CÚRAM Centre for Research in Medical Devices, School of Medicine, Regenerative Medicine Institute (REMEDI), University of Galway, Galway, Ireland.
Nephrology Department, Galway University Hospitals, Saolta University Health Care Group, Galway, Ireland.
J Am Soc Nephrol. 2023 May 1;34(5):793-808. doi: 10.1681/ASN.0000000000000083. Epub 2023 Jan 26.
CKD is accompanied by abnormal inflammation, which contributes to progressive loss of functional renal tissue and accelerated cardiovascular disease. Although studies have documented that dysregulation of monocyte maturation and function is associated with CKD and its complications, it is not well characterized. This study reveals that a distinctive human monocyte subtype with high propensity for releasing proinflammatory mediators and activating endothelial cells is increased in adults with CKD compared with adults with high cardiovascular risk and normal kidney function. It also demonstrates that human monocyte adhesion to endothelial layers and responses to specific inflammatory migration signals are enhanced in CKD. These findings offer insights into the mechanisms of CKD-associated intravascular and localized inflammation and may suggest potential targets for therapeutic interventions.
Cardiovascular disease (CVD) in patients with CKD is associated with increased circulating intermediate monocytes (IMs). Dysregulation of monocyte maturation and function is associated with CKD and its complications, but it is incompletely characterized.
To explore monocyte repertoire abnormalities in CKD, we studied properties of monocyte subpopulations, including IM subpopulations distinguished by HLA-DR expression level, in individuals with or without CKD. Using flow cytometry, we profiled monocyte populations in blood samples from adults with CKD, healthy volunteers (HVs), and patient controls (PCs) with high CVD risk. Monocyte subpopulations were also derived from single-cell RNA-sequencing profiles of paired blood and biopsy samples from kidney transplant recipients. We quantified intracellular cytokine production, migration, and endothelial adhesion in ex vivo assays of PBMCs.
Of four predefined blood monocyte subpopulations, only HLA-DR hi IMs were increased in individuals with CKD compared with HVs and PCs. In HVs and patients with CKD, LPS-stimulated HLA-DR hi IMs isolated from blood produced higher amounts of TNF and IL-1 β than other monocyte populations. Single-cell analysis revealed four monocyte clusters common to blood and kidneys, including an HLA-DR hi IM-like cluster that was enriched in kidneys versus blood. Migration toward CCL5 and CX3CL1 and adhesion to primary endothelial cell layers were increased in monocyte subpopulations in individuals with CKD compared with HVs. Monocyte adhesion to endothelial cells was partly dependent on CX3CR1/CX3CL1 interaction.
CKD is associated with an increased number of a distinctive proinflammatory IM subpopulation and abnormalities of monocyte migration and endothelial adhesion. Dysregulated monocyte maturation and function may represent targetable factors contributing to accelerated CVD in CKD.
CKD 伴有异常炎症，这导致了功能性肾组织的进行性丧失和加速的心血管疾病。尽管研究已经证明单核细胞成熟和功能的失调与 CKD 及其并发症有关，但尚未得到很好的描述。本研究表明，与高心血管风险和正常肾功能的成年人相比，CKD 成年人中具有高释放促炎介质和激活内皮细胞倾向的独特人类单核细胞亚型增加。它还表明，在 CKD 中，单核细胞与内皮层的粘附以及对特定炎症迁移信号的反应增强。这些发现为 CKD 相关的血管内和局部炎症的机制提供了深入了解，并可能提示潜在的治疗干预靶点。
CKD 患者的心血管疾病（CVD）与循环中间单核细胞（IM）的增加有关。单核细胞成熟和功能的失调与 CKD 及其并发症有关，但尚未完全描述。
为了探讨 CKD 中单核细胞谱异常，我们研究了单核细胞亚群的特性，包括通过 HLA-DR 表达水平区分的 IM 亚群，这些亚群存在于有无 CKD 的个体中。使用流式细胞术，我们对来自 CKD 患者、健康志愿者（HV）和具有高 CVD 风险的患者对照（PC）的血液样本中的单核细胞群体进行了分析。单核细胞亚群也来自肾移植受者的血液和活检样本的单细胞 RNA 测序谱。我们定量了 PBMCs 中细胞内细胞因子产生、迁移和内皮粘附的情况。
在四个预先定义的血液单核细胞亚群中，只有 HLA-DR hi IM 在 CKD 患者中与 HV 和 PC 相比增加。在 HV 和 CKD 患者中，与其他单核细胞群体相比，从血液中分离出的 LPS 刺激的 HLA-DR hi IM 产生了更高量的 TNF 和 IL-1β。单细胞分析显示，血液和肾脏中共有四个单核细胞簇，包括在肾脏中比血液中更丰富的 HLA-DR hi IM 样簇。与 HV 相比，CKD 患者的单核细胞亚群向 CCL5 和 CX3CL1 的迁移以及与原代内皮细胞层的粘附增加。单核细胞与内皮细胞的粘附部分依赖于 CX3CR1/CX3CL1 相互作用。
CKD 与独特的促炎 IM 亚群数量增加以及单核细胞迁移和内皮粘附异常有关。单核细胞成熟和功能的失调可能代表导致 CKD 中加速 CVD 的可靶向因素。
