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MZB1-mediated IgA secretion suppresses the development and progression of colorectal cancer triggered by gut inflammation MZB1 介导的 IgA 分泌可抑制肠道炎症引发的结直肠癌的发展和恶化。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-01 DOI: 10.1016/j.mucimm.2023.12.002
Yue Tang , Xiaoqian Feng , Qing Lu , Chaoqun Cui , Meiping Yu , Zichao Wen , Yingying Luan , Lulu Dong , Ziying Hu , Runyun Zhang , Chunhui Lu , Jie Liu , Reiko Shinkura , Koji Hase , Ji-Yang Wang

Colorectal cancer (CRC) ranks among the top causes of mortality globally. Gut inflammation is one crucial risk factor that augments CRC development since patients suffering from inflammatory bowel disease have an increased incidence of CRC. The role of immunoglobulin (Ig)A in maintaining gut homeostasis and preventing inflammation has been well established. Our earlier work demonstrated that the marginal zone and B1 cell-specific protein (MZB1) promotes gut IgA secretion and its absence results in pronounced dextran sulfate sodium salt (DSS)-induced colitis. In the present study, we explored the role of MZB1 in CRC development using the azoxymethane (AOM)/DSS-induced CRC model. We observed an increase in both the number and size of the tumor nodules in Mzb1−/− mice compared with Mzb1+/+ mice. The increase in CRC development and progression in Mzb1−/− mice was associated with reduced intestinal IgA levels, altered gut flora, and more severe gut and systemic inflammation. Oral administration of the monoclonal IgA, W27, alleviated both the gut inflammation and AOM/DSS-induced CRC. Notably, cohousing Mzb1+/+ and Mzb1−/− mice from the 10th day after birth led to similar CRC development. Our findings underscore the pivotal role of MZB1-mediated IgA secretion in suppressing the onset and progression of CRC triggered by gut inflammation. Moreover, our study highlights the profound impact of microbiota composition, modulated by gut IgA levels, on gut inflammation. Nonetheless, establishing a direct correlation between the severity of colitis and subsequent CRC development and the presence or absence of a particular microbiota is challenging.

结肠直肠癌(CRC)在全球死亡原因中名列前茅。肠道炎症是诱发 CRC 的一个重要风险因素,因为患有炎症性肠病的患者会增加 CRC 的发病率。IgA 在维持肠道平衡和预防炎症方面的作用已得到公认。我们早前的研究表明,边缘区和 B1 细胞特异性蛋白(MZB1)能促进肠道 IgA 分泌,缺失该蛋白会导致明显的右旋糖酐硫酸钠盐(DSS)诱导的结肠炎。在本研究中,我们利用偶氮甲烷(AOM)/DSS诱导的结直肠癌模型探讨了MZB1在结直肠癌发展中的作用。与 Mzb1+/+ 小鼠相比,我们观察到 Mzb1-/- 小鼠肿瘤结节的数量和大小均有所增加。Mzb1-/-小鼠CRC发病和进展的增加与肠道IgA水平降低、肠道菌群改变以及更严重的肠道和全身炎症有关。口服单克隆 IgA W27 可减轻肠道炎症和 AOM/DSS 诱导的 CRC。值得注意的是,Mzb1+/+和Mzb1-/-小鼠从出生后第10天开始同群饲养会导致相似的CRC发展。我们的发现强调了 MZB1 介导的 IgA 分泌在抑制肠道炎症引发的 CRC 的发生和发展中的关键作用。此外,我们的研究还凸显了微生物群组成对肠道炎症的深远影响,而肠道 IgA 水平则可调节微生物群组成。尽管如此,要在结肠炎的严重程度和随后的 CRC 发展与特定微生物群的存在与否之间建立直接的相关性仍具有挑战性。
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引用次数: 0
PD-1 signaling in neonates restrains CD8+ T cell function and protects against respiratory viral immunopathology 新生儿体内的 PD-1 信号抑制 CD8+ T 细胞功能并保护其免受呼吸道病毒免疫病理的影响。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-01 DOI: 10.1016/j.mucimm.2023.12.004
Taylor Eddens , Olivia B. Parks , Yu Zhang , Michelle L. Manni , Jean-Laurent Casanova , Masato Ogishi , John V. Williams

