sequencing, ELISA, calcium imaging, and immunofluorescence.

We found that OPN3 expression was increased in KCs of skin lesion from patients with AD and MC903-induced AD mouse model, but not patients with psoriasis or imiquimod-induced psoriasis mouse model. Type 2 cytokines induced OPN3 expression in KCs, which upregulated the production of proinflammatory cytokine IL-36γ, TNF-α, IL-8, and IL-1β. Notably, light exposure exaggerated skin inflammation in mouse model of AD, but not psoriasis. Moreover, light triggered the production of proinflammatory cytokines in KCs through OPN3-mediated calcium influx and sphingosine 1-phosphate-sphingosine 1-phosphate receptor signaling.

OPN3 plays a microenvironment-specific proinflammatory role in KCs upon light exposure, and may serve as a candidate of therapeutic targets for AD.