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Cutting Edge: Low-dose Recombinant IL-2 Treatment Prevents Autoantibody Responses in Systemic Lupus Erythematosus via Regulatory T Cell-independent Depletion of T Follicular Helper Cells. 前沿:小剂量重组IL-2治疗通过调节性T细胞对T滤泡辅助细胞的依赖性消耗,预防系统性红斑狼疮的自身抗体反应。
IF 3.6 3区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-15 DOI: 10.4049/jimmunol.2400264
Silvia Santana, Amber Papillion, Jeremy B Foote, Holly Bachus, Beatriz León, Carmen De Miguel, André Ballesteros-Tato

The expansion of T follicular helper (Tfh) cells correlates with disease progression in human and murine systemic lupus erythematosus (SLE). Unfortunately, there are no therapies to deplete Tfh cells. Importantly, low-dose rIL-2-based immunotherapy shows potent immunosuppressive effects in SLE patients and lupus-prone mice, primarily attributed to the expansion of regulatory T cells (Tregs). However, IL-2 can also inhibit Tfh cell differentiation. In this study, we investigate the potential of low-dose rIL-2 to deplete Tfh cells and prevent autoantibody responses in SLE. Our data demonstrate that low-dose rIL-2 efficiently depletes autoreactive Tfh cells and prevents autoantibody responses in lupus-prone mice. Importantly, this immunosuppressive effect was independent of the presence of Tregs. The therapeutic potential of eliminating Tfh cells was confirmed by selectively deleting Tfh cells in lupus-prone mice. Our findings demonstrate the critical role of Tfh cells in promoting autoantibody responses and unveil, (to our knowledge), a novel Treg-independent immunosuppressive function of IL-2 in SLE.

T 滤泡辅助细胞(Tfh)的扩增与人类和小鼠系统性红斑狼疮(SLE)的病情发展相关。遗憾的是,目前还没有能消耗Tfh细胞的疗法。重要的是,以低剂量 rIL-2 为基础的免疫疗法对系统性红斑狼疮患者和狼疮易感小鼠显示出强大的免疫抑制作用,这主要归因于调节性 T 细胞(Tregs)的扩增。然而,IL-2 也能抑制 Tfh 细胞的分化。在这项研究中,我们探讨了低剂量 rIL-2 在消耗 Tfh 细胞和预防系统性红斑狼疮自身抗体反应方面的潜力。我们的数据表明,低剂量的rIL-2能有效消耗狼疮易感小鼠的自身反应性Tfh细胞,并预防自身抗体反应。重要的是,这种免疫抑制作用与Tregs的存在无关。通过在狼疮易感小鼠体内选择性地删除 Tfh 细胞,证实了消除 Tfh 细胞的治疗潜力。我们的研究结果证明了Tfh细胞在促进自身抗体反应中的关键作用,并(就我们所知)揭示了IL-2在系统性红斑狼疮中的一种独立于Treg的新型免疫抑制功能。
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引用次数: 0
Podosome Nucleation Is Facilitated by Multivalent Interactions between Syk and ITAM-containing Membrane Complexes. Syk与含ITAM的膜复合物之间的多价相互作用促进了荚膜体的形成
IF 3.6 3区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-01 DOI: 10.4049/jimmunol.2400031
Sina Ghasempour, Aleixo M Muise, Spencer A Freeman

Immune cells survey their microenvironment by forming dynamic cellular protrusions that enable chemotaxis, contacts with other cells, and phagocytosis. Podosomes are a unique type of protrusion structured by an adhesive ring of active integrins that surround an F-actin-rich core harboring degradative proteases. Although the features of podosomes, once-established, have been well defined, the steps that lead to podosome formation remain poorly understood by comparison. In this study, we report that spleen tyrosine kinase (Syk) is a critical regulator of podosome formation. Deletion of Syk or targeting its kinase activity eliminated the ability for murine macrophages to form podosomes. We found that the kinase activity of Syk was important for the phosphorylation of its substrates, HS1 and Pyk2, both of which regulate podosome formation. Additionally, before podosomes form, we report that the tandem Src homology 2 domains of Syk afforded multivalent clustering of ITAM-containing adaptors that associated with integrins to structure platforms that initiate podosomes. We therefore propose that Syk has a dual role in regulating podosomes: first, by facilitating the assembly of multivalent signaling hubs that nucleate their formation and second, by sustaining tyrosine kinase activity of the podosomes once they form against their substrates. In cells expressing recently identified gain-of-function variants of SYK, podosomes were dysregulated. These results implicate SYK in the (patho)physiological functions of podosomes in macrophages.

