A spatially coordinated keratinocyte–fibroblast circuit recruits MMP9+ myeloid cells to drive type I interferon-driven inflammation in photosensitive autoimmunity

Product:

Inflammation Panel 250

Topic:

Inflammation

Disease Area:

photosensitivity

Sample Type:

Blister Fluid

Topic/Product:

Inflammation Panel 250

Disease Area:

photosensitivity

Sample Type:

Blister Fluid

Abstract

Photosensitivity is central to cutaneous lupus erythematosus and dermatomyositis (DM), but the mechanisms linking UVB exposure to tissue-specific autoimmunity are poorly defined. Using single-cell RNA sequencing, spatial transcriptomics, proteomics, UVB provocation and in vitro modeling, we identify MMP9⁺CD14⁺ myeloid cells as critical mediators of photosensitivity. These cells expand significantly in lesional skin, produce interferon-β (IFNβ) and colocalize with cytotoxic CD4⁺ T cells at the dermal–epidermal junction. Keratinocytes activate fibroblasts in the superficial dermis, prompting them to release chemokines (CCL2, CCL19, CCL7, CCL8) that recruit MMP9⁺CD14⁺ cells. In vitro, type I interferon-primed keratinocytes exposed to UVB release cytokines activating dendritic cells, mirroring in vivo responses. UVB irradiation of non-lesional skin of patients with DM rapidly recruits these myeloid cells. In a clinical proof-of-concept study, anti-type I interferon treatment with anifrolumab prevented UVB-induced myeloid infiltration and reduced photosensitivity. Therefore, targeting MMP9⁺CD14⁺ cells may offer therapeutic potential for managing photosensitive autoimmune skin conditions.

Authors & Affiliations

Yuqing Wang¹˒⁸, Khashayar Afshari²˒⁸, Nazgol-Sadat Haddadi²˒⁸, Carolina Salomão Lopes¹, Chee-Huat Linus Eng³, Leah M. Whiteman⁴, Nuria Martinez², Pyae P. Kyawe², Ksenia S. Anufrieva⁵, Kevin Wei⁵, Kirsten Frieda³, Misha Rosenbach⁶, Ruth Ann Vleugels⁷, Stefania Gallucci⁴, John E. Harris², Mehdi Rashighi²˒⁹, and Manuel Garber¹˒⁹

¹ Department of Genomics and Computational Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
² Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, USA
³ Spatial Genomics, Pasadena, CA, USA
⁴ Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
⁵ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital at Harvard Medical School, Boston, MA, USA
⁶ Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA
⁷ Department of Dermatology, Brigham and Women’s Hospital at Harvard Medical School, Boston, MA, USA
⁸ These authors contributed equally: Yuqing Wang, Khashayar Afshari, Nazgol-Sadat Haddadi
⁹ These authors jointly supervised this work: Mehdi Rashighi, Manuel Garber

Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition. He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.