Suppressors of cGAS-STING are downregulated during fin-limb regeneration and aging in aquatic vertebrates.
Suppressors of cGAS-STING are downregulated during fin-limb regeneration and aging in aquatic vertebrates.
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DOI：
10.1002/jez.b.23227
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发表时间：
2023-10
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影响因子：
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通讯作者：
Sabateeshan Mathavarajah;Andrew W. Thompson;M. Stoyek;T. A. Quinn;Stéphane Roy;I. Braasch;G. Dellaire
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作者：
Sabateeshan Mathavarajah;Andrew W. Thompson;M. Stoyek;T. A. Quinn;Stéphane Roy;I. Braasch;G. Dellaire
在水生脊椎动物肢体和鳍再生的早期阶段（即，鱼类和两栖类），芽基经历先天免疫信号传导途径的转录重布线以促进免疫细胞募集。在哺乳动物中，先天免疫信号传导的一个基本组成部分是胞质DNA传感途径cGAS-STING。然而，cGAS-STING途径在多大程度上影响水生动物的再生尚不清楚。在有颌脊椎动物中，cGAS-STING活性的负调节是通过胞质DNA的抑制子如Trex 1、Pml和PML样外显子9（Plex 9）外切核酸酶来完成的。在这里，我们研究这些抑制cGAS-STING，以及炎症基因和cGAS活性在尾鳍和肢体再生过程中使用斑点雀鳝（Lepisosteus oculatus）和蝾螈（Ambystoma mexicanum）模型物种，并在斑马鱼（Danio rerio）的年龄相关的衰老。在受伤的雀鳝和蝾螈的再生芽基中，我们观察到炎症基因表达增加，包括干扰素基因和白细胞介素6和8。我们还观察到在伤口愈合的早期阶段美西螈Trex 1和gar pml表达的减少，这与CGAS活性的显著增加相关。与此相反，在创伤愈合过程中，plex9.1基因的表达没有改变。然而，我们观察到plex9.1在老年斑马鱼衰老的心脏组织中的表达降低，其中2 '3'-cGAMP水平升高。最后，我们证明了一个类似的模式Trex 1，pml，和plex9.1基因调控跨物种响应外源性2 '3'-cGAMP。因此，在肢鳍再生的早期阶段，Pml、Trex 1和Plex9.1核酸外切酶被下调，可能是为了允许进化上古老的cGAS-STING活性促进炎症和免疫细胞的募集。
During the early stages of limb and fin regeneration in aquatic vertebrates (i.e., fishes and amphibians), blastema undergo transcriptional rewiring of innate immune signaling pathways to promote immune cell recruitment. In mammals, a fundamental component of innate immune signaling is the cytosolic DNA sensing pathway, cGAS-STING. However, to what extent the cGAS-STING pathway influences regeneration in aquatic anamniotes is unknown. In jawed vertebrates, negative regulation of cGAS-STING activity is accomplished by suppressors of cytosolic DNA such as Trex1, Pml, and PML-like exon 9 (Plex9) exonucleases. Here, we examine the expression of these suppressors of cGAS-STING, as well as inflammatory genes and cGAS activity during caudal fin and limb regeneration using the spotted gar (Lepisosteus oculatus) and axolotl (Ambystoma mexicanum) model species, and during age-related senescence in zebrafish (Danio rerio). In the regenerative blastema of wounded gar and axolotl, we observe increased inflammatory gene expression, including interferon genes and interleukins 6 and 8. We also observed a decrease in axolotl Trex1 and gar pml expression during the early phases of wound healing which correlates with a dramatic increase in cGAS activity. In contrast, the plex9.1 gene does not change in expression during wound healing in gar. However, we observed decreased expression of plex9.1 in the senescing cardiac tissue of aged zebrafish, where 2'3'-cGAMP levels are elevated. Finally, we demonstrate a similar pattern of Trex1, pml, and plex9.1 gene regulation across species in response to exogenous 2'3'-cGAMP. Thus, during the early stages of limb-fin regeneration, Pml, Trex1, and Plex9.1 exonucleases are downregulated, presumably to allow an evolutionarily ancient cGAS-STING activity to promote inflammation and the recruitment of immune cells.