Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States.
Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
Front Immunol. 2022 Jun 10;13:930397. doi: 10.3389/fimmu.2022.930397. eCollection 2022.
Metabolic disorders (i.e., hyperglycemia, hyperlipidemia, and hyperinsulinemia) cause increased secretion of inflammatory cytokines/chemokines, leading to gradual loss of cardiac resident macrophage population and increased accumulation of inflammatory monocytes/macrophages in the heart. Such self-perpetuating effect may contribute to the development of cardiomyopathy during diabetes. Recent meta-analysis data reveal that lipocalin 10 (Lcn10) is significantly downregulated in cardiac tissue of patients with heart failure but is increased in the blood of septic patients. However, the functional role of Lcn10 in cardiac inflammation triggered by metabolic disorders has never been investigated. In this study, we demonstrate that the expression of Lcn10 in macrophages was significantly decreased under multiple metabolic stress conditions. Furthermore, Lcn10-null macrophages exhibited pro-inflammatory phenotype in response to inflammation stimuli. Next, using a global Lcn10-knockout (KO) mouse model to induce type-2 diabetes (T2D), we observed that loss of Lcn10 promoted more pro-inflammatory macrophage infiltration into the heart, compared to controls, leading to aggravated insulin resistance and impaired cardiac function. Similarly, adoptive transfer of Lcn10-KO bone marrow cells into X-ray irradiated mice displayed higher ratio of pro-/anti-inflammatory macrophages in the heart and worsened cardiac function than those mice received wild-type (WT) bone marrows upon T2D conditions. Mechanistically, RNA-sequencing analysis showed that Nr4a1, a nuclear receptor known to have potent anti-inflammatory effects, is involved in Lcn10-mediated macrophage activation. Indeed, we found that nuclear translocation of Nr4a1 was disrupted in Lcn10-KO macrophages upon stimulation with LPS + IFNγ. Accordingly, treatment with Cytosporone B (CsnB), an agonist of Nr4a1, attenuated the pro-inflammatory response in Lcn10-null macrophages and partially improved cardiac function in Lcn10-KO diabetic mice. Together, these findings indicate that loss of Lcn10 skews macrophage polarization to pro-inflammatory phenotype and aggravates cardiac dysfunction during type-2 diabetes through the disruption of Nr4a1-mediated anti-inflammatory signaling pathway in macrophages. Therefore, reduction of Lcn10 expression observed in diabetic macrophages may be responsible for the pathogenesis of diabetes-induced cardiac dysfunction. It suggests that Lcn10 might be a potential therapeutic factor for diabetic heart failure.
代谢紊乱（如高血糖、高血脂和高胰岛素血症）会导致炎症细胞因子/趋化因子的过度分泌，导致心脏常驻巨噬细胞群逐渐减少，炎症单核细胞/巨噬细胞在心脏中的积累增加。这种自我维持的效应可能导致糖尿病期间心肌病的发展。最近的荟萃分析数据表明，脂钙蛋白 10（Lcn10）在心衰患者的心脏组织中显著下调，但在脓毒症患者的血液中增加。然而，Lcn10 在代谢紊乱引发的心脏炎症中的功能作用从未被研究过。在这项研究中，我们证明了在多种代谢应激条件下，巨噬细胞中 Lcn10 的表达显著降低。此外，Lcn10 缺陷型巨噬细胞在炎症刺激下表现出促炎表型。接下来，使用全局 Lcn10 敲除（KO）小鼠模型诱导 2 型糖尿病（T2D），我们观察到与对照组相比，Lcn10 的缺失促进了更多的促炎巨噬细胞浸润心脏，导致胰岛素抵抗加剧和心脏功能受损。同样，将 Lcn10-KO 骨髓细胞过继转移到 X 射线照射的小鼠中，在 T2D 条件下，与接受野生型（WT）骨髓的小鼠相比，心脏中促炎/抗炎巨噬细胞的比例更高，心脏功能更差。从机制上讲，RNA 测序分析表明，Nr4a1 是一种具有强大抗炎作用的核受体，参与 Lcn10 介导的巨噬细胞激活。事实上，我们发现 LPS+IFNγ 刺激后，Lcn10-KO 巨噬细胞中 Nr4a1 的核转位被破坏。因此，Nr4a1 的激动剂 Cytosporone B（CsnB）的治疗减弱了 Lcn10 缺陷型巨噬细胞的促炎反应，并部分改善了 Lcn10-KO 糖尿病小鼠的心脏功能。总之，这些发现表明，Lcn10 的缺失使巨噬细胞向促炎表型极化，并通过破坏巨噬细胞中 Nr4a1 介导的抗炎信号通路，在 2 型糖尿病期间加重心脏功能障碍。因此，糖尿病巨噬细胞中观察到的 Lcn10 表达减少可能是糖尿病诱导的心脏功能障碍发病机制的原因。这表明 Lcn10 可能是糖尿病性心力衰竭的潜在治疗因子。
