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
DOI: 10.1002/art.42807
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.
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://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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