Disease associated monocytes contribute to the inflammatory milieu in hidradenitis suppurativa and have dysregulated expression of transposable elements

Abstract

Abstract Hidradenitis suppurativa (HS), an inflammatory skin-disease, manifests as painful lesions in intertriginous skin. Despite their central role in innate immunity the role of monocytes in HS is largely unknown. Here we utilized cytometry by time-of-flight (CyTOF), imaging CyTOF (IMC), cellular indexing of transcriptomes and epitopes by sequencing (CITEseq), spatial transcriptomics (ST), and our recently developed database (HSOmicsDB) to characterize the systemic and cutaneous immune response in patients with HS. CITEseq found differential genes in circulating immune cells from HS patients enriched for cellular activation and extravasation. CyTOF immune profiling of fresh whole-blood samples found decreased frequency of classical Mos (C.Mos), which had increased expression of skin homing chemokine receptors. IMC found C.Mos infiltrated lesional dermis and tunnel regions, but not perilesional (PL) skin. Patients with HS showed increased proportions of activated C.Mo subclusters and a population of SOD2+ C.Mos expressing genes downstream of viral sensing pathways. SOD2 +C.Mos expressed high levels of neutrophil attracting chemokines. ST found SOD2 +C.Mos localized to regions of active inflammation and dermal tunnels. HSOmicsDB showed Mos and Macs expressed SOD2 +C.Mo genes, which were enriched in lesions, but not PL skin. Finally, we show that SOD2 +C.mos in HS have dysregulated expression of transposable elements (TEs), which may be activating viral sensing mechanisms in patients with HS. Together our data shows monocytes in HS function to recruit neutrophils to lesional HS skin, and provides the first evidence implicating TEs as disease promoting factors in HS by leading to C.Mo dysregulation. Supported By NIH/NIAMS, R01AR078688-01A1 and R21AR079089-01A1