In:
Arthritis & Rheumatology, Wiley
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
2326-5191
,
2326-5205
Language:
English
Publisher:
Wiley
Publication Date:
2024
detail.hit.zdb_id:
2754614-7
