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

被引：0

作者：

Schaelter, Fabian ^{[1
,2
,3
]}

Azizov, Vugar ^{[1
,2
,3
]}

Frech, Michael ^{[1
,2
,3
]}

Duerholz, Kerstin ^{[1
,2
,3
]}

Schmid, Eva ^{[1
,2
,3
]}

Hendel, Anna ^{[1
,2
,3
]}

Sarfati, Ilann ^{[1
,2
,3
]}

Maeda, Yuichi ^{[1
,2
,3
,4
]}

Sokolova, Maria ^{[1
,2
,3
]}

Miyagawa, Ippei ^{[1
,2
,3
,5
]}

Focke, Kristin ^{[1
,2
,3
]}

Sarter, Kerstin ^{[1
,2
,3
]}

van Baarsen, Lisa G. M. ^{[6
,7
]}

Krautwald, Stefan ^{[8
]}

Schett, Georg ^{[1
,2
,3
]}

Zaiss, Mario M. ^{[1
,2
,3
]}

机构：

[1] Friedrich Alexander Univ Erlangen Nurnberg FAU, Dept Internal Med Rheumatol & Immunol 3, Erlangen, Germany

[2] Univ klinikum Erlangen, Erlangen, Germany

[3] Friedrich Alexander Univ Erlangen Nurnberg, Deutsch Zent Immuntherapie DZI, Erlangen, Germany

[4] Osaka Univ, Grad Sch Med, Dept Microbiol & Immunol, Lab Immune Regulat, Osaka, Japan

[5] Univ Occupat & Environm Hlth, Sch Med, Dept Internal Med 1, Kitakyushu, Japan

[6] Amsterdam Infect & Immun Inst, Dept Rheumatol & Clin Immunol, Amsterdam UMC, Amsterdam, Netherlands

[7] Univ Amsterdam, Amsterdam, Netherlands

[8] Univ Hosp Schleswig Holstein, Dept Nephrol & Hypertens, Kiel, Germany

来源：

ARTHRITIS & RHEUMATOLOGY | 2024年 / 76卷 / 06期

关键词：

FIBROBLASTIC RETICULAR CELLS; NERVE GROWTH-FACTOR; RHEUMATOID-ARTHRITIS; TRK FAMILY; T-CELLS; EXPRESSION; ANTIBODIES; CCL19;

D O I：

10.1002/art.42807

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective. The 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. Methods. CCL19(+) lymph node stromal cells were spatiotemporally depleted for five 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-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. 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 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. Conclusion. CCL19(+) 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.

引用

页码：857 / 868

页数：12