MyD88 mediates the decision to die by apoptosis or necroptosis after UV irradiation.
MyD88 mediates the decision to die by apoptosis or necroptosis after UV irradiation.
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DOI：
10.1177/1753425913501706
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发表时间：
2014-07
期刊：
影响因子：
3.2
通讯作者：
Gaspari AA
中科院分区：
文献类型：
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作者：
Harberts E;Fishelevich R;Liu J;Atamas SP;Gaspari AA
紫外线辐射诱导的细胞损伤通常与细胞凋亡相关，并且已知会导致全身性免疫抑制。UV后如何决定进行细胞凋亡还不完全清楚。我们假设TLR信号传导的中心介质MyD 88决定UV暴露后的细胞命运。来自MyD 88种系缺陷小鼠（MyD 88 −/−）的永生化骨髓源性巨噬细胞（BMDM）和离体腹膜巨噬细胞（PM）在UV后的存活率显著高于野生型（WT）PM。与WT相比，MyD 88 −/−动物PM和表皮中UV诱导的细胞凋亡（DNA梯状）减少。在MyD 88 −/− PM中，caspase 3和促坏死凋亡蛋白RIP 1的切割减少，促炎性TNF-α的转录和释放显著增加，表明坏死性凋亡而不是凋亡已经启动。体内研究证实了紫外线照射后的这一假设，在MyD 88 −/−皮肤切片中通过TUNEL和炎症显示出低凋亡。考虑到MyD 88参与许多TLR途径，比较了TLR 2-/-、TLR 4-/-和WT小鼠的BMDM，以获得UV诱导细胞凋亡的证据。只有TLR 4 −/− BMDM和PM具有与MyD 88 −/−相似的表型，表明TLR 4-MyD 88轴对细胞命运决定有重要贡献。我们的研究描述了紫外线后MyD 88信号传导的新细胞后果，并可能为减轻紫外线诱导的免疫抑制的疗法提供理论基础。
UV irradiation-induced cellular damage is classically associated with apoptosis and is known to result in systemic immunosuppression. How the decision to undergo apoptosis is made following UV is not fully understood. We hypothesize that a central mediator of TLR signaling, MyD88, determines cell fate after UV exposure. Survival after UV of immortalized bone marrow-derived macrophages (BMDM) and ex vivo peritoneal macrophages (PM) from MyD88 germline-deficient mice (MyD88−/−) was significantly higher than wild type (WT) PM. UV-induced apoptosis (DNA laddering) in PM and epidermis of MyD88−/− animals versus WT was decreased. In MyD88−/− PM, decreased cleavage of caspase 3, as well as pro-necroptotic protein, RIP1, and a significant increase in transcription and release of proinflammatory TNF-α, suggest that necroptosis, rather than apoptosis, has been initiated. In vivo studies confirm this hypothesis after UV, showing low apoptosis by TUNEL and inflammation in MyD88−/− skin sections. Considering that MyD88 participates in many TLR pathways, BMDM from TLR2−/−, TLR4−/− and WT mice were compared for evidence of UV-induced apoptosis. Only TLR4−/− BMDM and PM had a similar phenotype to MyD88−/−, suggesting that the TLR4– MyD88 axis importantly contributes to cell fate decision. Our study describes a new cellular consequence of MyD88 signaling after UV, and may provide rationale for therapies to mitigate UV-induced immunosuppression.
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发表时间：
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期刊：
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影响因子：
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