Pansclerotic morphea is characterized by IFN-γ responses priming dendritic cell fibroblast crosstalk to promote fibrosis.
Pansclerotic morphea is characterized by IFN-γ responses priming dendritic cell fibroblast crosstalk to promote fibrosis.
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DOI：
10.1172/jci.insight.171307
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发表时间：
2023-08-22
期刊：
影响因子：
8
通讯作者：
Khanna, Dinesh
中科院分区：
文献类型：
--
作者：
Xing, Enze;Ma, Feiyang;Wasikowski, Rachael;Billi, Allison C.;Gharaee-Kermani, Mehrnaz;Fox, Jennifer;Dobry, Craig;Victory, Amanda;Sarkar, Mrinal K.;Xing, Xianying;Plazyo, Olesya;Chen, Henry W.;Barber, Grant;Jacobe, Heidi;Tsou, Pei-Suen;Modlin, Robert L.;Varga, John;Kahlenberg, J. Michelle;Tsoi, Lam C.;Gudjonsson, Johann E.;Khanna, Dinesh
泛硬脑膜炎是一种罕见的破坏性疾病，其特征是广泛的软组织纤维化，继发性收缩和显著的发病率。PSM的发病机制尚不清楚，积极的免疫抑制治疗很少减缓疾病进展。我们的目的是表征驱动PSM的分子机制，并通过对7名健康对照和1名相隔12个月的PSM患者的皮损和非皮损皮肤活检进行单细胞和空间RNA-Seq来确定治疗靶向途径。然后，我们使用免疫染色和体外方法验证了我们的发现。纤维化皮肤的特征在于显著的II型IFN应答，伴随着浸润的髓样细胞、B细胞和T细胞，它们是主要的IFN-γ来源。我们发现了富含PSM的独特CXCL 9+成纤维细胞，其特征是趋化因子表达增加，包括CXCL 9、CXCL 10和CCL 2。CXCL 9+成纤维细胞与促纤维化C 0 L 8A 1+肌成纤维细胞相关，其具有富集的TGF-β反应。在体外，TGF-β和IFN-γ协同增加CXCL 9和CXCL 10的表达，促进IFN-γ应答的持续。此外，细胞间相互作用分析显示cDC 2B DC是CXCL 9+成纤维细胞和C 0 L 8A 1+肌成纤维细胞之间的关键通信枢纽。这些结果将PSM定义为以II型IFN应答为中心的炎症驱动的病症。这项工作确定了T细胞，cDC 2B和肌成纤维细胞之间的关键致病回路，并表明JAK 1/2抑制是PSM的潜在治疗选择。
Pansclerotic morphea (PSM) is a rare, devastating disease characterized by extensive soft tissue fibrosis, secondary contractions, and significant morbidity. PSM pathogenesis is unknown, and aggressive immunosuppressive treatments rarely slow disease progression. We aimed to characterize molecular mechanisms driving PSM and to identify therapeutically targetable pathways by performing single-cell and spatial RNA-Seq on 7 healthy controls and on lesional and nonlesional skin biopsies of a patient with PSM 12 months apart. We then validated our findings using immunostaining and in vitro approaches. Fibrotic skin was characterized by prominent type II IFN response, accompanied by infiltrating myeloid cells, B cells, and T cells, which were the main IFN-γ source. We identified unique CXCL9+ fibroblasts enriched in PSM, characterized by increased chemokine expression, including CXCL9, CXCL10, and CCL2. CXCL9+ fibroblasts were related to profibrotic COL8A1+ myofibroblasts, which had enriched TGF-β response. In vitro, TGF-β and IFN-γ synergistically increased CXCL9 and CXCL10 expression, contributing to the perpetuation of IFN-γ responses. Furthermore, cell-to-cell interaction analyses revealed cDC2B DCs as a key communication hub between CXCL9+ fibroblasts and COL8A1+ myofibroblasts. These results define PSM as an inflammation-driven condition centered on type II IFN responses. This work identified key pathogenic circuits between T cells, cDC2Bs, and myofibroblasts, and it suggests that JAK1/2 inhibition is a potential therapeutic option in PSM.
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DOI：
10.3899/jrheum.130029
发表时间：
2014-01
期刊：
The Journal of rheumatology
影响因子：
--
作者：
Kim A;Marinkovich N;Vasquez R;Jacobe HT
通讯作者：
Jacobe HT
DOI：
10.1084/jem.170.3.727
发表时间：
1989-09-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Khalil N;Bereznay O;Sporn M;Greenberg AH
通讯作者：
Greenberg AH
影响因子：
2.6
作者：
Mirizio E;Liu C;Yan Q;Waltermire J;Mandel R;Schollaert KL;Konnikova L;Wang X;Chen W;Torok KS
通讯作者：
Torok KS
影响因子：
4.8
作者：
Midgley, Adam C.;Rogers, Mathew;Steadman, Robert
通讯作者：
Steadman, Robert
影响因子：
13.8
作者：
Fett, Nicole;Werth, Victoria P.
通讯作者：
Werth, Victoria P.