免疫细胞通过形成动态细胞突起来观察微环境,从而实现趋化、与其他细胞接触和吞噬。荚膜是一种独特的突起,由活性整合素组成的粘附环环绕着富含降解蛋白酶的 F-肌动蛋白核心。虽然荚膜体一旦形成,其特征就已明确,但相比之下,人们对荚膜体形成的步骤仍然知之甚少。在这项研究中,我们发现脾脏酪氨酸激酶(Syk)是荚膜形成的关键调节因子。缺失Syk或以其激酶活性为靶点,可消除小鼠巨噬细胞形成荚膜的能力。我们发现,Syk的激酶活性对其底物HS1和Pyk2的磷酸化非常重要,而HS1和Pyk2都能调节荚膜的形成。此外,在荚膜体形成之前,我们报告称 Syk 的串联 Src 同源 2 结构域可使含 ITAM 的适配体多价聚类,这些适配体与整合素相关联,形成启动荚膜体的结构平台。因此,我们认为 Syk 在调控荚膜中具有双重作用:首先,它能促进多价信号枢纽的组装,使荚膜形成;其次,一旦荚膜形成,它能维持荚膜的酪氨酸激酶活性,以对抗其底物。在表达最近鉴定出的 SYK 功能增益变体的细胞中,荚膜被失调。这些结果表明,SYK 与巨噬细胞中荚膜的(病理)生理功能有关。
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引用次数: 0
Correction: Cutting Edge: LAG3 Dimerization Is Required for TCR/CD3 Interaction and Inhibition of Antitumor Immunity. 更正:前沿:LAG3 二聚化是 TCR/CD3 相互作用和抑制抗肿瘤免疫所必需的。
IF 3.6 3区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-01 DOI: 10.4049/jimmunol.2400421
Kieran Adam, Zhanna Lipatova, Maria Abdul Ghafoor Raja, Arjun K Mishra, Roy A Mariuzza, Creg J Workman, Dario A A Vignali
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引用次数: 0
Gpx4 Regulates Invariant NKT Cell Homeostasis and Function by Preventing Lipid Peroxidation and Ferroptosis. Gpx4 通过防止脂质过氧化和铁氧化调节不变 NKT 细胞的稳态和功能
IF 3.6 3区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-01 DOI: 10.4049/jimmunol.2400246
Sophia P M Sok, Kaitlyn Pipkin, Narcis I Popescu, Megan Reidy, Bin Li, Holly Van Remmen, Mike Kinter, Xiao-Hong Sun, Zhichao Fan, Meng Zhao

Invariant NKT (iNKT) cells are a group of innate-like T cells that plays important roles in immune homeostasis and activation. We found that iNKT cells, compared with CD4+ T cells, have significantly higher levels of lipid peroxidation in both mice and humans. Proteomic analysis also demonstrated that iNKT cells express higher levels of phospholipid hydroperoxidase glutathione peroxidase 4 (Gpx4), a major antioxidant enzyme that reduces lipid peroxidation and prevents ferroptosis. T cell-specific deletion of Gpx4 reduces iNKT cell population, most prominently the IFN-γ-producing NKT1 subset. RNA-sequencing analysis revealed that IFN-γ signaling, cell cycle regulation, and mitochondrial function are perturbed by Gpx4 deletion in iNKT cells. Consistently, we detected impaired cytokine production, elevated cell proliferation and cell death, and accumulation of lipid peroxides and mitochondrial reactive oxygen species in Gpx4 knockout iNKT cells. Ferroptosis inhibitors, iron chelators, vitamin E, and vitamin K2 can prevent ferroptosis induced by Gpx4 deficiency in iNKT cells and ameliorate the impaired function of iNKT cells due to Gpx4 inhibition. Last, vitamin E rescues iNKT cell population in Gpx4 knockout mice. Altogether, our findings reveal the critical role of Gpx4 in regulating iNKT cell homeostasis and function, through controlling lipid peroxidation and ferroptosis.

