CCL19‐Positive Lymph Node Stromal Cells Govern the Onset of Inflammatory Arthritis via Tropomyosin Receptor Kinase

Abstract

ObjectiveThe study objective was to assess the role of CCL19+ lymph node stromal cells of the joint‐draining popliteal lymph node (pLN) for the development of arthritis.MethodsCCL19+ lymph node stromal cells were spatiotemporally depleted for five days in the pLN before the onset of collagen‐induced arthritis (CIA) using Ccl19‐Cre × iDTR mice. In addition, therapeutic treatment with recombinant CCL19–immunoglobulin G (IgG), locally injected in the footpad, was used to confirm the results. RNA sequencing of lymph node stromal cells combined with T cell coculture assays using tropomyosin receptor kinase (Trk) family inhibitors together with in vivo local pLN small interfering RNA (siRNA) treatments were used to elucidate the pathway by which CCL19+ lymph node stromal cells initiate the onset of arthritis.ResultsSpatiotemporal 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 messenger RNA sequencing analyses showed that CCL19+ lymph node stromal cells down‐regulated 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 coculture assays. Similar effects were observed with the pan‐Trk inhibitor larotrectinib in cocultures of lymph node stromal cells of patients with rheumatoid arthritis and T cells. Finally, local pLN treatment with TrkA inhibitor and TrkA siRNA led to exacerbated arthritis scores.ConclusionCCL19+ lymph node stromal cells are crucially involved in the development of inflammatory arthritis. Therefore, targeting of CCL19+ lymph node stromal cells via TRK could provide a tool to prevent arthritis.