Translational targeting of inflammation and fibrosis in frozen shoulder: Molecular dissection of the T cell/IL-17A axis.
Translational targeting of inflammation and fibrosis in frozen shoulder: Molecular dissection of the T cell/IL-17A axis.
复制标题
DOI：
10.1073/pnas.2102715118
复制
发表时间：
2021-09-28
影响因子：
11.1
通讯作者：
Millar NL
中科院分区：
文献类型：
--
作者：
Akbar M;Crowe LAN;McLean M;Garcia-Melchor E;MacDonald L;Carter K;Fazzi UG;Martin D;Arthur A;Reilly JH;McInnes IB;Millar NL
冻结肩（FS）是一个典型的例子，一个普遍衰弱的病理性炎症性纤维化。使用的方法来解剖的分子途径subserving FS，我们证明了免疫细胞景观FS转移从主要的巨噬细胞T细胞的疾病。我们发现FS组织的T细胞能够分泌炎性细胞因子IL-17A，FS的成纤维细胞具有更高的受体IL-17RA表达。因此，FS成纤维细胞在IL-17 A刺激后产生更大的纤维化和炎症反应，其可以在使用抗IL-17 A抗体抑制NF-κ B途径或细胞因子阻断后消除。FS的这种单细胞解剖突出了具有疾病样特征的小分子和抗细胞因子衰减的T细胞驱动的疾病。冻结肩是一种常见的纤维增生性疾病，其特征是疼痛的隐匿性发作和肩关节活动范围受限，具有显著的社会经济影响。在这种普遍的纤维化疾病中，慢性炎症和基质重塑的病理生理机制尚不清楚;然而，越来越多的证据表明免疫生物学失调。IL-17A是与许多肌肉骨骼疾病中的炎症和组织重塑相关的关键细胞因子，因此，我们试图确定IL-17A在冻结肩免疫发病机制中的作用。我们展示了一个免疫细胞景观，从非病变组织中的主要巨噬细胞群体切换到疾病中富含T细胞的环境。此外，我们观察到IL-17A产生T细胞的亚群能够通过增强信号传导受体IL-17RA的表达在患病成纤维细胞中诱导促纤维化和炎症反应，使患病细胞对IL-17A更敏感。我们进一步确定IL-17 A对患病成纤维细胞的作用是TRAF-6/NF-κ B依赖性的，并且可以通过IKK β抑制剂或抗IL-17 A抗体治疗来抑制。因此，靶向IL-17A通路可能为这种常见的衰弱性疾病的管理提供未来的治疗方法。
Frozen shoulder (FS) is a classic example of a prevalent debilitating pathological inflammatory fibrosis. Using approaches to dissect the molecular pathways subserving FS, we demonstrate the immune cell landscape in FS shifts from primarily macrophages to T cells in disease. We find T cells from FS tissue are able to secrete the inflammatory cytokine IL-17A, and fibroblasts from FS have greater expression of the receptor IL-17RA. Thus, FS fibroblasts produce greater fibrotic and inflammatory responses following IL-17A stimulation, which can be abrogated following NF-κB pathway inhibition or cytokine blockade using an anti–IL-17A antibody. This single-cell dissection of FS highlights a T cell–driven disease with both small molecule and anti-cytokine attenuation of disease-like features. Frozen shoulder is a common fibroproliferative disease characterized by the insidious onset of pain and restricted range of shoulder movement with a significant socioeconomic impact. The pathophysiological mechanisms responsible for chronic inflammation and matrix remodeling in this prevalent fibrotic disorder remain unclear; however, increasing evidence implicates dysregulated immunobiology. IL-17A is a key cytokine associated with inflammation and tissue remodeling in numerous musculoskeletal diseases, and thus, we sought to determine the role of IL-17A in the immunopathogenesis of frozen shoulder. We demonstrate an immune cell landscape that switches from a predominantly macrophage population in nondiseased tissue to a T cell–rich environment in disease. Furthermore, we observed a subpopulation of IL-17A–producing T cells capable of inducing profibrotic and inflammatory responses in diseased fibroblasts through enhanced expression of the signaling receptor IL-17RA, rendering diseased cells more sensitive to IL-17A. We further established that the effects of IL-17A on diseased fibroblasts was TRAF-6/NF-κB dependent and could be inhibited by treatment with an IKKβ inhibitor or anti–IL-17A antibody. Accordingly, targeting of the IL-17A pathway may provide future therapeutic approaches to the management of this common, debilitating disease.
登录
查看更多内容
冻结肩部治疗的比较：系统评价和荟萃分析。
影响因子：
13.8
作者：
Challoumas D;Biddle M;McLean M;Millar NL
通讯作者：
Millar NL
DOI：
10.6061/clinics/2016(06)07
发表时间：
2016-07
期刊：
Clinics (Sao Paulo, Brazil)
影响因子：
--
作者：
Cohen C;Leal MF;Belangero PS;Figueiredo EA;Smith MC;Andreoli CV;de Castro Pochini A;Cohen M;Ejnisman B;Faloppa F
通讯作者：
Faloppa F
银屑病关节炎和牛皮癣中的Th17和Th22细胞。
影响因子：
4.9
作者：
Benham H;Norris P;Goodall J;Wechalekar MD;FitzGerald O;Szentpetery A;Smith M;Thomas R;Gaston H
通讯作者：
Gaston H
影响因子：
7.3
作者：
Brembilla NC;Senra L;Boehncke WH
通讯作者：
Boehncke WH
影响因子：
3
作者：
Hand, Campbell;Clipsham, Kim;Carr, Andrew J.
通讯作者：
Carr, Andrew J.