Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus
Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus
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DOI：
10.3389/fimmu.2020.00408
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发表时间：
2020-03-20
影响因子：
7.3
通讯作者：
Luo, Xin M.
中科院分区：
文献类型：
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作者：
Abdelhamid, Leila;Cabana-Puig, Xavier;Luo, Xin M.
我们之前的研究表明，维生素A的活性代谢物全反式维甲酸（tRA）加重了狼疮患者原有的自身免疫；然而，其在自身免疫发展之前的影响尚不清楚。在这里，我们使用一个pristane诱导的模型，我们表明在狼疮的起始和延续阶段给予tRA会产生不同的效果。与活动性疾病期间的tRA治疗不同，前列腺素前治疗通过增加肾脏前纤维化蛋白层粘连蛋白β 1的表达，激活骨髓常规树突状细胞（cdc），上调脾脏中ICAM-1和LFA-1的相互作用，加重肾小球肾炎，表明白细胞激活和运输的活跃过程。转录组学分析显示，在狼疮诱导之前，tRA显著上调了cDC激活和迁移相关基因的表达。另一方面，化疗后治疗没有显著改变肾小球肾炎的严重程度；相反，它发挥免疫抑制功能，减少循环和肾脏自身抗体的沉积，以及抑制促炎细胞因子和趋化因子的肾脏表达。总之，这些发现表明，根据给药时间，tRA对狼疮相关肾脏炎症的调节存在差异。有趣的是，在前列腺素治疗前和治疗后，tRA都能逆转前列腺素诱导的肠道渗漏，并以类似的方式调节肠道微生物群，这表明tRA影响狼疮起始和延续阶段的肠道微生物群独立机制。
We previously showed that all-trans-retinoic acid (tRA), an active metabolite of vitamin A, exacerbated pre-existing autoimmunity in lupus; however, its effects before the development of autoimmunity are unknown. Here, using a pristane-induced model, we show that tRA exerts differential effects when given at the initiation vs. continuation phase of lupus. Unlike tRA treatment during active disease, pre-pristane treatment with tRA aggravated glomerulonephritis through increasing renal expression of pro-fibrotic protein laminin beta 1, activating bone marrow conventional dendritic cells (cDCs), and upregulating the interaction of ICAM-1 and LFA-1 in the spleen, indicating an active process of leukocyte activation and trafficking. Transcriptomic analysis revealed that prior to lupus induction, tRA significantly upregulated the expression of genes associated with cDC activation and migration. Post-pristane tRA treatment, on the other hand, did not significantly alter the severity of glomerulonephritis; rather, it exerted immunosuppressive functions of decreasing circulatory and renal deposition of autoantibodies as well as suppressing the renal expression of proinflammatory cytokines and chemokines. Together, these findings suggest that tRA differentially modulate lupus-associated kidney inflammation depending on the time of administration. Interestingly, both pre- and post-pristane treatments with tRA reversed pristane-induced leaky gut and modulated the gut microbiota in a similar fashion, suggesting a gut microbiota-independent mechanism by which tRA affects the initiation vs. continuation phase of lupus.