Psoriasiform Inflammation Is Associated with Mitochondrial Fission/GDAP1L1 Signaling in Macrophages.
Psoriasiform Inflammation Is Associated with Mitochondrial Fission/GDAP1L1 Signaling in Macrophages.
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巨噬细胞中银屑病炎症与线粒体裂变/GDAP1L1信号传导相关
DOI：
10.3390/ijms221910410
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发表时间：
2021-09-27
影响因子：
5.6
通讯作者：
Fang JY
中科院分区：
文献类型：
--
作者：
Alalaiwe A;Chen CY;Chang ZY;Sung JT;Chuang SY;Fang JY
虽然银屑病被称为T细胞和树突状细胞驱动的皮肤炎症疾病，但据报道巨噬细胞也在其发展中发挥了一些作用。然而，激活的巨噬细胞的信号通路有助于银屑病还没有完全理解。因此，我们的目的是探索巨噬细胞如何启动和维持银屑病的可能机制。以咪喹莫特（imiquimod，IMQ）诱导分化的THP 1细胞作为巨噬细胞活化模型。IMQ还用于在小鼠中产生银屑病样病变。巨噬细胞的转录组学分析显示，IMQ干预后促炎介质和GDAP 1 L1的表达大幅增加。短发夹RNA（sh RNA）去除GDAP 1 L1可抑制巨噬细胞释放细胞因子。GDAP 1 L1通过激活丝裂原活化蛋白激酶（MAPK）和核因子（NF）-κB通路的磷酸化来调节细胞因子的产生。除GDAP 1 L1外，另一种线粒体分裂因子Drp 1在IMQ刺激后从胞浆易位到线粒体，随后根据免疫荧光成像显示线粒体断裂。将氯膦酸盐脂质体注射到小鼠体内以消耗天然巨噬细胞，以检查后者对IMQ诱导的炎症的能力。然后将具有或不具有GDAP 1 L1沉默的THP 1细胞移植到小鼠中以监测巨噬细胞的沉积。我们发现皮肤和淋巴结中有显著的THP 1积累。在IMQ处理的动物中GDAP 1 L1的沉默将银屑病样严重程度评分从8降低至2。在耗尽GDAP 1 L1后，淋巴结中的THP 1募集减少了3倍。皮肤组织学显示GDAP 1 L1介导的巨噬细胞活化诱导中性粒细胞趋化和角质形成细胞过度增殖。因此，线粒体分裂可以是对抗银屑病炎症的靶点。
While psoriasis is known as a T cell- and dendritic cell-driven skin inflammation disease, macrophages are also reported to play some roles in its development. However, the signaling pathway of activated macrophages contributing to psoriasis is not entirely understood. Thus, we aimed to explore the possible mechanisms of how macrophages initiate and sustain psoriasis. The differentiated THP1 cells, stimulated by imiquimod (IMQ), were utilized as the activated macrophage model. IMQ was also employed to produce psoriasis-like lesions in mice. A transcriptomic assay of macrophages revealed that the expressions of pro-inflammatory mediators and GDAP1L1 were largely increased after an IMQ intervention. The depletion of GDAP1L1 by short hairpin (sh)RNA could inhibit cytokine release by macrophages. GDAP1L1 modulated cytokine production by activating the phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB pathways. Besides GDAP1L1, another mitochondrial fission factor, Drp1, translocated from the cytosol to mitochondria after IMQ stimulation, followed by the mitochondrial fragmentation according to the immunofluorescence imaging. Clodronate liposomes were injected into the mice to deplete native macrophages for examining the latter’s capacity on IMQ-induced inflammation. The THP1 cells, with or without GDAP1L1 silencing, were then transplanted into the mice to monitor the deposition of macrophages. We found a significant THP1 accumulation in the skin and lymph nodes. The silencing of GDAP1L1 in IMQ-treated animals reduced the psoriasiform severity score from 8 to 2. After depleting GDAP1L1, the THP1 recruitment in the lymph nodes was decreased by 3-fold. The skin histology showed that the GDAP1L1-mediated macrophage activation induced neutrophil chemotaxis and keratinocyte hyperproliferation. Thus, mitochondrial fission can be a target for fighting against psoriatic inflammation.
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影响因子：
5.4
作者：
Jabeen M;Boisgard AS;Danoy A;El Kholti N;Salvi JP;Boulieu R;Fromy B;Verrier B;Lamrayah M
通讯作者：
Lamrayah M
影响因子：
4.7
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影响因子：
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影响因子：
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作者：
Chuang SY;Chen CY;Yang SC;Alalaiwe A;Lin CH;Fang JY
通讯作者：
Fang JY
影响因子：
3.3
作者：
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通讯作者：
Lee, Dong-Seok