Strong upregulation of inflammatory genes accompanies photoreceptor demise in canine models of retinal degeneration.
Strong upregulation of inflammatory genes accompanies photoreceptor demise in canine models of retinal degeneration.
复制标题
DOI：
10.1371/journal.pone.0177224
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Aguirre GD
中科院分区：
文献类型：
--
作者：
Appelbaum T;Santana E;Aguirre GD
我们对比分析了早发性犬人视网膜色素变性rcd1、xlpra2和erd模型以及晚发性xlpra1模型炎症反应的复杂模式。免疫应答基因和蛋白的表达随光感受器变性时间的变化而变化。对光受体死亡高峰前后的早发模型进行基因表达分析，发现多个免疫应答基因参与其中，包括编码NLRP3炎性小体成分、其底物、pro-IL1B、pro-IL18以及IL1B、IL18和TLR4通路的常见成分的基因。在两种激活的caspase-1裂解产物IL1B和IL18中，只有IL1B在rcd1和xlpra2中被检测到，而前体IL18在相同的蛋白提取物中未被加工，这突出了IL1B途径的重要性。总体免疫反应在rcd1中最突出，其次是xlpra2， erd中最不突出。值得注意的是，在rcd1和xlpra2中，而不是在erd中，免疫反应的早期诱导伴随着持续的视网膜内迁移和视网膜小胶质细胞的激活。最后，在所有早发模型中，抗炎因子的延迟激活不足以抵消快速进展的炎症。与早发模型相反，在迟发性xlpra1视网膜中，促炎基因的一个子集在任何与疾病相关的结构变化发生之前就被高度上调，但被充分的抗炎反应所抵消。结果表明，在视网膜变性动物模型中，免疫反应上调伴随着疾病的进展，以及早期抗炎治疗的潜在益处。
We have analyzed the complex pattern of the inflammatory response in early-onset canine models of human retinitis pigmentosa, rcd1, xlpra2 and erd, as well as late-onset xlpra1, in comparative manner. The time course of immune response genes and proteins expression was examined along the timeline of photoreceptors degeneration. Gene expression analysis of the early-onset models prior to and after the peak of photoreceptors death identified the involvement of multiple immune response genes including those encoding constituents of the NLRP3 inflammasome, its substrates, pro-IL1B, pro-IL18, and common components of IL1B, IL18 and TLR4 pathways. Out of two activated caspase-1 cleavage products, IL1B and IL18, only IL1B was detected in rcd1 and xlpra2 while precursor IL18 remained unprocessed in the same protein extract highlighting prominence of IL1B pathway. An overall immune response was most prominent in rcd1 followed by xlpra2 and least prominent in erd. Noticeably, in rcd1 and xlpra2, but not in erd, early induction of the immune response was accompanied by sustained intraretinal migration and activation of retinal microglia. Lastly, delayed activation of the anti-inflammatory factors in all early-onset models was insufficient to counterbalance rapidly progressing inflammation. In contrast to early-onset models, in late-onset xlpra1 retinas a subset of the pro-inflammatory genes was highly upregulated long before any disease-related structural changes occurred, but was counterbalanced by an adequate anti-inflammatory response. Results point out to upregulated immune response accompanying disease progression in animal models of retinal degeneration, and to potential benefits of early anti-inflammatory therapy.