Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom.
Wales Kidney Research Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Front Immunol. 2023 Oct 2;14:1240679. doi: 10.3389/fimmu.2023.1240679. eCollection 2023.
Chronic Kidney Disease (CKD) is associated with markedly increased cardiovascular (CV) morbidity and mortality. Chronic inflammation, a hallmark of both CKD and CV diseases (CVD), is believed to drive this association. Pro-inflammatory endogenous TLR agonists, Damage-Associated Molecular Patterns (DAMPs), have been found elevated in CKD patients' plasma and suggested to promote CVD, however, confirmation of their involvement, the underlying mechanism(s), the extent to which individual DAMPs contribute to vascular pathology in CKD and the evaluation of potential therapeutic strategies, have remained largely undescribed. A multi-TLR inhibitor, soluble TLR2, abrogated chronic vascular inflammatory responses and the increased aortic atherosclerosis-associated gene expression observed in nephropathic mice, without compromising infection clearance. Mechanistically, we confirmed elevation of 4 TLR DAMPs in CKD patients' plasma, namely Hsp70, Hyaluronic acid, HMGB-1 and Calprotectin, which displayed different abilities to promote key cellular responses associated with vascular inflammation and progression of atherosclerosis in a TLR-dependent manner. These included loss of trans-endothelial resistance, enhanced monocyte migration, increased cytokine production, and foam cell formation by macrophages, the latter via cholesterol efflux inhibition. Calprotectin and Hsp70 most consistently affected these functions. Calprotectin was further elevated in CVD-diagnosed CKD patients and strongly correlated with the predictor of CV events CRP. In nephropathic mice, Calprotectin blockade robustly reduced vascular chronic inflammatory responses and pro-atherosclerotic gene expression in the blood and aorta. Taken together, these findings demonstrated the critical extent to which the DAMP-TLR pathway contributes to vascular inflammatory and atherogenic responses in CKD, revealed the mechanistic contribution of specific DAMPs and described two alternatives therapeutic approaches to reduce chronic vascular inflammation and lower CV pathology in CKD.
慢性肾脏病（CKD）与心血管（CV）发病率和死亡率的显著增加有关。慢性炎症是 CKD 和心血管疾病（CVD）的标志，据信它推动了这种关联。促炎内源性 TLR 激动剂，损伤相关分子模式（DAMPs），已在 CKD 患者的血浆中发现升高，并被认为可促进 CVD，但对其参与、潜在机制、个体 DAMPs 对 CKD 血管病理学的贡献程度以及评估潜在的治疗策略，仍在很大程度上未被描述。一种多 TLR 抑制剂，可溶性 TLR2，可消除肾病小鼠中观察到的慢性血管炎症反应和与动脉粥样硬化相关的基因表达增加，而不会影响感染清除。从机制上讲，我们证实了 CKD 患者血浆中 4 种 TLR DAMPs（热休克蛋白 70、透明质酸、HMGB-1 和钙卫蛋白）的升高，它们以 TLR 依赖的方式显示出不同的能力，可促进与血管炎症和动脉粥样硬化进展相关的关键细胞反应。这些反应包括跨内皮阻力丧失、单核细胞迁移增强、细胞因子产生增加和泡沫细胞形成，后者通过胆固醇外排抑制。钙卫蛋白和热休克蛋白 70 最一致地影响这些功能。钙卫蛋白在 CVD 诊断的 CKD 患者中进一步升高，并与心血管事件的预测因子 CRP 强烈相关。在肾病小鼠中，钙卫蛋白阻断可显著减少血管慢性炎症反应和促动脉粥样硬化基因表达在血液和主动脉中。总之，这些发现表明 DAMP-TLR 途径在 CKD 中对血管炎症和动脉粥样形成反应的贡献程度至关重要，揭示了特定 DAMPs 的机制贡献，并描述了两种减少 CKD 中慢性血管炎症和降低 CV 病理的替代治疗方法。
