Spatial characterization of interface dermatitis in cutaneous lupus reveals novel chemokine ligand-receptor pairs that drive disease

Authors

Saeed Shakiba, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Nazgol-Sadat Haddadi, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Khashayar Afshari, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Janet E. Lubov, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Haya S. Raef, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Robert Li, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Ümmügülsüm Yildiz-Altay, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Mridushi Daga, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Maggi Ahmed Refat, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Evangeline Kim, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Johanna Galindo de Laflin, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Andressa Akabane, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Priscilla Romano, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Jane Vongvirath, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Shany Sherman, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Elizabeth MacDonald, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
James P. Strassner, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Liang Zhang, NanoString Technologies, Seattle, WA, USA.
Michael Leon, NanoString Technologies, Seattle, WA, USA.
Christina E. Baer, UMass Chan Medical School, Sanderson Center for Optical Experimentation, Dept of Microbiology and Physiological Systems, Worcester, MA, USA.
Karen Dresser, UMass Chan Medical School, Dept of Pathology, Worcester, MA, USA.
Yan Liang, NanoString Technologies, Seattle, WA, USA.
James B. Whitley, Dartmouth Hitchcock Medical Center, Dept of Medicine, Lebanon, NH, USA.
Sladjana Skopelja-Gardner, Dartmouth Hitchcock Medical Center, Dept of Medicine, Lebanon, NH, USA.
John E. Harris, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
April Deng, UMass Chan Medical School, Dept of Pathology, Worcester, MA, USA.
Matthew D. Vesely, Yale University School of Medicine, Dept of Dermatology, New Haven, CT, USA.
Mehdi Rashighi, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.
Jillian Richmond, UMass Chan Medical School, Dept of Dermatology, Worcester, MA, USA.

Document Type

Article

Publication Title

bioRxiv : the preprint server for biology

Abstract

BACKGROUND: Chemokines play critical roles in the recruitment and activation of immune cells in both homeostatic and pathologic conditions. Here, we examined chemokine ligand-receptor pairs to better understand the immunopathogenesis of cutaneous lupus erythematosus (CLE), a complex autoimmune connective tissue disorder. OBJECTIVES: Our objectives were to (1) characterize the cellular and proteomic constitution of interface dermatitis in CLE using blister biopsies, (2) map chemokine:ligand receptor pairs that govern recruitment of immune cells to form interface dermatitis in CLE, and (3) perform unbiased analyses in tandem on different clinical subtypes to identify novel genes and proteins underlying discoid versus subacute CLE. METHODS: We used suction blister biopsies to measure cellular infiltrates with spectral flow cytometry in the interface dermatitis reaction, as well as 184 protein analytes in interstitial skin fluid using 96-plex immunoassay targeted proteomics. Flow and 96-plex immunoassay data concordantly demonstrated significant increases in T cells and antigen presenting cells (APCs). We also performed spatial transcriptomics and spatial proteomics of punch biopsies using digital spatial profiling (DSP) technology on CLE skin and healthy margin controls to examine discreet locations within the tissue. RESULTS: Spatial and 96-plex immunoassay data confirmed elevation of interferon (IFN) and IFN-inducible CXCR3 chemokine ligands. Comparing involved versus uninvolved keratinocytes in CLE samples revealed upregulation of essential inflammatory response genes in areas near interface dermatitis, including AIM2. 96-plex immunoassay data confirmed upregulation of Caspase 8, IL-18 which is the final product of AIM2 activation, and induced chemokines including CCL8 and CXCL6 in CLE lesional samples. Chemotaxis assays using PBMCs from healthy and CLE donors revealed that T cells are equally poised to respond to CXCR3 ligands, whereas CD14+CD16+ APC populations are more sensitive to CXCL6 via CXCR1 and CD14+ are more sensitive to CCL8 via CCR2. CONCLUSIONS: Taken together, our data map a pathway from keratinocyte injury to lymphocyte recruitment in CLE via AIM2-Casp8-IL-18-CXCL6/CXCR1 and CCL8/CCR2, and IFNG/IFNL1-CXCL9/CXCL11-CXCR3, and identify potential novel biomarkers of disease.

DOI

10.1101/2024.01.05.574422

Publication Date

5-22-2025

Recommended Citation

Shakiba, Saeed; Haddadi, Nazgol-Sadat; Afshari, Khashayar; Lubov, Janet E.; Raef, Haya S.; Li, Robert; Yildiz-Altay, Ümmügülsüm; Daga, Mridushi; Refat, Maggi Ahmed; Kim, Evangeline; de Laflin, Johanna Galindo; Akabane, Andressa; Romano, Priscilla; Vongvirath, Jane; Sherman, Shany; MacDonald, Elizabeth; Strassner, James P.; Zhang, Liang; Leon, Michael; Baer, Christina E.; Dresser, Karen; Liang, Yan; Whitley, James B.; Skopelja-Gardner, Sladjana; Harris, John E.; Deng, April; Vesely, Matthew D.; Rashighi, Mehdi; and Richmond, Jillian, "Spatial characterization of interface dermatitis in cutaneous lupus reveals novel chemokine ligand-receptor pairs that drive disease" (2025). Internal Medicine. 289.
https://scholar.bridgeporthospital.org/internal_medicine/289

Identifier

38260617 (pubmed); PMC10802382 (pmc); 10.1101/2024.01.05.574422 (doi); 2024.01.05.574422 (pii)