Profibrotic Subsets of SPP1⁺ Macrophages and POSTN⁺ Fibroblasts Contribute to Fibrotic Scarring in Acne Keloidalis

Acne keloidalis is a primary scarring alopecia characterized by longstanding inflammation in the scalp causing keloid-like scar formation and hair loss. Histologically, acne keloidalis is characterized by mixed leukocytic infiltrates in the acute stage followed by a granulomatous reaction and extensive fibrosis in the later stages. To further explore its pathogenesis, bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics were applied to occipital scalp biopsy specimens of lesional and adjacent no-lesional skin in patients with clinically active disease. Unbiased clustering revealed 19 distinct cell populations, including 2 notable populations: POSTN⁺ fibroblasts with enriched extracellular matrix signatures and SPP1⁺ myeloid cells with an M2 macrophage phenotype. Cell communication analyses indicated that fibroblasts and myeloid cells communicated by SPP1 signaling networks in lesional skin. A reverse transcriptomics in silico approach identified corticosteroids as possessing the capability to reverse the gene expression signatures of SPP1⁺ myeloid cells and POSTN⁺ fibroblasts. Intralesional corticosteroid injection greatly reduced SPP1 and POSTN gene expression as well as acne keloidalis disease activity. Spatial transcriptomics and immunofluorescence staining verified microanatomic specificity of SPP1⁺ myeloid cells and POSTN⁺ fibroblasts with disease activity. In summary, the communication between POSTN⁺ fibroblasts and SPP1⁺ myeloid cells by SPP1 axis may contribute to the pathogenesis of acne keloidalis.