Iron Research Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY.
Department of Pediatrics, Albert Einstein College of Medicine, New York, NY.
Blood. 2023 Jun 22;141(25):3091-3108. doi: 10.1182/blood.2022018026.
Sickle cell disease (SCD) is hallmarked by an underlying chronic inflammatory condition, which is contributed by heme-activated proinflammatory macrophages. Although previous studies addressed heme ability to stimulate macrophage inflammatory skewing through Toll-like receptor4 (TLR4)/reactive oxygen species signaling, how heme alters cell functional properties remains unexplored. Macrophage-mediated immune cell recruitment and apoptotic cell (AC) clearance are relevant in the context of SCD, in which tissue damage, cell apoptosis, and inflammation occur owing to vaso-occlusive episodes, hypoxia, and ischemic injury. Here we show that heme strongly alters macrophage functional response to AC damage by exacerbating immune cell recruitment and impairing cell efferocytic capacity. In SCD, heme-driven excessive leukocyte influx and defective efferocytosis contribute to exacerbated tissue damage and sustained inflammation. Mechanistically, these events depend on heme-mediated activation of TLR4 signaling and suppression of the transcription factor proliferator-activated receptor γ (PPARγ) and its coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α). These changes reduce efferocytic receptor expression and promote mitochondrial remodeling, resulting in a coordinated functional and metabolic reprogramming of macrophages. Overall, this results in limited AC engulfment, impaired metabolic shift to mitochondrial fatty acid β-oxidation, and, ultimately, reduced secretion of the antiinflammatory cytokines interleukin-4 (IL-4) and IL-10, with consequent inhibition of continual efferocytosis, resolution of inflammation, and tissue repair. We further demonstrate that impaired phagocytic capacity is recapitulated by macrophage exposure to plasma of patients with SCD and improved by hemopexin-mediated heme scavenging, PPARγ agonists, or IL-4 exposure through functional and metabolic macrophage rewiring. Our data indicate that therapeutic improvement of heme-altered macrophage functional properties via heme scavenging or PGC1α/PPARγ modulation significantly ameliorates tissue damage associated with SCD pathophysiology.
镰状细胞病（SCD）的特征是存在潜在的慢性炎症状态，这是由血红素激活的促炎巨噬细胞引起的。尽管先前的研究已经确定了血红素通过 Toll 样受体 4（TLR4）/活性氧信号来刺激巨噬细胞炎症偏向，但血红素如何改变细胞的功能特性仍未被探索。巨噬细胞介导的免疫细胞募集和凋亡细胞（AC）清除在 SCD 中是相关的，在 SCD 中，由于血管阻塞发作、缺氧和缺血性损伤，会发生组织损伤、细胞凋亡和炎症。在这里，我们表明血红素通过加剧免疫细胞募集和损害细胞吞噬能力来强烈改变巨噬细胞对 AC 损伤的功能反应。在 SCD 中，血红素驱动的过度白细胞内流和缺陷的吞噬作用导致组织损伤加剧和炎症持续。从机制上讲，这些事件取决于血红素介导的 TLR4 信号激活和转录因子过氧化物酶体增殖物激活受体 γ（PPARγ）及其共激活因子过氧化物酶体增殖物激活受体 γ 共激活因子 1α（PGC1α）的抑制。这些变化降低了吞噬受体的表达，并促进了线粒体重塑，从而导致巨噬细胞的协调功能和代谢重编程。总的来说，这导致 AC 吞噬作用有限，代谢向线粒体脂肪酸β-氧化的转变受损，最终导致抗炎细胞因子白细胞介素 4（IL-4）和白细胞介素 10（IL-10）的分泌减少，从而导致吞噬作用持续、炎症消退和组织修复受限。我们进一步证明，通过巨噬细胞暴露于 SCD 患者的血浆中可以重现吞噬能力受损，并且通过血红素结合蛋白介导的血红素清除、PPARγ 激动剂或白细胞介素 4 暴露可以通过功能和代谢的巨噬细胞重编程来改善吞噬能力受损。我们的数据表明，通过血红素清除或 PGC1α/PPARγ 调节来改善血红素改变的巨噬细胞功能特性的治疗方法，可以显著改善与 SCD 病理生理学相关的组织损伤。
