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A case of refractory systemic lupus erythematosus with monocytosis exhibiting somatic KRAS mutation 难治性系统性红斑狼疮伴单核细胞增多症表现为体细胞KRAS突变1例
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-04-01 DOI: 10.1186/s41232-022-00195-w
S. Law, S. Akizuki, A. Morinobu, K. Ohmura
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引用次数: 2
Editorial: Towards a better understanding of the physiology of the lymphatics 社论:为了更好地理解淋巴的生理学
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-03-31 DOI: 10.1186/s41232-022-00200-2
Masayuki Miyasaka
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引用次数: 1
Generation of a BAC transgenic mouse strain that expresses CreERT and a fluorescent protein under the transcriptional control of the Fzd5 locus 在Fzd5基因座转录控制下表达CreERT和荧光蛋白的BAC转基因小鼠株的产生
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2022-03-01 DOI: 10.1186/s41232-022-00194-x
S. Miyagi, Y. Kato, Ayako Watanabe, K. Miyamoto, Rintaro Yoshikawa, K. Hagiya, D. Hirano, Y. Matsuzaki
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引用次数: 0
Endothelial-specific depletion of TGF-β signaling affects lymphatic function. 内皮特异性TGF-β信号的缺失影响淋巴功能。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-12-01 DOI: 10.1186/s41232-021-00185-4
Kunpei Fukasawa, Kako Hanada, Kei Ichikawa, Masanori Hirashima, Takahiro Takagi, Susumu Itoh, Testuro Watabe, Fumiko Itoh

Background: Transforming growth factor (TGF)-β is a multifunctional cytokine involved in cell differentiation, cell proliferation, and tissue homeostasis. Although TGF-β signaling is essential for maintaining blood vessel functions, little is known about the role of TGF-β in lymphatic homeostasis.

Methods: To delineate the role of TGF-β signaling in lymphatic vessels, TβRIIfl/fl mice were crossed with Prox1-CreERT2 mice to generate TβRIIfl/fl; Prox1-CreERT2 mice. The TβRII gene in the lymphatic endothelial cells (LECs) of the conditional knockout TβRIIiΔLEC mice was selectively deleted using tamoxifen. The effects of TβRII gene deletion on embryonic lymphangiogenesis, postnatal lymphatic structure and drainage function, tumor lymphangiogenesis, and lymphatic tumor metastasis were investigated.

Results: Deficiency of LEC-specific TGF-β signaling in embryos, where lymphangiogenesis is active, caused dorsal edema with dilated lymphatic vessels at E13.5. Postnatal mice in which lymphatic vessels had already been formed displayed dilation and increased bifurcator of lymphatic vessels after tamoxifen administration. Similar dilation was also observed in tumor lymphatic vessels. The drainage of FITC-dextran, which was subcutaneously injected into the soles of the feet of the mice, was reduced in TβRIIiΔLEC mice. Furthermore, Lewis lung carcinoma cells constitutively expressing GFP (LLC-GFP) transplanted into the footpads of the mice showed reduced patellar lymph node metastasis.

Conclusion: These data suggest that TGF-β signaling in LECs maintains the structure of lymphatic vessels and lymphatic homeostasis, in addition to promoting tumor lymphatic metastasis. Therefore, suppression of TGF-β signaling in LECs might be effective in inhibiting cancer metastasis.

背景:转化生长因子(TGF)-β是一种参与细胞分化、细胞增殖和组织稳态的多功能细胞因子。尽管TGF-β信号对于维持血管功能至关重要,但TGF-β在淋巴稳态中的作用知之甚少。方法:为研究TGF-β信号在淋巴管中的作用,将TβRIIfl/fl小鼠与Prox1-CreERT2小鼠杂交生成TβRIIfl/fl;Prox1-CreERT2老鼠。条件敲除TβRIIiΔLEC小鼠淋巴内皮细胞(LECs)中的TβRII基因使用他莫昔芬选择性删除。研究了TβRII基因缺失对胚胎淋巴管生成、出生后淋巴管结构和引流功能、肿瘤淋巴管生成和淋巴肿瘤转移的影响。结果:在淋巴管生成活跃的胚胎中,lec特异性TGF-β信号缺乏导致E13.5时背侧水肿伴淋巴管扩张。他莫昔芬给药后,已经形成淋巴管的产后小鼠淋巴管扩张,分叉增加。肿瘤淋巴管也出现类似的扩张。TβRIIiΔLEC小鼠脚底皮下注射fitc -葡聚糖后,其排液减少。此外,将组成型表达GFP (LLC-GFP)的Lewis肺癌细胞移植到小鼠脚垫后,其髌骨淋巴结转移减少。结论:TGF-β信号通路在促进肿瘤淋巴转移的同时,还能维持淋巴管结构和淋巴稳态。因此,抑制上皮细胞TGF-β信号可能有效抑制肿瘤转移。
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引用次数: 7
Interleukin-6: evolving role in the management of neuropathic pain in neuroimmunological disorders. 白细胞介素-6:在神经免疫疾病神经性疼痛管理中的演变作用。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-11-02 DOI: 10.1186/s41232-021-00184-5
Kenichi Serizawa, Haruna Tomizawa-Shinohara, Shota Miyake, Kenji Yogo, Yoshihiro Matsumoto