不变NKT(iNKT)细胞是一类先天性类T细胞,在免疫稳态和激活中发挥着重要作用。我们发现,与 CD4+ T 细胞相比,iNKT 细胞在小鼠和人类体内的脂质过氧化水平明显更高。蛋白质组分析还表明,iNKT 细胞表达较高水平的磷脂氢过氧化物酶谷胱甘肽过氧化物酶 4 (Gpx4),这是一种主要的抗氧化酶,可减少脂质过氧化并防止铁变态反应。T 细胞特异性缺失 Gpx4 会减少 iNKT 细胞数量,其中最突出的是产生 IFN-γ 的 NKT1 亚群。RNA序列分析表明,iNKT细胞中的IFN-γ信号传导、细胞周期调控和线粒体功能都受到了Gpx4缺失的干扰。同样,我们在 Gpx4 基因敲除的 iNKT 细胞中检测到细胞因子生成受损、细胞增殖和细胞死亡增加、脂质过氧化物和线粒体活性氧积累。铁跃迁抑制剂、铁螯合剂、维生素 E 和维生素 K2 可防止 iNKT 细胞因 Gpx4 缺乏而诱导铁跃迁,并改善 iNKT 细胞因 Gpx4 抑制而受损的功能。最后,维生素 E 能拯救 Gpx4 基因敲除小鼠的 iNKT 细胞群。总之,我们的研究结果揭示了 Gpx4 通过控制脂质过氧化和铁变态反应在调节 iNKT 细胞稳态和功能方面的关键作用。
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引用次数: 0
Cell-surface Milieu Remodeling in Human Dendritic Cell Activation. 人类树突状细胞活化过程中的细胞表面环境重塑
IF 3.6 3区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-01 DOI: 10.4049/jimmunol.2400089
Namrata D Udeshi, Charles Xu, Zuzhi Jiang, Shihong Max Gao, Qian Yin, Wei Luo, Steven A Carr, Mark M Davis, Jiefu Li

Dendritic cells (DCs) are specialized sentinel and APCs coordinating innate and adaptive immunity. Through proteins on their cell surface, DCs sense changes in the environment, internalize pathogens, present processed Ags, and communicate with other immune cells. By combining chemical labeling and quantitative mass spectrometry, we systematically profiled and compared the cell-surface proteomes of human primary conventional DCs (cDCs) in their resting and activated states. TLR activation by a lipopeptide globally reshaped the cell-surface proteome of cDCs, with >100 proteins upregulated or downregulated. By simultaneously elevating positive regulators and reducing inhibitory signals across multiple protein families, the remodeling creates a cell-surface milieu promoting immune responses. Still, cDCs maintain the stimulatory-to-inhibitory balance by leveraging a distinct set of inhibitory molecules. This analysis thus uncovers the molecular complexity and plasticity of the cDC cell surface and provides a roadmap for understanding cDC activation and signaling.

树突状细胞(DC)是协调先天性免疫和适应性免疫的特化哨兵和 APC。通过细胞表面的蛋白质,树突状细胞能感知环境变化、内化病原体、呈现加工过的抗体并与其他免疫细胞交流。通过结合化学标记和定量质谱法,我们系统分析并比较了静息和活化状态下人类原代常规 DCs(cDCs)的细胞表面蛋白质组。一种脂肽对 TLR 的激活全面重塑了 cDCs 的细胞表面蛋白质组,上调或下调的蛋白质超过 100 种。通过同时提高多个蛋白家族的正调控因子和降低抑制信号,重塑创造了一种促进免疫反应的细胞表面环境。尽管如此,cDC 仍通过利用一系列独特的抑制分子来维持刺激与抑制之间的平衡。因此,这项分析揭示了 cDC 细胞表面的分子复杂性和可塑性,为了解 cDC 的活化和信号传导提供了路线图。
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引用次数: 0
Cutting Edge: Retinoic Acid Promotes Brain-homing of CD8+ T Cells during Congenital Cytomegalovirus Infection. 前沿:视黄酸在先天性巨细胞病毒感染过程中促进 CD8+ T 细胞的脑归属。
IF 3.6 3区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-01 DOI: 10.4049/jimmunol.2400150
Zachary T Hilt, Wisler Charles, Taha Ali, Casey V Smith, Shide Zhang, Samantha P Wesnak, Norah L Smith, Brian D Rudd

