Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA; Division of Critical Care Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA.
Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Kidney Int. 2023 Mar;103(3):514-528. doi: 10.1016/j.kint.2022.10.008. Epub 2022 Nov 9.
The most common cause of acute kidney injury (AKI) in critically ill patients is sepsis. Kidney macrophages consist of both F4/80 and CD11b cells. The role of macrophage subpopulations in septic AKI pathogenesis remains unclear. As F4/80 macrophages are reported to contribute to immunomodulation following injury, we hypothesized that selective depletion of F4/80 macrophages would worsen septic AKI. F4/80 macrophages were depleted via diphtheria toxin injection in CD11cCre(+)/CX3CR1 (F4/80 MKO mice) compared to CD11cCre(-)/CX3CR1 (F4/80 MWT) mice. F4/80 MWT and F4/80 MKO mice were subjected to sham or cecal ligation and puncture to induce sepsis. Compared to F4/80 MWT mice, F4/80 MKO mice displayed worsened septic AKI at 24 hours as measured by serum creatinine and histologic injury scoring. Kidneys from F4/80 MKO mice elaborated higher kidney interleukin-6 levels. Mechanistically, single cell RNA sequencing identified a macrophage-endothelial cell immunoregulatory axis that underlies interleukin-6 expression. F4/80 macrophages expressed interleukin-1 receptor antagonist and limited interleukin-6 expression in endothelial cells. In turn, anti-interleukin-6 therapy ameliorated septic AKI in F4/80 MKO mice. Thus, F4/80 macrophages express interleukin-1 receptor antagonist and constrain interleukin-6 generation from endothelial cells to limit septic AKI, representing a targetable cellular crosstalk in septic AKI. These findings are particularly relevant owing to the efficacy of anti-interleukin-6 therapies during COVID-19 infection, a disease associated with high rates of AKI and endothelial dysfunction.
在危重病患者中，急性肾损伤（AKI）最常见的原因是脓毒症。肾脏巨噬细胞包括 F4/80 和 CD11b 细胞。巨噬细胞亚群在脓毒症 AKI 发病机制中的作用尚不清楚。由于 F4/80 巨噬细胞被报道在损伤后有助于免疫调节，我们假设选择性耗尽 F4/80 巨噬细胞会加重脓毒症 AKI。通过在 CD11cCre(+)/CX3CR1（F4/80 MKO 小鼠）而非 CD11cCre(-)/CX3CR1（F4/80 MWT）小鼠中注射白喉毒素来耗尽 F4/80 巨噬细胞。F4/80 MWT 和 F4/80 MKO 小鼠接受假手术或盲肠结扎和穿刺以诱导脓毒症。与 F4/80 MWT 小鼠相比，F4/80 MKO 小鼠在 24 小时时表现出更严重的脓毒症 AKI，表现为血清肌酐和组织学损伤评分升高。F4/80 MKO 小鼠的肾脏中白细胞介素-6 水平更高。从机制上讲，单细胞 RNA 测序确定了一个巨噬细胞-内皮细胞免疫调节轴，该轴是白细胞介素-6 表达的基础。F4/80 巨噬细胞表达白细胞介素-1 受体拮抗剂，并限制内皮细胞中白细胞介素-6 的表达。反过来，抗白细胞介素-6 治疗改善了 F4/80 MKO 小鼠的脓毒症 AKI。因此，F4/80 巨噬细胞表达白细胞介素-1 受体拮抗剂，并限制内皮细胞中白细胞介素-6 的产生以限制脓毒症 AKI，这代表了脓毒症 AKI 中可靶向的细胞串扰。这些发现特别相关，因为抗白细胞介素-6 疗法在 COVID-19 感染期间有效，COVID-19 感染与 AKI 和内皮功能障碍的高发病率相关。
