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

Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferative keratinocytes and a dysregulated cytokine milieu, perpetuating a self-reinforcing inflammatory cycle. Despite the key involvement of keratinocytes in this pathogenic loop, the molecular pathogenesis remains incompletely understood. Here, we identify chitinase-like protein CHI3L2 as a key mediator. Elevated CHI3L2 levels were detected in serum and lesional skin from patients with psoriasis, predominantly in keratinocytes, as also verified by single-cell RNA sequencing and spatial transcriptomic analyses. In vitro stimulation of keratinocytes with M5 cytokine cocktail (IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α) increased CHI3L2 expression, demonstrating that CHI3L2 is inducible under inflammatory conditions. Transgenic mice expressing human CHI3L2 exhibited aggravated psoriasis-like phenotypes in both imiquimod- and mannan-induced psoriasis models, characterized by epidermal hyperplasia and scaling. To dissect the role of CHI3L2, we used recombinant protein injection, parabiosis, and bone marrow transplantation, identifying keratinocytes as the primary source of pathogenic CHI3L2. This was further confirmed by keratinocyte-specific CHI3L2 knockin mice. CHI3L2 functions in the HaCaT cell line and primary keratinocytes were investigated by recombinant CHI3L2 administration or CHI3L2 knockout. CHI3L2 disrupted phospholipid homeostasis, leading to altered inflammatory responses, proliferation, and differentiation of keratinocytes. CHI3L2 activated secretory phospholipase A2, elevating lysophosphatidylcholine, thereby establishing an autocrine loop perpetuating keratinocyte inflammation and reshaping the immune microenvironment. Therapeutic neutralization of CHI3L2 with antibodies or intervention of phospholipid pathway ameliorated skin inflammation in mouse psoriasis models. Our findings reveal CHI3L2 as an important regulator of keratinocyte-driven lipid remodeling and inflammation in psoriasis, highlighting potential as a therapeutic target.