Cold Stress Activates ACSL1+ Macrophages in a Fatty Acid-Dependent Manner to Exacerbate Psoriasis

The relapse of psoriasis precludes a complete cure and can result in multisystem comorbidities, making relapse prevention a critical clinical challenge. Clinically, psoriasis tends to worsen or relapse in winter, but the underlying mechanisms remain unclear. In this study, we utilized an imiquimod (IMQ)-induced psoriasis-like mouse model to investigate the role of cold stress in the exacerbation of psoriasis during winter. Our data indicate that cold stress significantly aggravates IMQ-induced psoriatic lesions. While cold stress alone does not directly induce psoriasis, it can promote the development of psoriasis-like lesions in mice exposed to low doses of IMQ. Single-nucleus transcriptome analysis demonstrated that cold stress leads to the remodelling of macrophage phenotypes in psoriatic lesions, with a notable increase in ACSL1+ macrophages. These cells exhibit higher intracellular neutral lipid content and produce more IL-1β, which in turn stimulates γδT cells to secrete more IL-17A. The increase of ACSL1+ macrophages is associated with cold stress-induced lipid synthesis in dermal adipocytes. Notably, the number of ACSL1+ IL-1β + macrophages is significantly increased in the skin of psoriasis patients in winter. Therefore, targeting the formation of ACSL1+ macrophages may be a potential strategy to prevent the worsening of psoriasis in winter.