Spatial characterization of interface dermatitis in cutaneous lupus reveals novel chemokine ligand-receptor pairs that drive disease.
Spatial characterization of interface dermatitis in cutaneous lupus reveals novel chemokine ligand-receptor pairs that drive disease.
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皮肤狼疮界面皮炎的空间特征揭示了驱动疾病的新型趋化因子配体-受体对。
DOI：
10.1101/2024.01.05.574422
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
MacDonald,E
中科院分区：
文献类型：
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作者：
Shakiba,Saeed;Haddadi,Nazgol-Sadat;Afshari,Khashayar;Lubov,JanetE;Raef,HayaS;Li,Robert;Yildiz-Altay,Ümmügülsüm;Daga,Mridushi;Refat,MaggiAhmed;Kim,Evangeline;deLaflin,JohannaGalindo;Akabane,Andressa;Sherman,Shany;MacDonald,E
趋化因子在稳态和病理条件下免疫细胞的募集和活化中起关键作用。在这里，我们研究了趋化因子配体受体对，以更好地了解皮肤红斑狼疮（CLE），一个复杂的自身免疫性结缔组织疾病的免疫发病机制。我们使用抽吸水泡活检来测量界面皮炎反应中的光谱流式细胞术的细胞浸润，以及使用Olink靶向蛋白质组学测量间质皮肤液中的184种蛋白质分析物。Flow和Olink数据一致地证明T细胞和抗原呈递细胞（APC）显著增加。我们还使用数字空间轮廓（DSP）技术对CLE皮肤和健康边缘对照进行了打孔活检的空间转录组学和空间蛋白质组学研究，以检查组织内的离散位置。空间和Olink数据证实了干扰素（IFN）和IFN诱导的CXCR 3趋化因子配体的升高。比较CLE样本中受累与未受累的角质形成细胞，发现界面皮炎附近区域的基本炎症反应基因上调，包括AIM 2。我们的Olink数据证实了CLE病变样品中Caspase 8、IL-18（AIM 2活化的最终产物）和诱导的趋化因子（包括CCL 8和CXCL 6）的上调。使用来自健康和CLE供体的PBMC的趋化性测定揭示了T细胞同样准备响应CXCR 3配体，而CD 14 + CD 16 + APC群体通过CXCR 1对CXCL 6更敏感，并且CD 14+通过CCR 2对CCL 8更敏感。综上所述，我们的数据绘制了CLE中从角质形成细胞损伤到淋巴细胞募集的途径，该途径是通过AIM 2-Casp 8-IL-18-CXCL 6/CXCR 1和CCL 8/CCR 2以及IFNG/IFNL 1-CXCL 9/CXCL 11-CXCR 3。
Chemokines play critical roles in the recruitment and activation of immune cells in both homeostatic and pathologic conditions. Here, we examined chemokine ligand-receptor pairs to better understand the immunopathogenesis of cutaneous lupus erythematosus (CLE), a complex autoimmune connective tissue disorder. We used suction blister biopsies to measure cellular infiltrates with spectral flow cytometry in the interface dermatitis reaction, as well as 184 protein analytes in interstitial skin fluid using Olink targeted proteomics. Flow and Olink data concordantly demonstrated significant increases in T cells and antigen presenting cells (APCs). We also performed spatial transcriptomics and spatial proteomics of punch biopsies using digital spatial profiling (DSP) technology on CLE skin and healthy margin controls to examine discreet locations within the tissue. Spatial and Olink data confirmed elevation of interferon (IFN) and IFN-inducible CXCR3 chemokine ligands. Comparing involved versus uninvolved keratinocytes in CLE samples revealed upregulation of essential inflammatory response genes in areas near interface dermatitis, including AIM2. Our Olink data confirmed upregulation of Caspase 8, IL-18 which is the final product of AIM2 activation, and induced chemokines including CCL8 and CXCL6 in CLE lesional samples. Chemotaxis assays using PBMCs from healthy and CLE donors revealed that T cells are equally poised to respond to CXCR3 ligands, whereas CD14+CD16+ APC populations are more sensitive to CXCL6 via CXCR1 and CD14+ are more sensitive to CCL8 via CCR2. Taken together, our data map a pathway from keratinocyte injury to lymphocyte recruitment in CLE via AIM2-Casp8-IL-18-CXCL6/CXCR1 and CCL8/CCR2, and IFNG/IFNL1-CXCL9/CXCL11-CXCR3.