Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
FASEB J. 2024 Dec 15;38(23):e70216. doi: 10.1096/fj.202402318R.
Severe acute kidney injury (AKI) is a risk factor for the future development of chronic kidney disease (CKD), and macrophages are an essential cell group implicated in injury, repair, and fibrosis during this progress. However, the underlying mechanism of how macrophages participate in the development of the disease is largely unclear. CD11b (Integrin α) is highly expressed in monocytes/macrophages and has been verified to mediate broad functions. We found that CD11b-knockout mice were protected from the ischemia/reperfusion-induced AKI-to-CKD process. Additionally, renal macrophages from the kidneys of CD11b-deficient mice presented an M2-like, anti-inflammatory phenotype. We demonstrated both in vitro and in vivo that enhanced alternative activation in CD11b-knockout macrophages is regulated by the interleukin (IL)-4/signal transducer and activator of transcription (STAT) 6 axis, which is mediated by the inactivation of the Src-family kinase (SFK) member Lyn. Importantly, the therapeutical administration of CD11b-neutralizing antibody can effectively prevent AKI-to-CKD progress. Thus, our study verifies that CD11b plays a critical role in limiting the alternative activation of macrophages and may be a potential therapeutic target during the AKI-to-CKD process.
严重急性肾损伤（AKI）是慢性肾脏病（CKD）未来发展的一个危险因素，巨噬细胞是在这一进展过程中参与损伤、修复和纤维化的重要细胞群。然而，巨噬细胞如何参与疾病发展的潜在机制在很大程度上尚不清楚。CD11b（整合素α）在单核细胞/巨噬细胞中高度表达，并已被证实介导广泛的功能。我们发现 CD11b 敲除小鼠对缺血/再灌注诱导的 AKI 向 CKD 过程具有保护作用。此外，来自 CD11b 缺陷小鼠肾脏的肾巨噬细胞呈现 M2 样、抗炎表型。我们在体外和体内都证明了 CD11b 敲除巨噬细胞中增强的替代激活受白细胞介素（IL）-4/信号转导和转录激活因子（STAT）6 轴的调节，该轴由 Src 家族激酶（SFK）成员 Lyn 的失活介导。重要的是，CD11b 中和抗体的治疗性给药可有效预防 AKI 向 CKD 的进展。因此，我们的研究证实 CD11b 在限制巨噬细胞的替代激活中起着关键作用，并且在 AKI 向 CKD 过程中可能是一个潜在的治疗靶点。
