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：
10.1101/2020.09.16.299420
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发表时间：
2020-09
期刊：
影响因子：
9.8
通讯作者：
Koutarou Nakamura;Seiichiro Sakai;Jun Tsuyama;Akari Nakamura;Kento Otani;Kumiko Kurabayashi;Yoshiko Yogiash
中科院分区：
文献类型：
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作者：
Koutarou Nakamura;Seiichiro Sakai;Jun Tsuyama;Akari Nakamura;Kento Otani;Kumiko Kurabayashi;Yoshiko Yogiash
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，我们报告了DJ-1，它在细胞内发挥抗氧化蛋白的作用，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（BBM）产生多种炎性细胞因子。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中，并与浸润的骨髓细胞的表面直接接触。施用抗DJ-1的抗体抑制浸润免疫细胞中炎性细胞因子的表达并减轻缺血性神经元损伤。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。DJ-1作为神经元中的细胞保护性抗氧化蛋白已被彻底研究。然而，在这里，我们证明，细胞外释放的DJ-1触发缺血性中风后的神经毒性炎症。细胞内DJ-1增加响应于缺血神经元中的氧化应激，但如果缺血应激导致坏死细胞死亡，则DJ-1在细胞外释放。释放的DJ-1与浸润性骨髓细胞表面上的TLR 2和TLR 4相互作用，并引发缺血后炎症，导致缺血性中风的病理学恶化。因此，细胞外DJ-1是以前未知的致炎DAMP，并且可能是用于预防炎症和神经退行性疾病进展的治疗干预的推定靶标。
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). 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 hours after stroke onset and makes direct contact with the surfaces of infiltrating myeloid cells. Administration of an antibody against DJ-1 suppresses the expression of inflammatory cytokines in infiltrating immune cells and attenuates 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. Significance statement DJ-1 has been thoroughly investigated as a cytoprotective antioxidant protein in neurons. However, here we demonstrate that extracellularly released DJ-1 triggers neurotoxic inflammation after ischemic stroke. Intracellular DJ-1 increases in response to oxidative stress in ischemic neurons, but if ischemic stresses result in necrotic cell death, DJ-1 is released extracellularly. Released DJ-1 interacts with TLR2 and TLR4 on the surface of infiltrating myeloid cells and triggers post-ischemic inflammation, leading to the exacerbated pathologies of ischemic stroke. Thus, extracellular DJ-1 is a previously unknown inflammatogenic DAMP, and may be a putative target for therapeutic intervention to prevent progression of inflammatory and neurodegenerative diseases.