Background: Neuropathic pain in neuroimmunological disorders refers to pain caused by a lesion or disease of the somatosensory system such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). MS and NMOSD are autoimmune disorders of the central nervous system, and ≥ 50% of patients with these disorders experience chronic neuropathic pain. The currently available medications for the management of neuropathic pain have limited effectiveness in patients with MS and NMOSD, and there is an unmet medical need to identify novel therapies for the management of chronic neuropathic pain in these patients. In this review article, we summarize the role of interleukin-6 (IL-6) in the pathogenesis of MS and NMOSD and the ameliorative effects of anti-IL-6 therapies in mouse models of experimental autoimmune encephalomyelitis (EAE).

Main body: Intraperitoneal injection of MR16-1, an anti-IL-6 receptor (IL-6R) antibody, reduced mechanical allodynia and spontaneous pain in EAE mice, which was attributed to a reduction in microglial activation and inhibition of the descending pain inhibitory system. The effect of anti-IL-6 therapies in ameliorating neuropathic pain in the clinical setting is controversial; a reduction in pain intensity has been reported with an anti-IL-6 antibody in four studies, namely a case report, a pilot study, a retrospective observational study, and a case series. Pain intensity was evaluated using a numerical rating scale (NRS), with a lower score indicating lesser pain. A reduction in the NRS score was reported in all four studies. However, in two randomized controlled trials of another anti-IL-6R antibody, the change in the visual analog scale pain score was not statistically significantly different when compared with placebo. This was attributed to the low mean pain score at baseline in both the trials and the concomitant use of medications for pain in one of the trials, which may have masked the effects of the anti-IL-6R antibody on neuropathic pain.

Conclusion: Thus, anti-IL-6 therapies might have a potential to reduce neuropathic pain, but further investigations are warranted to clarify the effect of inhibition of IL-6 signaling on neuropathic pain associated with MS and NMOSD.

背景:神经免疫疾病中的神经性疼痛是指由躯体感觉系统病变或疾病引起的疼痛,如多发性硬化症(MS)和视神经脊髓炎频谱障碍(NMOSD)。MS和NMOSD是中枢神经系统的自身免疫性疾病,≥50%的患者经历慢性神经性疼痛。目前可用的治疗神经性疼痛的药物对多发性硬化症和NMOSD患者的疗效有限,并且在治疗这些患者的慢性神经性疼痛方面存在未满足的医学需求。本文综述了白细胞介素-6 (IL-6)在MS和NMOSD发病机制中的作用,以及抗IL-6治疗对实验性自身免疫性脑脊髓炎(EAE)小鼠模型的改善作用。主体:腹腔注射抗il -6受体(IL-6R)抗体MR16-1,可减轻EAE小鼠的机械性异常性疼痛和自发性疼痛,其原因是减少了小胶质细胞的激活,抑制了下行疼痛抑制系统。抗il -6治疗在改善神经性疼痛的临床效果是有争议的;在四项研究中,抗il -6抗体可减轻疼痛强度,分别是病例报告、初步研究、回顾性观察研究和病例系列研究。采用数值评定量表(NRS)评估疼痛强度,评分越低疼痛越轻。所有四项研究都报告了NRS评分的降低。然而,在另一种抗il - 6r抗体的两项随机对照试验中,与安慰剂相比,视觉模拟量表疼痛评分的变化无统计学意义。这是由于两项试验的基线平均疼痛评分较低,其中一项试验同时使用了治疗疼痛的药物,这可能掩盖了抗il - 6r抗体对神经性疼痛的作用。结论:因此,抗IL-6治疗可能具有减轻神经性疼痛的潜力,但需要进一步的研究来阐明抑制IL-6信号对MS和NMOSD相关神经性疼痛的影响。
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引用次数: 8
Isolation and characterization of neural stem/progenitor cells in the subventricular zone of the naked mole-rat brain. 裸鼹鼠脑脑室下区神经干/祖细胞的分离与表征。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-11-01 DOI: 10.1186/s41232-021-00182-7
Yuki Yamamura, Yoshimi Kawamura, Yuki Oiwa, Kaori Oka, Nobuyuki Onishi, Hideyuki Saya, Kyoko Miura

Background: The naked mole-rat (NMR) is the longest-lived rodent with a maximum lifespan of more than 37 years and shows a negligible senescence phenotype, suggesting that tissue stem cells of NMRs are highly capable of maintaining homeostasis. However, the properties of NMR tissue stem cells, including neural stem cells (NSCs), are largely unclear.