The most common congenital viral infection is CMV, which leads to numerous neurologic disabilities. Using a mouse model of congenital CMV, we previously determined that Ag-specific CD8+ T cells traffic to the brain in a CCR9-dependent manner. The mechanism by which these CD8+ T cells acquire a CCR9-dependent "brain-tropic" phenotype remains unclear. In this study, we identify the key factor that imprints brain homing specificity on CD8+ T cells, the source of production, and the location where CCR9 expression is induced. Specifically, we discovered that CCR9 is induced on CD8+ T cells by retinoic acid-producing CD8α+ dendritic cells in the cervical lymph node postinfection. We found that retinoic acid is important for CD8+ T cells to establish tissue residency in the brain. Collectively, our data expand the role of retinoic acid during infection and mechanistically demonstrate how CD8+ T cells are primed to protect the brain during congenital viral infection.

最常见的先天性病毒感染是 CMV,它会导致多种神经系统残疾。我们曾利用小鼠先天性 CMV 模型确定,Ag 特异性 CD8+ T 细胞以 CCR9 依赖性方式进入大脑。这些 CD8+ T 细胞获得 CCR9 依赖性 "趋脑 "表型的机制仍不清楚。在这项研究中,我们确定了使 CD8+ T 细胞具有脑归属特异性的关键因素、产生来源以及诱导 CCR9 表达的位置。具体来说,我们发现视黄酸可诱导感染后颈淋巴结中产生 CD8α+ 树突状细胞的 CD8+ T 细胞表达 CCR9。我们发现,视黄酸对 CD8+ T 细胞在大脑中建立组织驻留非常重要。总之,我们的数据拓展了视黄酸在感染过程中的作用,并从机理上证明了CD8+ T细胞如何在先天性病毒感染过程中保护大脑。
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引用次数: 0
TLR3/TRIF and MAVS Signaling Is Essential in Regulating Mucosal T Cell Responses during Rotavirus Infection. 轮状病毒感染期间,TLR3/TRIF 和 MAVS 信号在调控黏膜 T 细胞反应中至关重要。
IF 3.6 3区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-01 DOI: 10.4049/jimmunol.2300867
Rong-Rong Zhang, Xue-Yao Yang, Yong-Lei Yang, Tian-Kui Guo, Jing-Shu Huang, Ying-Shi Yang, Chun-Wei Shi, Gui-Lian Yang, Hai-Bin Huang, Jian-Zhong Wang, Yan-Long Jiang, Xin Cao, Nan Wang, Yan Zeng, Wen-Tao Yang, Chun-Feng Wang

The functions of the natural dsRNA sensors TLR3 (TRIF) and RIG-I (MAVS) are crucial during viral challenge and have not been accurately clarified in adaptive immune responses to rotavirus (RV) infection. In this study, we found that RV infection caused severe pathological damage to the small intestine of TLR3-/- and TRIF-/- mice. Our data found that dendritic cells from TLR3-/- and TRIF-/- mice had impaired Ag presentation to the RV and attenuated initiation of T cells upon viral infection. These attenuated functions resulted in impaired CD4+ T and CD8+ T function in mice lacking TLR3-TRIF signaling postinfection. Additionally, attenuated proliferative capacity of T cells from TLR3-/- and TRIF-/- mice was observed. Subsequently, we observed a significant reduction in the absolute number of memory T cells in the spleen and mesenteric lymph node (MLN) of TRIF-/- recipient mice following RV infection in a bone marrow chimeric model. Furthermore, there was reduced migration of type 2 classical dendritic cells from the intestine to MLNs after RV infection in TLR3-/- and TRIF-/- mice. Notably, RV infection resulted in attenuated killing of spleen and MLN tissues in TRIF-/- and MAVS-/- mice. Finally, we demonstrated that RV infection promoted apoptosis of CD8+ T cells in TRIF-/- and TLR3-/-MAVS-/- mice. Taken together, our findings highlight an important mechanism of TLR3 signaling through TRIF in mucosal T cell responses to RV and lay the foundation for the development of a novel vaccine.

