Peptidylarginine Deiminase 4 Promotes the Renal Infiltration of Neutrophils and Exacerbates the TLR7 Agonist-Induced Lupus Mice
Peptidylarginine Deiminase 4 Promotes the Renal Infiltration of Neutrophils and Exacerbates the TLR7 Agonist-Induced Lupus Mice
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DOI：
10.3389/fimmu.2020.01095
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发表时间：
2020-06-23
影响因子：
7.3
通讯作者：
Fujio, Keishi
中科院分区：
文献类型：
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作者：
Hanata, Norio;Shoda, Hirofumi;Fujio, Keishi
由PADI4编码的PAD4在免疫系统中发挥重要作用，但其在狼疮性肾炎发病机制中的作用仍存在争议。研究PAD4在狼疮模型小鼠中的病理作用。分析了咪喹莫特(imiquimod，ImQ)诱导的野生型(WT)和Padi4基因敲除(KO)小鼠狼疮模型。检测尿蛋白、血清抗双链DNA(抗dsDNA)抗体和肾组织浸润性细胞。采用过继转移和黏附实验检测中性粒细胞的迁移和黏附。Padi4KO小鼠与WT小鼠相比，在蛋白尿进展方面有明显改善，但血清抗dsDNA抗体和免疫复合物在肾小球中的沉积没有差异。Padi4KO小鼠肾脏中性粒细胞浸润减少。过继转移的Padi4KO中性粒细胞在ImQ处理的WT小鼠肾脏中迁移减少，与ICAM-1的粘附性受损。Padi4KO中性粒细胞p38丝裂原活化蛋白激酶(MAPK)通路上调减少。Toll样受体7(TLR7)刺激的Padi4KO中性粒细胞p38MAPK的磷酸化水平降低，p38MAPK支架蛋白JNK相关的亮氨酸拉链蛋白(JLP)的表达降低。来自杂合子JlpKO小鼠的中性粒细胞与ICAM-1的粘附性减弱，并减少了向ImQ处理的WT小鼠肾脏的迁移。这些结果提示PAD4-p38MAPK通路在TLR7激动剂诱导的狼疮性肾炎肾脏中性粒细胞浸润中起关键作用，并提示中性粒细胞介导的肾脏炎症的重要性。抑制PAD4-p38MAPK通路可能有助于制定治疗狼疮性肾炎的新策略。
Peptidylarginine deiminase 4 (PAD4), encoded byPADI4, plays critical roles in the immune system; however, its contribution to the pathogenesis of lupus nephritis remains controversial. The pathological roles of PAD4 were investigated in lupus model mice. An imiquimod (IMQ)-induced lupus model was analyzed in wild-type (WT) andPadi4-knockout (KO) mice. Proteinuria, serum anti-double stranded DNA (anti-dsDNA) antibody, and renal infiltrated cells were evaluated. Neutrophil migration and adhesion were assessed using adoptive transfer and adhesion assay. PAD4-regulated pathways were identified by RNA-sequencing ofPadi4KO neutrophils.Padi4KO mice exhibited significant improvements in proteinuria progression compared with WT mice, whereas, serum anti-dsDNA antibody and immune complex deposition in the glomeruli showed no difference between both mice strains.Padi4KO mice showed decreased neutrophil infiltration in the kidneys. Adoptively transferredPadi4KO neutrophils showed decreased migration to the kidneys of IMQ-treated WT mice, and adhesion to ICAM-1 was impaired inPadi4 KO neutrophils.Padi4KO neutrophils exhibited reduced upregulation of p38 mitogen-activated protein kinase (MAPK) pathways. Toll-like receptor 7 (TLR7)-primedPadi4KO neutrophils demonstrated reduced phosphorylation of p38 MAPK and lower expression of JNK-associated leucine zipper protein (JLP), a p38 MAPK scaffold protein. Neutrophils from heterozygousJlpKO mice showed impaired adhesion to ICAM-1 and decreased migration to the kidneys of IMQ-treated WT mice. These results indicated a pivotal role of PAD4-p38 MAPK pathway in renal neutrophil infiltration in TLR7 agonist-induced lupus nephritis, and the importance of neutrophil-mediated kidney inflammation. Inhibition of the PAD4-p38 MAPK pathway may help in formulating a novel therapeutic strategy against lupus nephritis.