Methods: Neural stem/progenitor cells (NS/PCs) were isolated from the subventricular zone of the neonate NMR brain (NMR-NS/PCs) and cultured in neurosphere and adherent culture conditions. Expression of NSC markers and markers of neurons, astrocytes, and oligodendrocytes was analyzed by immunocytochemistry. In adherent culture conditions, the proliferation rate and cell cycle of NMR-NS/PCs were assessed and compared with those of NS/PCs from mice (mouse-NS/PCs). The DNA damage response to γ-irradiation was analyzed by immunocytochemistry and reverse transcription-quantitative PCR.

Results: NMR-NS/PCs expressed several NSC markers and differentiated into neurons, astrocytes, and oligodendrocytes. NMR-NS/PCs proliferated markedly slower than mouse-NS/PCs, and a higher percentage of NMR-NS/PCs than mouse-NS/PCs was in G0/G1 phase. Notably, upon γ-irradiation, NMR-NS/PCs exhibited a faster initiation of the DNA damage response and were less prone to dying than mouse-NS/PCs.

Conclusions: NMR-NS/PCs were successfully isolated and cultured. The slow proliferation of NMR-NS/PCs and their resistance to DNA damage may help to prevent stem cell exhaustion in the brain during the long lifespan of NMRs. Our findings provide novel insights into the mechanism underlying delayed aging of NMRs. Further analysis of NMR tissue stem cells may lead to the development of new strategies that can prevent aging in humans.

背景:裸鼹鼠(NMR)是最长寿的啮齿动物,最大寿命超过37年,衰老表型可以忽略不计,这表明裸鼹鼠的组织干细胞具有高度的维持体内平衡的能力。然而,核磁共振组织干细胞,包括神经干细胞(NSCs)的性质在很大程度上是不清楚的。方法:从新生儿核磁共振脑(NMR-NS/PCs)脑室下区分离神经干/祖细胞(NS/PCs),在神经球和贴壁培养条件下培养。免疫细胞化学分析NSC标记物及神经元、星形胶质细胞和少突胶质细胞标记物的表达。在贴壁培养条件下,评估NMR-NS/PCs的增殖率和细胞周期,并与小鼠的NS/PCs进行比较(小鼠-NS/PCs)。采用免疫细胞化学和逆转录-定量PCR方法分析γ辐照对小鼠DNA损伤的影响。结果:NMR-NS/PCs表达多种NSC标记物,并分化为神经元、星形胶质细胞和少突胶质细胞。NMR-NS/PCs的增殖速度明显低于小鼠- ns /PCs,且处于G0/G1期的NMR-NS/PCs比例高于小鼠- ns /PCs。值得注意的是,在γ辐照下,NMR-NS/PCs比小鼠- ns /PCs表现出更快的DNA损伤反应启动和更少的死亡倾向。结论:NMR-NS/PCs分离培养成功。NMR-NS/PCs的缓慢增殖及其对DNA损伤的抵抗力可能有助于在nmr的长寿命期间防止大脑干细胞衰竭。我们的发现为nmr延迟衰老的机制提供了新的见解。对核磁共振组织干细胞的进一步分析可能会导致人类预防衰老的新策略的发展。
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引用次数: 4
Molecular biology of autoinflammatory diseases. 自身炎症性疾病的分子生物学。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-10-11 DOI: 10.1186/s41232-021-00181-8
Junya Masumoto, Wei Zhou, Shinnosuke Morikawa, Sho Hosokawa, Haruka Taguchi, Toshihiro Yamamoto, Mie Kurata, Naoe Kaneko

The long battle between humans and various physical, chemical, and biological insults that cause cell injury (e.g., products of tissue damage, metabolites, and/or infections) have led to the evolution of various adaptive responses. These responses are triggered by recognition of damage-associated molecular patterns (DAMPs) and/or pathogen-associated molecular patterns (PAMPs), usually by cells of the innate immune system. DAMPs and PAMPs are recognized by pattern recognition receptors (PRRs) expressed by innate immune cells; this recognition triggers inflammation. Autoinflammatory diseases are strongly associated with dysregulation of PRR interactomes, which include inflammasomes, NF-κB-activating signalosomes, type I interferon-inducing signalosomes, and immuno-proteasome; disruptions of regulation of these interactomes leads to inflammasomopathies, relopathies, interferonopathies, and proteasome-associated autoinflammatory syndromes, respectively. In this review, we discuss the currently accepted molecular mechanisms underlying several autoinflammatory diseases.

