Crucial Role of AIM/CD5L in the Development of Glomerular Inflammation in IgA Nephropathy
Crucial Role of AIM/CD5L in the Development of Glomerular Inflammation in IgA Nephropathy
复制标题
DOI：
10.1681/asn.2019100987
复制
发表时间：
2020-09-01
影响因子：
13.6
通讯作者：
Suzuki, Yusuke
中科院分区：
文献类型：
--
作者：
Takahata, Akiko;Arai, Satoko;Suzuki, Yusuke
背景
IgA肾病（IgAN）始于肾小球中异常的IgA沉积，进展为IgM/IgG/补体共沉积，并导致慢性炎症和肾小球损伤。然而，驱动这种炎症级联反应的机制一直不清楚。最近，巨噬细胞凋亡抑制因子（AIM）蛋白被证明可在多种病理条件下调节巨噬细胞的功能，从而深刻影响包括急性肾损伤（AKI）在内的肾脏疾病的进展。一种自发性IgA肾病模型，即分组的ddY（gddY）小鼠，揭示了在IgA沉积后，AIM对整体炎症性肾小球损伤的必要性。
方法
我们使用CRISPR/Cas9建立了一个AIM缺陷型IgA肾病模型（AIM⁻/⁻gddY），并将其表型与野生型gddY（给予或不给予重组AIM）进行比较。还构建了一个IgA缺陷型IgA肾病模型（IgA⁻/⁻gddY）以进一步确定AIM的作用。
结果
在人类和小鼠的IgA肾病中，AIM与肾小球中的IgA/IgM/IgG共定位，而对照肾脏未显示AIM沉积。尽管AIM⁻/⁻gddY显示出与野生型gddY相当水平的IgA沉积，但它们未出现IgM/IgG补体的肾小球积聚、CD45⁺白细胞浸润以及炎症/纤维化基因的上调，表明对肾小球病变以及蛋白尿/血尿具有保护作用。给予重组AIM可重建IgA肾病表型，导致IgM/IgG/补体与IgA共沉积。在IgA⁻/⁻gddY小鼠中既未观察到自发性IgM/IgG共沉积，也未观察到疾病发生。
结论
AIM可能有助于肾小球中稳定的免疫复合物形成，从而促进IgA肾病的进展。因此，基于其在IgA肾病炎症起始中的作用，阻断AIM沉积或使其与IgM/IgG解离可能成为一个新的治疗靶点。
Background IgA nephropathy (IgAN) begins with aberrant IgA deposition in glomeruli, progresses to IgM/IgG/complement codeposition, and results in chronic inflammation and glomerular damage. However, the mechanism that drives such phlogogenic cascade has been unclear. Recently, apoptosis inhibitor of macrophage (AIM) protein was shown to modulate macrophages' function in various pathologic conditions, thereby profoundly affecting the progression of renal disorders, including AKI. A spontaneous IgAN model, grouped ddY (gddY) mouse, revealed the requirement of AIM for the overall inflammatory glomerular injury following IgA deposition.Methods We established an AIM-deficient IgAN model (AIM(-/-)gddY) using CRISPR/Cas9 and compared its phenotype with that of wild-type gddY with or without recombinant AIM administration. An IgA-deficient IgAN model (IgA(-/-)gddY) was also generated to further determine the role of AIM.Results In both human and murine IgAN, AIM colocalized with IgA/IgM/IgG in glomeruli, whereas control kidneys did not exhibit AIM deposition. Although AIM(-/-)gddY showed IgA deposition at levels comparable with those of wild-type gddY, they did not exhibit glomerular accumulation of IgM/IgG complements, CD45(+) leukocyte infiltration, and upregulation of inflammatory/fibrogenic genes, indicating protection from glomerular lesions and proteinuria/hematuria. Recombinant AIM administration reconstituted the IgAN phenotype, resulting in IgM/IgG/complement IgA codeposition. Neither spontaneous IgM/IgG codeposition nor disease was observed in IgA(-/-)gddY mice.Conclusions AIM may contribute to stable immune complex formation in glomeruli, thereby facilitating IgAN progression. Therefore, AIM deposition blockage or disassociation from IgM/IgG may present a new therapeutic target on the basis of its role in IgAN inflammation initiation.