天然dsRNA传感器TLR3(TRIF)和RIG-I(MAVS)的功能在病毒挑战过程中至关重要,但在轮状病毒(RV)感染的适应性免疫反应中的功能尚未得到准确阐明。在这项研究中,我们发现 RV 感染会对 TLR3-/- 和 TRIF-/- 小鼠的小肠造成严重的病理损伤。我们的数据发现,TLR3-/-和TRIF-/-小鼠的树突状细胞向RV呈递Ag的功能受损,病毒感染时T细胞的启动功能减弱。这些功能的减弱导致感染后缺乏 TLR3-TRIF 信号传导的小鼠 CD4+ T 和 CD8+ T 功能受损。此外,我们还观察到 TLR3-/- 和 TRIF-/- 小鼠的 T 细胞增殖能力减弱。随后,我们在骨髓嵌合模型中观察到,在RV感染后,TRIF-/-受体小鼠脾脏和肠系膜淋巴结(MLN)中记忆T细胞的绝对数量显著减少。此外,TLR3-/-和TRIF-/-小鼠感染RV后,2型经典树突状细胞从肠道向MLN的迁移减少。值得注意的是,RV 感染导致 TRIF-/- 和 MAVS-/- 小鼠脾脏和 MLN 组织的杀伤力减弱。最后,我们证实 RV 感染促进了 TRIF-/- 和 TLR3-/-MAVS-/- 小鼠 CD8+ T 细胞的凋亡。综上所述,我们的研究结果强调了 TLR3 信号通过 TRIF 在粘膜 T 细胞对 RV 的反应中的重要机制,并为新型疫苗的开发奠定了基础。
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引用次数: 0
Late-life Attenuation of Cytomegalovirus-mediated CD8 T Cell Memory Inflation: Shrinking of the Cytomegalovirus Latency Niche. 晚期巨细胞病毒介导的 CD8 T 细胞记忆性炎症衰减:巨细胞病毒潜伏龛缩小。
IF 3.6 3区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-01 DOI: 10.4049/jimmunol.2400113
Christopher P Coplen, Sandip Ashok Sonar, Janko Ž Nikolich

CMV drives the accumulation of virus-specific, highly differentiated CD8 memory T cells (memory inflation [MI]). In mice, MI was shown to directly correlate with the CMV infection dose, yet the CMV-associated CD8 MI plateaus over time. It is unclear how MI is regulated with aging. We infected young mice with 102, 104, and 106 PFU of murine CMV and confirmed that MI magnitude was directly proportional to the infectious dose, reaching a setpoint by midlife. By old age, MI subsided, most prominently in mice infected with 106 PFU, and reached statistical parity between groups in 26-mo-old mice. This corresponded to an age-related loss in lymphatic endothelial cells in lymph nodes, recently shown to be sufficient to drive MI in mice. We propose that MI size and persistence over the lifespan is controlled by the size of the lymphatic endothelial cell niche, whose shrinking leads to reduced MI with aging.