Respiratory viral infections, including human metapneumovirus (HMPV), remain a leading cause of morbidity and mortality in neonates and infants. However, the mechanisms behind the increased sensitivity to those respiratory viral infections in neonates are poorly understood. Neonates, unlike adults, have several anti-inflammatory mechanisms in the lung, including elevated baseline expression of programmed death ligand 1 (PD-L1), a ligand for the inhibitory receptor programmed cell death protein 1 (PD-1). We thus hypothesized that neonates would rely on PD-1:PD-L1 signaling to restrain antiviral CD8 responses. To test this, we developed a neonatal primary HMPV infection model using wild-type C57BL/6 (B6) and Pdcd1-/- (lacking PD-1) mice. HMPV-infected neonatal mice had increased PD-L1/PD-L2 co-expression on innate immune cells but a similar number of antigen-specific CD8+ T cells and upregulation of PD-1 to that of adult B6 mice. Neonatal CD8+ T cells had reduced interferon‐gamma (IFN-γ), granzyme B, and interleukin-2 production compared with B6 adults. Pdcd1-/- neonatal CD8+ T cells had markedly increased production of IFN-γ and granzyme B compared with B6 neonates. Pdcd1-/- neonates had increased acute pathology with HMPV or influenza. Pdcd1-/- neonates infected with HMPV had long-term changes in pulmonary physiology with evidence of immunopathology and a persistent CD8+ T-cell response with increased granzyme B production. Using single-cell ribonucleic acid sequencing from a child lacking PD-1 signaling, a similar activated CD8+ T-cell signature with increased granzyme B expression was observed. These data indicate that PD-1 signaling critically limits CD8+ T-cell effector functions and prevents immunopathology in response to neonatal respiratory viral infections.

包括人类偏肺病毒(HMPV)在内的呼吸道病毒感染仍然是新生儿和婴儿发病和死亡的主要原因。然而,人们对新生儿对这些呼吸道病毒感染的敏感性增加背后的机制却知之甚少。与成人不同,新生儿的肺部具有多种抗炎机制,包括抑制受体 PD-1 的配体 PD-L1 的基线表达升高。因此,我们假设新生儿会依赖 PD-1:PD-L1 信号来抑制抗病毒 CD8 反应。为了验证这一假设,我们使用 WT C57BL/6 (B6) 和 Pdcd1-/-(缺乏 PD-1)小鼠建立了新生儿原发性 HMPV 感染模型。与成年 B6 小鼠相比,HMPV 感染的新生小鼠先天性免疫细胞上的 PD-L1/PD-L2 共表达增加,但抗原特异性 CD8+ T 细胞的数量和 PD-1 的上调情况相似。与成年 B6 小鼠相比,新生儿 CD8+ T 细胞产生的 IFN-γ、粒酶 B 和 IL-2 减少了。与 B6 新生儿相比,Pdcd1-/-新生 CD8+ T 细胞产生的 IFN-γ 和颗粒酶 B 明显增加。Pdcd1-/-新生儿在感染HMPV或流感后急性病理变化增加。感染了HMPV的Pdcd1-/-新生儿的肺部生理机能会发生长期变化,并伴有免疫病理和CD8+T细胞持续反应的证据,同时颗粒酶B的生成也会增加。通过对缺乏 PD-1 信号的患儿进行单细胞 RNA 测序,观察到了类似的活化 CD8+ T 细胞特征,颗粒酶 B 表达增加。这些数据表明,PD-1 信号传导严重限制了 CD8+ T 细胞效应功能,并防止了新生儿呼吸道病毒感染引起的免疫病理反应。
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引用次数: 0
A bacterial vesicle-based pneumococcal vaccine against influenza-mediated secondary Streptococcus pneumoniae pulmonary infection 基于细菌囊泡的肺炎球菌疫苗可预防流感介导的继发性肺炎链球菌肺部感染。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-04-01 DOI: 10.1016/j.mucimm.2024.01.002
Saugata Majumder , Peng Li , Shreya Das , Tanvir Noor Nafiz , Sudeep Kumar , Guangchun Bai , Hazel Dellario , Haixin Sui , Ziqiang Guan , Roy Curtiss 3rd , Yoichi Furuya , Wei Sun

Streptococcus pneumoniae (Spn) is a common pathogen causing a secondary bacterial infection following influenza, which leads to severe morbidity and mortality during seasonal and pandemic influenza. Therefore, there is an urgent need to develop bacterial vaccines that prevent severe post-influenza bacterial pneumonia. Here, an improved Yersinia pseudotuberculosis strain (designated as YptbS46) possessing an Asd+ plasmid pSMV92 could synthesize high amounts of the Spn pneumococcal surface protein A (PspA) antigen and monophosphoryl lipid A as an adjuvant. The recombinant strain produced outer membrane vesicles (OMVs) enclosing a high amount of PspA protein (designated as OMV-PspA). A prime-boost intramuscular immunization with OMV-PspA induced both memory adaptive and innate immune responses in vaccinated mice, reduced the viral and bacterial burden, and provided complete protection against influenza-mediated secondary Spn infection. Also, the OMV-PspA immunization afforded significant cross-protection against the secondary Spn A66.1 infection and long-term protection against the secondary Spn D39 challenge. Our study implies that an OMV vaccine delivering Spn antigens can be a new promising pneumococcal vaccine candidate.

肺炎链球菌(Spn)是流感后引起继发性细菌感染的常见病原体,在季节性流感和流感大流行期间会导致严重的发病率和死亡率。因此,迫切需要开发能预防流感后重症细菌性肺炎的细菌疫苗。在本研究中,一株改良的假结核耶尔森菌(命名为 YptbS46)具有 Asd+ 质粒 pSMV92,能合成大量 Spn 肺炎球菌表面蛋白 A(PspA)抗原和作为佐剂的单磷脂 A。重组菌株能产生包裹大量 PspA 蛋白的外膜囊泡(OMV)(命名为 OMV-PspA)。用 OMV-PspA 进行肌肉注射,可诱导接种小鼠产生记忆性适应性免疫反应和先天性免疫反应,减少病毒和细菌负担,并对流感介导的 Spn 继发感染提供完全保护。此外,OMV-PspA 免疫对 Spn A66.1 的继发感染具有显著的交叉保护作用,并对 Spn D39 的继发感染具有长期保护作用。我们的研究表明,提供 Spn 抗原的 OMV 疫苗可以成为一种新的有前途的肺炎球菌候选疫苗。
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引用次数: 0
Intraepithelial lymphocytes promote intestinal regeneration through CD160/HVEM signaling 上皮内淋巴细胞通过 CD160/HVEM 信号促进肠道再生
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-04-01 DOI: 10.1016/j.mucimm.2024.02.004
Jiaoyan Huang , Xin Zhang , Hongkai Xu , Liuhui Fu , Yuke Liu , Jie Zhao , Jida Huang , Zuodong Song , Mingzhao Zhu , Yang-Xin Fu , Ye-Guang Chen , Xiaohuan Guo

Chemotherapy and radiotherapy frequently lead to intestinal damage. The mechanisms governing the repair or regeneration of intestinal damage are still not fully elucidated. Intraepithelial lymphocytes (IELs) are the primary immune cells residing in the intestinal epithelial layer. However, whether IELs are involved in intestinal epithelial injury repair remains unclear. Here, we found that IELs rapidly infiltrated the intestinal crypt region and are crucial for the recovery of the intestinal epithelium post-chemotherapy. Interestingly, IELs predominantly promoted intestinal regeneration by modulating the proliferation of transit-amplifying (TA) cells. Mechanistically, the expression of CD160 on IELs allows for interaction with herpes virus entry mediator (HVEM) on the intestinal epithelium, thereby activating downstream nuclear factor kappa (NF-κB) signaling and further promoting intestinal regeneration. Deficiency in either CD160 or HVEM resulted in reduced proliferation of intestinal progenitor cells, impaired intestinal damage repair, and increased mortality following chemotherapy. Remarkably, the adoptive transfer of CD160-sufficient IELs rescued the Rag1 deficient mice from chemotherapy-induced intestinal inflammation. Overall, our study underscores the critical role of IELs in intestinal regeneration and highlights the potential applications of targeting the CD160-HVEM axis for managing intestinal adverse events post-chemotherapy and radiotherapy.

化疗和放疗经常导致肠道损伤。肠道损伤的修复或再生机制仍未完全阐明。上皮内淋巴细胞(IELs)是驻留在肠上皮细胞层的主要免疫细胞。然而,IELs 是否参与肠上皮损伤修复仍不清楚。在这里,我们发现 IELs 快速浸润肠隐窝区域,对化疗后肠上皮的恢复至关重要。有趣的是,IELs主要通过调节转运扩增(TA)细胞的增殖来促进肠道再生。从机理上讲,IELs上CD160的表达可与肠上皮的HVEM相互作用,从而激活下游NF-κB信号,进一步促进肠道再生。CD160或HVEM的缺乏会导致肠祖细胞增殖减少、肠损伤修复受损以及化疗后死亡率升高。值得注意的是,CD160充足的IELs被收养性转移能挽救Rag1缺乏的小鼠,使其免于化疗引起的肠道炎症。总之,我们的研究强调了IELs在肠道再生中的关键作用,并突出了靶向CD160-HVEM轴在控制化疗和放疗后肠道不良反应方面的潜在应用。
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引用次数: 0
The intestinal microbiota modulates the transcriptional landscape of iNKT cells at steady-state and following antigen exposure 肠道微生物群调节 iNKT 细胞在稳态和抗原暴露后的转录结构。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-04-01 DOI: 10.1016/j.mucimm.2024.02.002
Qiaochu Lin , Meggie Kuypers , Yuriy Baglaenko , Eric Cao , Kebria Hezaveh , Tijana Despot , Carolina de Amat Herbozo , Mayra Cruz Tleugabulova , Juan Mauricio Umaña , Tracy L. McGaha , Dana J. Philpott , Thierry Mallevaey

Invariant Natural Killer T (iNKT) cells are unconventional T cells that respond to microbe-derived glycolipid antigens. iNKT cells exert fast innate effector functions that regulate immune responses in a variety of contexts, including during infection, cancer, or inflammation. The roles these unconventional T cells play in intestinal inflammation remain poorly defined and vary based on the disease model and species. Our previous work suggested that the gut microbiota influenced iNKT cell functions during dextran sulfate sodium-induced colitis in mice. This study, shows that iNKT cell homeostasis and response following activation are altered in germ-free mice. Using prenatal fecal transplant in specific pathogen-free mice, we show that the transcriptional signatures of iNKT cells at steady state and following αGC-mediated activation in vivo are modulated by the microbiota. Our data suggest that iNKT cells sense the microbiota at homeostasis independently of their T cell receptors. Finally, iNKT cell transcriptional signatures are different in male and female mice. Collectively, our findings suggest that sex and the intestinal microbiota are important factors that regulate iNKT cell homeostasis and responses. A deeper understanding of microbiota-iNKT cell interactions and the impact of sex could improve the development of iNKT cell-based immunotherapies.

不变型杀伤性 T 细胞(iNKT)是对微生物衍生的糖脂抗原做出反应的非常规 T 细胞。iNKT 细胞具有快速的先天效应功能,可在感染、癌症或炎症等多种情况下调节免疫反应。这些非常规 T 细胞在肠道炎症中所起的作用仍未明确,而且因疾病模型和物种而异。我们之前的研究表明,在葡聚糖硫酸钠诱导的小鼠结肠炎中,肠道微生物群会影响 iNKT 细胞的功能。在这项研究中,我们发现无菌小鼠的 iNKT 细胞稳态和激活后的反应发生了改变。通过在特异性无病原体小鼠体内进行产前粪便移植,我们发现 iNKT 细胞在稳态和αGC 介导的体内激活后的转录特征受到微生物群的调节。我们的数据表明,iNKT 细胞在平衡状态下对微生物群的感知与它们的 TCR 无关。最后,雌雄小鼠的 iNKT 细胞转录特征也不同。总之,我们的研究结果表明,性别和肠道微生物群是调节 iNKT 细胞平衡和反应的重要因素。更深入地了解微生物群与 iNKT 细胞之间的相互作用以及性别的影响可以改善基于 iNKT 细胞的免疫疗法的开发。
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引用次数: 0
IL-1α is required for T cell-driven weight loss after respiratory viral infection 呼吸道病毒感染后,T 细胞驱动的体重减轻需要 IL-1α。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-04-01 DOI: 10.1016/j.mucimm.2024.02.005
Ziyin Wang , Leah F. Cuthbertson , Chubicka Thomas , Hadijatou J Sallah , Lucy G. Mosscrop , Haoyuan Li , Tiina Talts , Kartik Kumar , Miriam F. Moffatt , John S. Tregoning

Respiratory viral infections remain a major cause of hospitalization and death worldwide. Patients with respiratory infections often lose weight. While acute weight loss is speculated to be a tolerance mechanism to limit pathogen growth, severe weight loss following infection can cause quality of life deterioration. Despite the clinical relevance of respiratory infection-induced weight loss, its mechanism is not yet completely understood. We utilized a model of CD 8+ T cell-driven weight loss during respiratory syncytial virus (RSV) infection to dissect the immune regulation of post-infection weight loss. Supporting previous data, bulk RNA sequencing indicated significant enrichment of the interleukin (IL)-1 signaling pathway after RSV infection. Despite increased viral load, infection-associated weight loss was significantly reduced after IL-1α (but not IL-1β) blockade. IL-1α depletion resulted in a reversal of the gut microbiota changes observed following RSV infection. Direct nasal instillation of IL-1α also caused weight loss. Of note, we detected IL-1α in the brain after either infection or nasal delivery. This was associated with changes in genes controlling appetite after RSV infection and corresponding changes in signaling molecules such as leptin and growth/differentiation factor 15. Together, these findings indicate a lung-brain-gut signaling axis for IL-1α in regulating weight loss after RSV infection.

呼吸道病毒感染仍然是全球住院和死亡的主要原因。呼吸道感染患者通常会体重减轻。据推测,急性体重减轻是一种限制病原体生长的耐受机制,而感染后严重的体重减轻会导致生活质量下降。尽管呼吸道感染引起的体重减轻与临床相关,但其机制尚未完全明了。我们利用呼吸道合胞病毒(RSV)感染期间 CD8+ T 细胞驱动的体重减轻模型来剖析感染后体重减轻的免疫调节。大量 RNASeq 研究表明,RSV 感染后 IL-1 信号通路显著富集,这与之前的数据相吻合。尽管病毒载量增加,但阻断IL-1α(而非IL-1β)后,感染相关的体重下降明显减少。抑制IL-1α可逆转RSV感染后观察到的肠道微生物群变化。直接从鼻腔灌入IL-1α也会导致体重下降。值得注意的是,无论是感染还是鼻腔灌注,我们都在大脑中检测到了IL-1α。这与 RSV 感染后控制食欲基因的变化以及瘦素和 GDF15 等信号分子的相应变化有关。这些发现共同表明,IL-1α在调节RSV感染后体重减轻的过程中起着肺-脑-肠信号轴的作用。
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引用次数: 0
A Trefoil factor 3-Lingo2 axis restrains proliferative expansion of type-1 T helper cells during GI nematode infection 在消化道线虫感染过程中,三叶草因子 3-Lingo2 轴抑制了 1 型 T 辅助细胞的增殖扩张。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-04-01 DOI: 10.1016/j.mucimm.2024.02.003
Lucas M. Ethgen , Christopher Pastore , Cailu Lin , Danielle R Reed , Li-Yin Hung , Bonnie Douglas , Dominic Sinker , De'Broski R. Herbert , Nicole M. Belle

Host defense at the mucosal interface requires collaborative interactions between diverse cell lineages. Epithelial cells damaged by microbial invaders release reparative proteins such as the Trefoil factor family (TFF) peptides that functionally restore barrier integrity. However, whether TFF peptides and their receptors also serve instructive roles for immune cell function during infection is incompletely understood. Here, we demonstrate that the intestinal trefoil factor, TFF3, restrains (T cell helper) TH1 cell proliferation and promotes host-protective type 2 immunity against the gastrointestinal parasitic nematode Trichuris muris. Accordingly, T cell-specific deletion of the TFF3 receptor, leucine-rich repeat and immunoglobulin containing nogo receptor 2 (LINGO2), impairs TH2 cell commitment, allows proliferative expansion of interferon (IFN)g+ cluster of differentiation (CD)4+ TH1 cells and blocks normal worm expulsion through an IFNg-dependent mechanism. This study indicates that TFF3, in addition to its known tissue reparative functions, drives anti-helminth immunity by controlling the balance between TH1/TH2 subsets.

黏膜界面的宿主防御需要不同细胞系之间的协作互动。被微生物入侵者破坏的上皮细胞会释放修复蛋白,如三叶草因子家族(TFF)肽,从而在功能上恢复屏障的完整性。然而,人们对 TFF 肽及其受体是否还能在感染期间对免疫细胞的功能起到指导作用尚不完全清楚。在这里,我们证明了肠道三叶草因子 TFF3 能抑制 TH1 细胞增殖并促进宿主保护性 2 型免疫,以对抗肠道寄生线虫毛滴虫。因此,T细胞特异性缺失TFF3受体Lingo2会损害TH2细胞的承诺,允许IFNγ+CD4+ TH1细胞增殖扩张,并通过IFNγ依赖性机制阻止正常的蠕虫驱逐。这项研究表明,TFF3除了具有已知的组织修复功能外,还能通过控制TH1/TH2亚群之间的平衡来驱动抗蠕虫免疫。
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引用次数: 0
Deficiency of immunoglobulin IgSF6 enhances antibacterial effects by promoting endoplasmic reticulum stress and the inflammatory response in intestinal macrophages 缺乏免疫球蛋白 IgSF6 会促进肠道巨噬细胞的 ER 应激和炎症反应,从而增强抗菌效果。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-04-01 DOI: 10.1016/j.mucimm.2024.02.006
Yuting Wu , Panrui Zhang , Tianlu Shi , Dan Cao , Wen Pan

Immunoglobulin superfamily (IgSF) members are known for their role as glycoproteins expressed on the surface of immune cells, enabling protein-protein interactions to sense external signals during immune responses. However, the functions of immunoglobulins localized within subcellular compartments have been less explored. In this study, we identified an endoplasmic reticulum (ER)-localized immunoglobulin, IgSF member 6 (IgSF6), that regulates ER stress and the inflammatory response in intestinal macrophages. Igsf6 expression is sustained by microbiota and significantly upregulated upon bacterial infection. Mice lacking Igsf6 displayed resistance to Salmonella typhimurium challenge but increased susceptibility to dextran sulfate sodium-induced colitis. Mechanistically, deficiency of Igsf6 enhanced inositol-requiring enzyme 1α/-X-box binding protein 1 pathway, inflammatory response, and reactive oxygen species production leading to increased bactericidal activity of intestinal macrophages. Inhibition of reactive oxygen species or inositol-requiring enzyme 1α-X-box binding protein 1 pathway reduced the advantage of Igsf6 deficiency in bactericidal capacity. Together, our findings provide insight into the role of IgSF6 in intestinal macrophages that modulate the ER stress response and maintain intestinal homeostasis.

免疫球蛋白超家族(IgSF)成员因其作为表达在免疫细胞表面的糖蛋白而为人所知,在免疫反应过程中,它们可以通过蛋白质之间的相互作用来感知外部信号。然而,人们对定位在亚细胞区室中的免疫球蛋白的功能探索较少。在这项研究中,我们发现了一种定位于ER的免疫球蛋白--IgSF成员6(IgSF6),它能调节ER应激和肠道巨噬细胞的炎症反应。Igsf6的表达受微生物群的维持,并在细菌感染时显著上调。缺乏 Igsf6 的小鼠对 S. