Extracellular DJ-1 induces sterile inflammation in the ischemic brain.
Extracellular DJ-1 induces sterile inflammation in the ischemic brain.
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DOI：
10.1371/journal.pbio.3000939
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发表时间：
2021-05
期刊：
影响因子：
9.8
通讯作者：
Shichita T
中科院分区：
文献类型：
--
作者：
Nakamura K;Sakai S;Tsuyama J;Nakamura A;Otani K;Kurabayashi K;Yogiashi Y;Masai H;Shichita T
炎症与各种疾病的发作和进展有关，包括大脑病理学。在这里，我们报告说，DJ-1，它在细胞内发挥作用，作为一种抗氧化蛋白，作为一种损伤相关的分子模式（DAMP），并触发炎症，如果从死细胞释放到细胞外空间。我们首次发现重组DJ-1蛋白诱导骨髓源性巨噬细胞（BMDCs）和树突状细胞（BMDCs）产生多种炎症细胞因子。我们进一步鉴定了DJ-1的αG和αH螺旋中激活Toll样受体2（TLR 2）和TLR 4的独特肽序列。在缺血性脑中，DJ-1在中风发作后24小时内从坏死的神经元释放到细胞外空间，并与浸润的髓样细胞中的TLR 2和TLR 4直接接触。虽然在大脑中动脉闭塞的小鼠模型中DJ-1缺乏并没有减弱神经元损伤，但浸润免疫细胞中的炎性细胞因子表达显著降低。接下来，我们发现施用抗体来中和细胞外DJ-1抑制脑缺血后炎症并减弱缺血性神经元损伤。我们的研究结果证明了DJ-1作为DAMP的一种以前未知的功能，并表明细胞外DJ-1可能是预防组织损伤和神经退行性疾病中炎症的治疗靶点。此前已证明抗氧化蛋白DJ-1的细胞内表达具有神经保护作用。这项研究表明，坏死神经元细胞外释放的DJ-1是无菌炎症的触发因素，可促进缺血性卒中后神经元损伤和神经功能缺损。
Inflammation is implicated in the onset and progression of various diseases, including cerebral pathologies. Here, we report that DJ-1, which plays a role within cells as an antioxidant protein, functions as a damage-associated molecular pattern (DAMP) and triggers inflammation if released from dead cells into the extracellular space. We first found that recombinant DJ-1 protein induces the production of various inflammatory cytokines in bone marrow–derived macrophages (BMMs) and dendritic cells (BMDCs). We further identified a unique peptide sequence in the αG and αH helices of DJ-1 that activates Toll-like receptor 2 (TLR2) and TLR4. In the ischemic brain, DJ-1 is released into the extracellular space from necrotic neurons within 24 h after stroke onset and makes direct contact with TLR2 and TLR4 in infiltrating myeloid cells. Although DJ-1 deficiency in a murine model of middle cerebral artery occlusion did not attenuate neuronal injury, the inflammatory cytokine expression in infiltrating immune cells was significantly decreased. Next, we found that the administration of an antibody to neutralize extracellular DJ-1 suppressed cerebral post-ischemic inflammation and attenuated ischemic neuronal damage. Our results demonstrate a previously unknown function of DJ-1 as a DAMP and suggest that extracellular DJ-1 could be a therapeutic target to prevent inflammation in tissue injuries and neurodegenerative diseases. Intracellular expression of the antioxidant protein DJ-1 has previously been shown to be neuroprotective. This study reveals that extracellularly released DJ-1 from necrotic neurons is a trigger of sterile inflammation that promotes neuronal injury and neurological deficits after ischemic stroke.
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影响因子：
64.5
作者：
Fan X;Rudensky AY
通讯作者：
Rudensky AY
影响因子：
3.7
作者：
Lev N;Barhum Y;Lotan I;Steiner I;Offen D
通讯作者：
Offen D
在人和小鼠大脑中氧化DJ-1的免疫染色。
DOI：
10.1097/nen.0000000000000087
发表时间：
2014-07
影响因子：
3.2
作者：
Saito Y;Miyasaka T;Hatsuta H;Takahashi-Niki K;Hayashi K;Mita Y;Kusano-Arai O;Iwanari H;Ariga H;Hamakubo T;Yoshida Y;Niki E;Murayama S;Ihara Y;Noguchi N
通讯作者：
Noguchi N
影响因子：
82.9
作者：
Rothhammer V;Mascanfroni ID;Bunse L;Takenaka MC;Kenison JE;Mayo L;Chao CC;Patel B;Yan R;Blain M;Alvarez JI;Kébir H;Anandasabapathy N;Izquierdo G;Jung S;Obholzer N;Pochet N;Clish CB;Prinz M;Prat A;Antel J;Quintana FJ
通讯作者：
Quintana FJ
影响因子：
56.9
作者：
Bonifati, V;Rizzu, P;Heutink, P
通讯作者：
Heutink, P