CMV 可促使病毒特异性、高度分化的 CD8 记忆 T 细胞(记忆膨胀 [MI])积累。在小鼠中,MI 与 CMV 感染剂量直接相关,但随着时间的推移,CMV 相关的 CD8 记忆 T 细胞的 MI 会趋于平稳。目前还不清楚随着年龄的增长,MI 是如何调节的。我们用 102、104 和 106 PFU 的小鼠 CMV 感染了年轻的小鼠,结果证实,MI 的大小与感染剂量成正比,到中年时达到一个设定点。到了老年,MI 有所减弱,在感染了 106 PFU 的小鼠中最为明显,在 26 个月大的小鼠中,各组之间达到了统计学上的均等。这与淋巴结中与年龄相关的淋巴内皮细胞的损失相对应,最近的研究表明,淋巴内皮细胞的损失足以驱动小鼠的MI。我们认为,MI 的大小和持续时间受淋巴内皮细胞生态位大小的控制,而淋巴内皮细胞生态位的萎缩会导致 MI 随年龄增长而减少。
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引用次数: 0
Glucocorticoids Suppress NF-κB-Mediated Neutrophil Control of Aspergillus fumigatus Hyphal Growth. 糖皮质激素抑制 NF-κB 介导的中性粒细胞对曲霉菌茎突生长的控制作用
IF 3.6 3区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-01 DOI: 10.4049/jimmunol.2400021
Savini U Thrikawala, Molly H Anderson, Emily E Rosowski

Glucocorticoids are a major class of therapeutic anti-inflammatory and immunosuppressive drugs prescribed to patients with inflammatory diseases, to avoid transplant rejection, and as part of cancer chemotherapy. However, exposure to these drugs increases the risk of opportunistic infections such as with the fungus Aspergillus fumigatus, which causes mortality in >50% of infected patients. The mechanisms by which glucocorticoids increase susceptibility to A. fumigatus are poorly understood. In this article, we used a zebrafish larva Aspergillus infection model to identify innate immune mechanisms altered by glucocorticoid treatment. Infected larvae exposed to dexamethasone succumb to infection at a significantly higher rate than control larvae. However, both macrophages and neutrophils are still recruited to the site of infection, and dexamethasone treatment does not significantly affect fungal spore killing. Instead, the primary effect of dexamethasone manifests later in infection with treated larvae exhibiting increased invasive hyphal growth. In line with this, dexamethasone predominantly inhibits neutrophil function rather than macrophage function. Dexamethasone-induced mortality also depends on the glucocorticoid receptor. Dexamethasone partially suppresses NF-κB activation at the infection site by inducing the transcription of IκB via the glucocorticoid receptor. Independent CRISPR/Cas9 targeting of IKKγ to prevent NF-κB activation also increases invasive A. fumigatus growth and larval mortality. However, dexamethasone treatment of IKKγ crispant larvae further increases invasive hyphal growth and host mortality, suggesting that dexamethasone may suppress other pathways in addition to NF-κB to promote host susceptibility. Collectively, we find that dexamethasone acts through the glucocorticoid receptor to suppress NF-κB-mediated neutrophil control of A. fumigatus hyphae in zebrafish larvae.

糖皮质激素是一类主要的治疗性抗炎药和免疫抑制剂,可用于治疗炎症性疾病、避免移植排斥反应以及作为癌症化疗的一部分。然而,接触这些药物会增加机会性感染的风险,例如真菌烟曲霉(Aspergillus fumigatus)会导致超过 50% 的感染者死亡。人们对糖皮质激素增加曲霉菌易感性的机制知之甚少。在这篇文章中,我们利用斑马鱼幼虫曲霉菌感染模型来确定糖皮质激素治疗改变的先天免疫机制。暴露于地塞米松的受感染幼虫的感染率明显高于对照幼虫。然而,巨噬细胞和中性粒细胞仍被招募到感染部位,地塞米松处理对真菌孢子的杀灭没有显著影响。相反,地塞米松的主要作用体现在感染后期,处理过的幼虫会表现出侵袭性芽胞生长增加。因此,地塞米松主要抑制的是中性粒细胞的功能,而不是巨噬细胞的功能。地塞米松诱导的死亡率还取决于糖皮质激素受体。地塞米松通过糖皮质激素受体诱导 IκB 转录,从而部分抑制感染部位的 NF-κB 激活。独立的 CRISPR/Cas9 靶向 IKKγ 以防止 NF-κB 激活也会增加侵袭性烟曲霉的生长和幼虫死亡率。然而,地塞米松处理 IKKγ 脆化幼虫会进一步增加侵袭性菌丝的生长和宿主死亡率,这表明地塞米松可能会抑制 NF-κB 以外的其他途径,以提高宿主的易感性。总之,我们发现地塞米松通过糖皮质激素受体抑制 NF-κB 介导的中性粒细胞对斑马鱼幼体中烟曲霉菌菌丝的控制。
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引用次数: 0
C1q/MASP Complexes-Hybrid Complexes of Classical and Lectin Pathway Proteins Are Found in the Circulation. 在血液循环中发现 C1q/MASP 复合物--经典蛋白和 Lectin 途径蛋白的杂交复合物。
IF 3.6 3区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-01 DOI: 10.4049/jimmunol.2400185
Anne Rosbjerg, Tereza Alica Plchová, Rafael Bayarri-Olmos, Bettina Eide Holm, Ida Sandau Pedersen, Mikkel-Ole Skjoedt, Peter Garred

