Ameliorated Renal Pathological Feature in MRL/MpJ-Faslpr/lpr Background Interleukin-36 Receptor-Deficient Mice
Ameliorated Renal Pathological Feature in MRL/MpJ-Faslpr/lpr Background Interleukin-36 Receptor-Deficient Mice
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DOI：
10.1093/micmic/ozac046
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发表时间：
2023-04-05
影响因子：
2.8
通讯作者：
Kon，Yasuhiro
中科院分区：
文献类型：
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作者：
Namba，Takashi;Ichii，Osamu;Kon，Yasuhiro
系统性自身免疫性疾病经常诱发狼疮性肾炎，导致肾脏中白细胞介素36受体（IL-36R）配体的平衡和表达改变，包括激动剂（IL-36α, β, γ）和拮抗剂（IL-36Ra, IL-38）。在此，我们建立并分析了狼疮性肾炎小鼠模型，MRL/MpJ-Faslpr/lprwith il - 36r敲除（KO），并与野生型（WT）小鼠进行比较。在这两种基因型中，免疫异常和肾功能指标是相似的，尽管雌性WT小鼠的血清自身抗体水平高于雄性。基因型之间IL-36R配体的表达在mRNA水平或IL-36α和IL-38评分上无显著差异。然而，与WT小鼠相比，IL-36R-KO小鼠的肾小球病变，特别是系膜基质扩张，在两性中都得到了显著改善。随着三级淋巴结构的发展，细胞向小管间质浸润的情况在基因型之间具有可比性。而在IL-36R-KO小鼠中，与WT小鼠IL-36α评分的正相关不明显。雌性IL-36R-KO小鼠的纤维化程度低于WT小鼠。重要的是，在两种基因型中，一些IL-36α+核与乙酰化赖氨酸和GCN5组蛋白乙酰转移酶共定位。因此，IL-36R配体，特别是IL-36α，通过IL-36R依赖性和IL-36R非依赖性途径参与狼疮性肾炎肾脏病理的进展。
Systemic autoimmune diseases frequently induce lupus nephritis, causing altered balance and expression of interleukin 36 receptor (IL-36R) ligands, including agonists (IL-36α, β, γ) and antagonists (IL-36Ra, IL-38), in kidneys. Here, we established and analyzed a mouse model of lupus nephritis, MRL/MpJ-Faslpr/lprwith IL-36R-knockout (KO), compared to wild-type (WT) mice. In both genotypes, indices for immune abnormalities and renal functions were comparable, although female WT mice showed higher serum autoantibody levels than males. IL-36R ligand expression did not differ significantly between genotypes at the mRNA level or in IL-36α and IL-38 scores. However, glomerular lesions, especially mesangial matrix expansion, were significantly ameliorated in both sexes of IL-36R-KO mice compared to WT mice. Cell infiltration into the tubulointerstitium with the development of tertiary lymphoid structures was comparable between genotypes. However, the positive correlation with the IL-36α score in WT mice was not evident in IL-36R-KO mice. Fibrosis was less in female IL-36R-KO mice than in WT mice. Importantly, some IL-36α+nuclei co-localized with acetylated lysine and GCN5 histone acetyltransferase, in both genotypes. Therefore, IL-36R ligands, especially IL-36α, contribute to the progression of renal pathology in lupus nephritis via IL-36R-dependent and IL-36R-independent pathways.