人类与导致细胞损伤的各种物理、化学和生物损伤(例如,组织损伤的产物、代谢物和/或感染)之间的长期斗争导致了各种适应性反应的进化。这些反应通常由先天免疫系统细胞对损伤相关分子模式(DAMPs)和/或病原体相关分子模式(PAMPs)的识别触发。DAMPs和PAMPs被先天免疫细胞表达的模式识别受体(PRRs)识别;这种识别会引发炎症。自身炎症性疾病与PRR相互作用组的失调密切相关,这些相互作用组包括炎性小体、NF-κ b激活信号小体、I型干扰素诱导信号小体和免疫蛋白酶体;这些相互作用组的调节中断分别导致炎性瘤病、炎性瘤病、干扰素病和蛋白酶体相关的自身炎症综合征。在这篇综述中,我们讨论了目前公认的几种自身炎症疾病的分子机制。
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引用次数: 9
A short review on lymphatic endothelial cell heterogeneity. 淋巴内皮细胞异质性研究综述。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-10-11 DOI: 10.1186/s41232-021-00183-6
Masayuki Miyasaka

Recent single-cell RNA sequencing studies in mouse and human have clearly indicated that lymphatic endothelial cells (LECs) consist of multiple cell subsets, each expressing a unique set of genes, residing in distinct locations in the body. These studies have also revealed a conserved pattern of gene expression in LECs across animal species, as well as specialized sets of genes unique to each species. However, the extent to which this heterogeneity is adaptive to the external milieu surrounding LECs has remained unclear. The transcriptional and regulatory pathways that program the different subsets of LECs also remain unexplored.

最近在小鼠和人类中进行的单细胞RNA测序研究清楚地表明,淋巴内皮细胞(LECs)由多个细胞亚群组成,每个细胞亚群表达一组独特的基因,位于体内不同的位置。这些研究还揭示了动物LECs中基因表达的保守模式,以及每个物种特有的特殊基因集。然而,这种异质性在多大程度上适应LECs周围的外部环境仍不清楚。编程LECs不同亚群的转录和调控途径也仍未被探索。
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引用次数: 1
Role of chaperone-mediated autophagy in the pathophysiology including pulmonary disorders. 伴蛋白介导的自噬在包括肺疾病在内的病理生理中的作用。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-10-01 DOI: 10.1186/s41232-021-00180-9
Yusuke Hosaka, Jun Araya, Yu Fujita, Kazuyoshi Kuwano

Autophagy is a highly conserved mechanism of delivering cytoplasmic components for lysosomal degradation. Among the three major autophagic pathways, chaperone-mediated autophagy (CMA) is primarily characterized by its selective nature of protein degradation, which is mediated by heat shock cognate 71 kDa protein (HSC70: also known as HSPA8) recognition of the KFERQ peptide motif in target proteins. Lysosome-associated membrane protein type 2A (LAMP2A) is responsible for substrate binding and internalization to lysosomes, and thus, the lysosomal expression level of LAMP2A is a rate-limiting factor for CMA. Recent advances have uncovered not only physiological but also pathological role of CMA in multiple organs, including neurodegenerative disorders, kidney diseases, liver diseases, heart diseases, and cancers through the accumulation of unwanted proteins or increased degradation of target proteins with concomitant metabolic alterations resulting from CMA malfunction. With respect to pulmonary disorders, the involvement of CMA has been demonstrated in lung cancer and chronic obstructive pulmonary disease (COPD) pathogenesis through regulating apoptosis. Further understanding of CMA machinery may shed light on the molecular mechanisms of refractory disorders and lead to novel treatment modalities through CMA modulation.

