Keratinocyte-derived CHI3L2 reprograms phospholipid metabolism to promote skin inflammation in psoriasis.

Elevated CHI3L2 in keratinocytes is linked to psoriasis, and transgenic mice expressing human CHI3L2 show aggravated psoriasis-like phenotypes in imiquimod- and mannan-induced models.

• Why it matters: Keratinocytes help perpetuate psoriasis inflammation, but the molecular mediator connecting cytokine dysregulation to lipid remodeling and inflammatory amplification is incompletely understood.
• What they did: Serum and lesional skin CHI3L2 were assessed in patients using single-cell RNA sequencing and spatial transcriptomics; inflammatory M5 cytokine cocktail increased CHI3L2 in keratinocytes, and keratinocyte source was tested via recombinant injection, parabiosis, bone marrow transplantation, and keratinocyte-specific CHI3L2 knockin mice.
• The result: CHI3L2 disrupted phospholipid homeostasis by activating secretory phospholipase A2, increasing lysophosphatidylcholine and promoting keratinocyte inflammation; neutralizing CHI3L2 antibodies or phospholipid-pathway intervention ameliorated mouse psoriasis inflammation.