Upregulation of PLOD2 expression promotes the development of psoriasis: A connection between keratinocytes and fibroblasts.

Abstract

Psoriasis is a type of chronic inflammatory skin disease, with a rising incidence and high recurrence rate over the past decades. The crosstalk between the epidermis and the dermis is crucial in psoriasis. Here, we found that procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), also known as lysyl hydroxylase 2 (LH2), may be a key component linking epidermal and dermal dysfunctions during the development of psoriasis. Upregulation of PLOD2 was closely related to collagen and fibrosis, indicating that fibroblasts played an essential role in the progression. PLOD2 expression was increased in psoriatic lesions in both patients and an imiquimod-induced mouse model, as well as in M5-induced HaCaT/HFF-1 coculture cells. When PLOD2 was inhibited, inflammatory responses were reduced both in vitro and in vivo, whereas overexpression of PLOD2 had the opposite effect. In this study, we demonstrated that PLOD2 could be transcriptionally activated by STAT3, leading to increased collagen I and cytokines/chemokines in the extracellular matrix, which promotes the proliferation of both fibroblasts and keratinocytes. Mechanistically, cytokines may facilitate the release of heparin-binding EGF-like growth factor (HB-EGF) by fibroblasts, which then leads to the phosphorylation of EGFR and stimulates STAT3 activation in keratinocytes, further inducing the upregulation of PLOD2. Ultimately, through this positive feedback loop, dermatitis symptoms aggravated, and psoriasis developed. Treatment with the PLOD2 inhibitor (compound 12) significantly ameliorated imiquimod-induced psoriatic symptoms by inactivating STAT3 and reducing cytokine levels. In summary, we have demonstrated that PLOD2 plays a crucial role in the pathogenesis of psoriasis and may serve as a therapeutic target in clinical settings.