Chemokines form complex signals during inflammation and disease that can be decoded by extracellular matrix proteoglycans.
Chemokines form complex signals during inflammation and disease that can be decoded by extracellular matrix proteoglycans.
复制标题
趋化因子在炎症和疾病期间形成复杂的信号，可以被细胞外基质蛋白聚糖解码。
DOI：
10.1126/scisignal.adf2537
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发表时间：
2023
影响因子：
7.3
通讯作者：
Ridley AJL
中科院分区：
文献类型：
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作者：
Ridley AJL
趋化因子驱动的白细胞募集是免疫应答和各种疾病的关键组成部分。在炎症性疾病中靶向趋化因子系统的治疗一直不成功，这归因于冗余。我们研究了为什么趋化因子具有特定的，专门的功能，正如多项研究所证明的那样。我们分析了编码趋化因子及其受体的基因在物种、组织和疾病中的表达。该分析揭示了复杂的表达模式，例如编码介导相同白细胞类型募集的多种趋化因子的基因在相同的背景下表达，例如编码CXCR3配体CXCL9、CXCL10和CXCL11的基因。通过生物物理方法，我们发现这些趋化因子与细胞外基质糖胺聚糖（ECM GAG）的相互作用差异，这是由特定GAG的硫酸化增强。最后，体内方法证明，GAG结合对于特定T细胞亚群的CXCL9依赖性募集是关键的，但对于其他T细胞亚群不是关键的，而与CXCR3表达无关。我们的数据表明，与ECM GAG的相互作用调节趋化因子是否呈现在细胞表面上或保持更可溶，从而影响趋化因子的可用性并确保趋化因子作用的特异性。我们的研究结果提供了一个机制的理解趋化因子介导的免疫细胞招募和确定策略，以针对特定的趋化因子在炎症性疾病。
Chemokine-driven leukocyte recruitment is a key component of the immune response and of various diseases. Therapeutically targeting the chemokine system in inflammatory disease has been unsuccessful, which has been attributed to redundancy. We investigated why chemokines instead have specific, specialized functions, as demonstrated by multiple studies. We analyzed the expression of genes encoding chemokines and their receptors across species, tissues, and diseases. This analysis revealed complex expression patterns such that genes encoding multiple chemokines that mediated recruitment of the same leukocyte type were expressed in the same context, such as the genes encoding the CXCR3 ligands CXCL9, CXCL10, and CXCL11. Through biophysical approaches, we showed that these chemokines differentially interacted with extracellular matrix glycosaminoglycans (ECM GAGs), which was enhanced by sulfation of specific GAGs. Last, in vivo approaches demonstrated that GAG binding was critical for the CXCL9-dependent recruitment of specific T cell subsets but not of others, irrespective of CXCR3 expression. Our data demonstrate that interactions with ECM GAGs regulated whether chemokines were presented on cell surfaces or remained more soluble, thereby affecting chemokine availability and ensuring specificity of chemokine action. Our findings provide a mechanistic understanding of chemokine-mediated immune cell recruitment and identify strategies to target specific chemokines during inflammatory disease.