CCL19‐positive lymph node stromal cells govern the onset of inflammatory arthritis via tropomyosin receptor kinase

Schälter F, Azizov V, Frech M, Dürholz K, Schmid E, Hendel A, Sarfati I, Maeda Y, Sokolova M, Miyagawa I, Focke K, Sarter-Zaiss K, van Baarsen LGM, Krautwald S, Schett G, Zaiss M (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Arthritis and Rheumatology Wiley

DOI: 10.1002/art.42807

Abstract

Objectives

To assess the role of CCL19+ lymph node stromal cells of the joint draining popliteal lymph node (pLN) for the development of arthritis.


Methods

CCL19+ lymph node stromal cells were spatiotemporally depleted for 5 days in the pLN before the onset of collagen-induced arthritis (CIA) using Ccl19-Cre x iDTR mice. In addition, therapeutic treatment with recombinant CCL19-IgG, locally injected in the footpad, was used to confirm the results. RNA sequencing of lymph node stromal cells combined with T cell co-culture assays using tropomyosin receptor kinase (Trk) family inhibitors together with in vivo local pLN siRNA treatments were used to elucidate the pathway by which CCL19+ lymph node stromal cells initiate the onset of arthritis.


Results

Spatiotemporal depletion of CCL19+ lymph node stromal cells prevented disease onset in CIA mice. These inhibitory effects could be mimicked by local CCL19-IgG treatment. The mRNA sequencing analyses showed that CCL19+ lymph node stromal cells downregulated the expression of the tropomyosin receptor kinase A (TrkA) just before disease onset. Blocking TrkA in lymph node stromal cells led to increased T cell proliferation in in vitro co-culture assays. Similar effects were observed with the pan-Trk inhibitor Larotrectinib in co-cultures of lymph node stromal cells of rheumatoid arthritis patients and T cells. Finally, local pLN treatment with TrkA inhibitor and TrkA siRNA led to exacerbated arthritis scores.


Conclusions

CCL19+ lymph node stromal cells are crucially involved in the development of inflammatory arthritis. Therefore, targeting of CCL19+ lymph node stromal cells via TRK kinases could provide a tool to prevent arthritis.

Authors with CRIS profile

Vugar Azizov Department of Medicine 3 – Rheumatology and Immunology Michael Frech Department of Medicine 3 – Rheumatology and Immunology Kerstin Dürholz Department of Medicine 3 – Rheumatology and Immunology Eva Schmid Department of Medicine 3 – Rheumatology and Immunology Anna Hendel Lehrstuhl für Innere Medizin III Ilann Sarfati Department of Medicine 3 – Rheumatology and Immunology Maria Sokolova Department of Medicine 3 – Rheumatology and Immunology Kristin Focke Lehrstuhl für Innere Medizin III Kerstin Sarter-Zaiss Department of Medicine 3 – Rheumatology and Immunology Georg Schett Lehrstuhl für Innere Medizin III Mario Zaiss Department of Medicine 3 – Rheumatology and Immunology

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

A092: Targeting draining lymph node scaffold cells to induce immune tolerance Sept. 1, 2020 - Feb. 29, 2024

Involved external institutions

University of Amsterdam NL Netherlands (NL) Universitätsklinikum Schleswig-Holstein (UKSH) DE Germany (DE)

How to cite

APA:

Schälter, F., Azizov, V., Frech, M., Dürholz, K., Schmid, E., Hendel, A.,... Zaiss, M. (2024). CCL19‐positive lymph node stromal cells govern the onset of inflammatory arthritis via tropomyosin receptor kinase. Arthritis and Rheumatology. https://dx.doi.org/10.1002/art.42807

MLA:

Schälter, Fabian, et al. "CCL19‐positive lymph node stromal cells govern the onset of inflammatory arthritis via tropomyosin receptor kinase." Arthritis and Rheumatology (2024).

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