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

Acne keloidalis (AK) is a primary scarring alopecia characterized by longstanding inflammation in the scalp causing keloid-like scar formation and hair loss. Histologically, AK 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 non-lesional skin in patients with clinically active disease. Unbiased clustering revealed 19 distinct cell populations, including two notable populations, POSTN+ fibroblasts with enriched extracellular matrix signatures and SPP1+ myeloid cells with a 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 AK disease activity. Spatial transcriptomics and immunofluorescence staining verified micro-anatomic 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 AK.