Complement pathways, traditionally regarded as separate entities in vitro, are increasingly noted for cross-communication and bypass mechanisms. Among these, the MBL/ficolin/CL-associated serine protease (MASP)-3, a component of lectin pathway pattern recognition molecules, has shown the ability to process critical substrates such as pro-factor D and insulin growth factor binding protein-5. Given shared features between lectin pathway pattern recognition molecules and C1q from the classical pathway, we hypothesized that C1q might be a viable in vivo binding partner for the MASPs. We used microscale thermophoresis, ELISA, and immunoprecipitation assays to detect C1q/MASP complexes and functionally assessed the complexes through enzymatic cleavage assays. C1q/MASP-3 complexes were detected in human serum and correlated well with MASP-3 serum levels in healthy individuals. The binding affinity between MASP-3 and C1q in vitro was in the nanomolar range, and the interaction was calcium-dependent, as demonstrated by their dissociation in the presence of EDTA. Furthermore, most of the circulating C1q-bound MASP-3 was activated. Based on immunoprecipitation, also C1q/MASP-2 complexes appeared to be present in serum. Finally, C1q/MASP-2 and C1q/MASP-3 in vitro complexes were able to cleave C4 and pro-factor D, respectively. Our study reveals the existence of C1q/MASP complexes in the circulation of healthy individuals, and both C1q/MASP-2 and C1q/MASP-3 complexes display proteolytic activity. Hence, this study uncovers a crosstalk route between complement pathways not previously described.

传统上被视为体外独立实体的补体通路,其交叉交流和旁路机制日益受到关注。其中,MBL/ficolin/CL 相关丝氨酸蛋白酶(MASP)-3 是凝集素途径模式识别分子的一个组成部分,它已显示出处理关键底物(如原因子 D 和胰岛素生长因子结合蛋白-5)的能力。鉴于凝集素通路模式识别分子与经典通路中的 C1q 之间的共同特征,我们假设 C1q 可能是 MASPs 的一个可行的体内结合伙伴。我们使用微尺度热泳、酶联免疫吸附和免疫沉淀试验检测 C1q/MASP 复合物,并通过酶裂解试验对复合物进行功能评估。在人体血清中检测到了 C1q/MASP-3 复合物,并与健康人血清中的 MASP-3 水平密切相关。在体外,MASP-3 和 C1q 的结合亲和力在纳摩尔范围内,这种相互作用是钙依赖性的,在 EDTA 存在下它们的解离就证明了这一点。此外,循环中与 C1q 结合的 MASP-3 大部分被活化。根据免疫沉淀法,血清中似乎也存在 C1q/MASP-2 复合物。最后,C1q/MASP-2 和 C1q/MASP-3 体外复合物能分别裂解 C4 和原因子 D。我们的研究揭示了健康人血液循环中存在 C1q/MASP 复合物,而且 C1q/MASP-2 和 C1q/MASP-3 复合物都显示出蛋白水解活性。因此,这项研究发现了一种以前从未描述过的补体途径之间的串联途径。
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Journal of immunology
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