自噬是一种高度保守的传递溶酶体降解细胞质成分的机制。在三种主要的自噬途径中,伴侣介导的自噬(CMA)主要以其蛋白质降解的选择性为特征,它是由热休克同源的71 kDa蛋白(HSC70:也称为HSPA8)对靶蛋白中KFERQ肽基元的识别介导的。溶酶体相关膜蛋白2A型(LAMP2A)负责底物与溶酶体的结合和内化,因此,溶酶体中LAMP2A的表达水平是CMA的限速因素。最近的进展揭示了CMA在多种器官中的生理和病理作用,包括神经退行性疾病、肾脏疾病、肝脏疾病、心脏病和癌症,通过积累不需要的蛋白质或增加靶蛋白的降解,伴随CMA功能障碍导致的代谢改变。在肺部疾病方面,CMA已被证明通过调节细胞凋亡参与肺癌和慢性阻塞性肺疾病(COPD)的发病机制。进一步了解CMA机制可能有助于揭示难治性疾病的分子机制,并通过CMA调节带来新的治疗方式。
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引用次数: 11
Synthesized HMGB1 peptide attenuates liver inflammation and suppresses fibrosis in mice. 合成HMGB1肽减轻小鼠肝脏炎症,抑制纤维化。
IF 8.1 3区 医学 Q2 IMMUNOLOGY Pub Date : 2021-09-27 DOI: 10.1186/s41232-021-00177-4
Shunsuke Nojiri, Atsunori Tsuchiya, Kazuki Natsui, Suguru Takeuchi, Takayuki Watanabe, Yuichi Kojima, Yusuke Watanabe, Hiroteru Kamimura, Masahiro Ogawa, Satoko Motegi, Takahiro Iwasawa, Takeki Sato, Masaru Kumagai, Yui Ishii, Tomomi Kitayama, Yu-Tung Li, Yuya Ouchi, Takashi Shimbo, Masaaki Takamura, Katsuto Tamai, Shuji Terai

The liver has a high regenerative ability and can induce spontaneous regression of fibrosis when early liver damage occurs; however, these abilities are lost when chronic liver damage results in decompensated cirrhosis. Cell therapies, such as mesenchymal stem cell (MSC) and macrophage therapies, have attracted attention as potential strategies for mitigating liver fibrosis. Here, we evaluated the therapeutic effects of HMGB1 peptide synthesized from box A of high mobility group box 1 protein. Liver damage and fibrosis were evaluated using a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. The effects of HMGB1 peptide against immune cells were evaluated by single-cell RNA-seq using liver tissues, and those against monocytes/macrophages were further evaluated by in vitro analyses. Administration of HMGB1 peptide did not elicit a rapid response within 36 h, but attenuated liver damage after 1 week and suppressed fibrosis after 2 weeks. Fibrosis regression developed over time, despite continuous liver damage, suggesting that administration of this peptide could induce fibrolysis. In vitro analyses could not confirm a direct effect of HMGB1 peptide against monocyte/macrophages. However, macrophages were the most affected immune cells in the liver, and the number of scar-associated macrophages (Trem2+Cd9+ cells) with anti-inflammatory markers increased in the liver following HMGB1 treatment, suggesting that indirect effects of monocytes/macrophages were important for therapeutic efficacy. Overall, we established a new concept for cell-free therapy using HMGB1 peptide for cirrhosis through the induction of anti-inflammatory macrophages.

肝脏具有较高的再生能力,早期肝损伤时可诱导纤维化自发消退;然而,当慢性肝损伤导致失代偿性肝硬化时,这些能力就会丧失。细胞疗法,如间充质干细胞(MSC)和巨噬细胞疗法,作为缓解肝纤维化的潜在策略而受到关注。本文以高迁移率组1蛋白盒A为原料合成HMGB1肽,对其治疗效果进行了评价。使用四氯化碳(CCl4)诱导的肝硬化小鼠模型评估肝损伤和纤维化。采用肝组织单细胞RNA-seq法评价HMGB1肽对免疫细胞的作用,并通过体外分析进一步评价HMGB1肽对单核/巨噬细胞的作用。HMGB1肽在36小时内没有引起快速反应,但在1周后减轻了肝损伤,在2周后抑制了纤维化。尽管肝损伤持续,但随着时间的推移,纤维化逐渐消退,这表明给药该肽可诱导纤维化。体外分析不能证实HMGB1肽对单核细胞/巨噬细胞的直接作用。然而,巨噬细胞是肝脏中受影响最大的免疫细胞,HMGB1治疗后肝脏中具有抗炎标志物的疤痕相关巨噬细胞(Trem2+Cd9+细胞)数量增加,表明单核/巨噬细胞的间接作用对治疗效果很重要。总之,我们通过诱导抗炎巨噬细胞,建立了利用HMGB1肽无细胞治疗肝硬化的新概念。
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引用次数: 7
期刊
Inflammation and Regeneration
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