Macrophage Phenotype Controls Long-Term AKI Outcomes-Kidney Regeneration versus Atrophy
Macrophage Phenotype Controls Long-Term AKI Outcomes-Kidney Regeneration versus Atrophy
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DOI：
10.1681/asn.2013020152
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发表时间：
2014-02-01
影响因子：
13.6
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
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作者：
Lech, Maciej;Groebmayr, Regina;Anders, Hans-Joachim
决定AKI后完全恢复与随后进行性CKD的机制在很大程度上是未知的。由于巨噬细胞调节炎症和上皮恢复，我们研究了巨噬细胞激活是否影响AKI的结果。IL-1受体相关激酶- m （IRAK-M）是一种巨噬细胞特异性toll样受体（TLR）和IL-1受体信号传导抑制剂，可阻止促炎表型的极化。在野生型小鼠肾缺血后，IRAK-M表达在AKI后3周内升高，随后下降。然而，IRAK-M基因缺失并不影响早期缺血性AKI的免疫病理和肾功能障碍。关于长期结果，野生型肾脏在AKI后5周内完全再生。相比之下，伊拉克- m -/-肾脏由于小管丢失而逐渐失去原有质量的三分之二，留下非小管肾小球和间质瘢痕。此外，M1巨噬细胞在肾间质室积聚，与促炎细胞因子和趋化因子的表达增加相一致。注射细菌CpG DNA在野生型小鼠中也能产生相同的效果，用依那西普阻断tnf - α部分阻止了IRAK-M-/-小鼠的肾萎缩。这些结果表明，在AKI愈合阶段诱导IRAK-M支持M1巨噬细胞和tnf α依赖性肾脏炎症的消退，允许损伤肾脏的结构再生和功能恢复。相反，IRAK-M功能丧失突变或短暂暴露于细菌DNA可能会导致持续的炎症性单核吞噬细胞浸润，从而损害肾脏再生并促进CKD。总之，这些结果支持IRAK-M在伤口愈合和组织再生调节中的新作用。
The mechanisms that determine full recovery versus subsequent progressive CKD after AKI are largely unknown. Because macrophages regulate inflammation as well as epithelial recovery, we investigated whether macrophage activation influences AKI outcomes. IL-1 receptor-associated kinase-M (IRAK-M) is a macrophage-specific inhibitor of Toll-like receptor (TLR) and IL-1 receptor signaling that prevents polarization toward a proinflammatory phenotype. In postischemic kidneys of wild-type mice, IRAK-M expression increased for 3 weeks after AKI and declined thereafter. However, genetic depletion of IRAK-M did not affect immunopathology and renal dysfunction during early postischemic AKI. Regarding long-term outcomes, wild-type kidneys regenerated completely within 5 weeks after AKI. In contrast, IRAK-M-/- kidneys progressively lost up to two-thirds of their original mass due to tubule loss, leaving atubular glomeruli and interstitial scarring. Moreover, M1 macrophages accumulated in the renal interstitial compartment, coincident with increased expression of proinflammatory cytokines and chemokines. Injection of bacterial CpG DNA induced the same effects in wild-type mice, and TNF-alpha blockade with etanercept partially prevented renal atrophy in IRAK-M-/- mice. These results suggest that IRAK-M induction during the healing phase of AKI supports the resolution of M1 macrophage- and TNF-alpha-dependent renal inflammation, allowing structural regeneration and functional recovery of the injured kidney. Conversely, IRAK-M loss-of-function mutations or transient exposure to bacterial DNA may drive persistent inflammatory mononuclear phagocyte infiltrates, which impair kidney regeneration and promote CKD. Overall, these results support a novel role for IRAK-M in the regulation of wound healing and tissue regeneration.