IFN Regulatory Factor 4 Controls Post-ischemic Inflammation and Prevents Chronic Kidney Disease
IFN Regulatory Factor 4 Controls Post-ischemic Inflammation and Prevents Chronic Kidney Disease
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DOI：
10.3389/fimmu.2019.02162
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发表时间：
2019-10-01
影响因子：
7.3
通讯作者：
Lech, Maciej
中科院分区：
文献类型：
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作者：
Lorenz, Georg;Moschovaki-Filippidou, Foteini;Lech, Maciej
肾脏缺血再灌注损伤（IRI）导致干扰素调节因子4（IRF 4）介导的急性炎症反应的反调节。除此之外，IRF 4在控制细胞因子环境、T细胞分化和巨噬细胞极化方面发挥重要作用。后者与组织重塑有关。因此，IRF 4在IRI后的长期结局方面的作用仍然难以捉摸。我们假设Irf 4（-/-）小鼠无法解决慢性炎症会促进慢性肾病（CKD）的进展。为了评估IRF 4在体内慢性对急性损伤的作用，采用急性IRI后慢性损伤的小鼠模型。IRI后10天内，Irf 4在肾组织中的表达增加。mRNA和蛋白质水平在IRI后5周保持较高水平，表明在慢性期具有调节功能。IRF 4缺陷的小鼠表现出肾小管细胞损失增加和浸润巨噬细胞清除缺陷。这些现象与促炎性巨噬细胞标志物的表达增加以及替代活化的巨噬细胞标志物的表达减少有关。此外，IRF 4缺陷小鼠表现出交替激活的巨噬细胞发育缺陷。在高血压肾病患者的人活检标本与活体供体标本中进一步观察到残留M1巨噬细胞特征的提示。因此，IRF 4可能通过使M2巨噬细胞极化和限制Th 1细胞因子应答来限制IRI后的CKD进展和肾纤维化。Irf 4（-/-）小鼠中替代巨噬细胞亚群的恶化在小鼠IRI后的长期过程中引起慢性肾内炎症、肾小管上皮细胞丢失和肾纤维化。这些发现对人类CKD的临床意义目前仍不确定，需要进一步研究。
Ischemia reperfusion injury (IRI) of the kidney results in interferon regulatory factor 4 (IRF4)-mediated counter-regulation of the acute inflammatory response. Beyond that, IRF4 exerts important functions in controlling the cytokine milieu, T-cell differentiation, and macrophage polarization. The latter has been implicated in tissue remodeling. It therefore remains elusive what the role of IRF4 is in terms of long-term outcome following IRI. We hypothesized that an inability to resolve chronic inflammation in Irf4(-/-) mice would promote chronic kidney disease (CKD) progression. To evaluate the effects of IRF4 in chronic upon acute injury in vivo, a mouse model of chronic injury following acute IRI was employed. The expression of Irf4 increased within 10 days after IRI in renal tissue. Both mRNA and protein levels remained high up to 5 weeks upon IRI, suggesting a regulatory function in the chronic phase. Mice deficient in IRF4 display increased tubular cell loss and defective clearance of infiltrating macrophages. These phenomena were associated with increased expression of pro-inflammatory macrophage markers together with reduced expression of alternatively activated macrophage markers. In addition, IRF4-deficient mice showed defective development of alternatively activated macrophages. Hints of a residual M1 macrophage signature were further observed in human biopsy specimens of patients with hypertensive nephropathy vs. living donor specimens. Thus, IRF4 restricts CKD progression and kidney fibrosis following IRI, potentially by enabling M2 macrophage polarization and restricting a Th1 cytokine response. Deteriorated alternative macrophage subpopulations in Irf4(-/-) mice provoke chronic intrarenal inflammation, tubular epithelial cell loss, and renal fibrosis in the long course after IRI in mice. The clinical significance of these finding for human CKD remains uncertain at present and warrants further studies.