2440: Synovial Shaping of Skin-derived Migrating Immune Cells Determines Initiation of Inflammation in Psoriatic Arthritis

Maria Gabriella Raimondo¹, Simon Rauber², Hashem Mohammadian³, Mario Angeli¹, Cong Xu¹, Aleix Rius Rigau⁴, Markus Luber¹, Hannah Labinsky⁵, Alina Ramming¹, Stefano Alivernini⁶, Jörg Distler¹, Ursula Fearon⁷, Douglas Veale⁸, Michael Sticherling⁹, Juan D Canete¹⁰, Georg Schett¹¹ and Andreas Ramming¹, ¹Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany, ²3 Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany. 4 Deutsches Zentrum für Immuntherapie, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany., Erlangen, Germany, ³Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany. Deutsches Zentrum für Immuntherapie, Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany, ⁴Department of Internal Medicine 3, Rheumatology and Clinical Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany, ⁵Medical Department II, Rheumatology, University Hospital Würzburg, Würzburg, Germany, ⁶Immunology Research Core Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Division of Rheumatology - Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore, Rome, Italy, ⁷Trinity College Dublin, Dublin, Ireland, ⁸St.Vincent's University Hosp, Dublin, Ireland, ⁹Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg & Universitätsklinikum Erlangen, Department of Dermatology, Erlangen, Germany, ¹⁰Hospital Clinic an IDIBAPS, Barcelona, Spain, ¹¹Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

Background/Purpose: Around 30% of the patients with psoriasis (PsO) develop psoriatic arthritis (PsA) overtime, suggesting the existence of a disease mediated skin-joint crosstalk. To date, it is still obscure why the inflammatory process in some patients with PsO is restrained to the skin, whereas in other patients it spreads to the joints. Using a pre-clinical model of PsA and PsO, we aimed to untangle the skin-joint axis and to address its role in PsA pathogenesis.

Methods: The IL-23 overexpression (IL-23OE) mouse model of PsO was performed in different genetic backgrounds of KAEDE-transgenic mice expressing a photo-convertible fluorescent reporter to assess cell trafficking from inflamed skin to the joints. Photoswitch from KAEDE^GREEN to KAEDE^RED of psoriatic skin lesions was obtained upon UV light irradiation. Skin-derived cell trafficking to the joints was detected by light sheet fluorescence microscopy (LSFM) and flow cytometry. Imaging flow cytometry was used to determine the immune nature of the migrating cells. Phenotypical characteristic of skin-derived migrating cells in joints was addressed by single-cell RNA-sequencing (scRNAseq) and functional assays. Data were validated in synovial biopsies from PsO and PsA patients by imaging mass cytometry.

Results: Psoriatic skin lesions were induced upon IL-23OE independently from the mouse strain, whereas the initiation of joint inflammation was dependent on the genetic background of the mice, as assessed by MRI scan and histological analysis. Immune cell migration from psoriatic skin to the joints was observed in both protected and non-protected mice from arthritis. ScRNAseq and computational analysis with RNA velocity approach indicates CD2+ MCHII+ monocytes as predominant cell type evading from the inflamed skin and entering the synovial tissue, with no frequency differences between PsO and PsA mice. No phenotypical differences were observed in the pre-differentiated stage of those monocytes in both, arthritis-protected and non-protected animals. However, once in the synovial tissue their further differentiation into macrophages resulted into two different phenotypes, with pro-inflammatory signatures in mice developing PsA. Interactome analyses between local differentiated skin-derived macrophages and tissue resident synovial cells highlighted the role of synovial sublining fibroblasts in shaping the fate of skin-derived macrophages into a protective phenotype without capacity to initiate the joint inflammatory process in PsO mice without arthritis. Imaging mass cytometry of synovial biopsies from patients with PsO and PsA identified niches of the synovial membrane that were either or not protected from inflammation by a similar fibroblastic fate as observed in the murine setting.

Conclusion: Skin derived monocytes play a major role in spreading the inflammation from psoriatic skin to the joints. However, it is upon interaction with the stromal-resident cells that the fate of the migrating monocytes is shaped towards joint protection or joint inflammation resembling PsA. These data might provide completely new diagnostic insights in assessing the risk of PsO patients to develop PsA.


M. Raimondo: None; S. Rauber: None; H. Mohammadian: None; M. Angeli: None; C. Xu: None; A. Rius Rigau: None; M. Luber: None; H. Labinsky: None; A. Ramming: None; S. Alivernini: None; J. Distler: None; U. Fearon: None; D. Veale: None; M. Sticherling: EI Lilly, 5, El Lilly, 6, Janssen, 5, 6, Novartis, 5, 6; J. Canete: None; G. Schett: None; A. Ramming: None.