CXCL10 secreted by SPRY1-deficient epidermal keratinocytes fuels joint inflammation in psoriatic arthritis via CD14 signaling.

Abstract

Psoriatic arthritis (PsA) is a multifaceted, chronic inflammatory disease affecting the skin, joints, and entheses, and it is a major comorbidity of psoriasis. Most patients with PsA present with psoriasis before articular involvement; however, the molecular and cellular mechanisms underlying the link between cutaneous psoriasis and PsA are poorly understood. Here, we found that epidermis-specific SPRY1-deficient mice spontaneously developed PsA-like inflammation involving both the skin and joints. Excessive CXCL10 was secreted by SPRY1-deficient epidermal keratinocytes through enhanced activation of JAK1/2/STAT1 signaling, and CXCL10 blockade attenuated PsA-like inflammation. Of note, CXCL10 was found to bind to CD14, but not CXCR3, to promote the TNF-α production of periarticular CD14hi macrophages via PI3K/AKT and NF-κB signaling pathways. Collectively, this study reveals that SPRY1 deficiency in the epidermis is sufficient to drive both skin and joint inflammation, and it identifies keratinocyte-derived CXCL10 and periarticular CD14hi macrophages as critical links in the skin-joint crosstalk leading to PsA. This keratinocyte SPRY1/CXCL10/periarticular CD14hi macrophage/TNF-α axis provides valuable insights into the mechanisms underlying the transition from psoriasis to PsA and suggests potential therapeutic targets for preventing this progression.