HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness
HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness
复制标题
类风湿性关节炎中含肝素结合表皮生长因子（HBEGF）的巨噬细胞可诱导成纤维细胞的侵袭性
DOI：
10.1126/scitranslmed.aau8587
复制
发表时间：
2019-05-08
影响因子：
17.1
通讯作者：
Donlin, Laura T.
中科院分区：
文献类型：
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作者：
Kuo, David;Ding, Jennifer;Donlin, Laura T.
巨噬细胞根据组织微环境中发现的信号调整其功能，假定有广泛的表型。对人类组织中巨噬细胞表型的详细了解是有限的。使用单细胞RNA测序，我们在自身免疫性疾病类风湿性关节炎(RA)患者的关节中定义了不同的巨噬细胞亚群，该疾病影响的人口比例类似于1%。我们所说的HBEGF(+)炎性巨噬细胞亚群在RA组织中丰富，由常驻成纤维细胞和细胞因子肿瘤坏死因子(TNF)形成。这些巨噬细胞以一种依赖于表皮生长因子受体的方式促进成纤维细胞的侵袭，表明在这种炎症环境中的细胞间串扰重塑了这两种细胞类型，并有助于成纤维细胞介导的关节破坏。在一项体外滑膜组织试验中，用于治疗RA患者的大多数药物都以HBEGF(+)炎症巨噬细胞为靶点；然而，在某些情况下，药物将它们重新定向到一种预计不会消炎的状态。这些数据突显了如何通过对局部巨噬细胞表型和细胞间相互作用的研究，在我们对慢性炎症的人体组织和药物影响的理解方面取得进展。
Macrophages tailor their function according to the signals found in tissue microenvironments, assuming a wide spectrum of phenotypes. A detailed understanding of macrophage phenotypes in human tissues is limited. Using single-cell RNA sequencing, we defined distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects similar to 1% of the population. The subset we refer to as HBEGF(+) inflammatory macrophages is enriched in RA tissues and is shaped by resident fibroblasts and the cytokine tumor necrosis factor (TNF). These macrophages promoted fibroblast invasiveness in an epidermal growth factor receptor-dependent manner, indicating that intercellular cross-talk in this inflamed setting reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo synovial tissue assay, most medications used to treat RA patients targeted HBEGF(+) inflammatory macrophages; however, in some cases, medication redirected them into a state that is not expected to resolve inflammation. These data highlight how advances in our understanding of chronically inflamed human tissues and the effects of medications therein can be achieved by studies on local macrophage phenotypes and intercellular interactions.