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 leading to 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 later stages. To further explore its pathogenesis, bulk RNA-sequencing and single-cell RNA sequencing were applied to scalp biopsy specimens of lesional and adjacent non-lesional skin in patients with clinically active disease. Unbiased clustering revealed 18 distinct cell populations, including two notable populations, POSTN+ fibroblasts with enriched extracellular matrix signatures, and SPP1+ myeloid cells M2 macrophages. Cell communication analyses indicate that fibroblasts and myeloid cells communicate by collagen and SPP1 signaling networks in lesional skin. Tissue immunofluorescence staining demonstrated SPP1+ myeloid cells and POSTN+ fibroblasts at the upper segment of outer root sheath of the hair follicle in the subacute stage, confirming micro-anatomic specificity with relevant disease activity. Therapy with intralesional corticosteroids reduced SPP1 and POSTN expression, and lessened AK progression. In summary, the communication between POSTN+ fibroblasts and SPP1+ myeloid cells by collagen and SPP1 axis may contribute to the pathogenesis of AK.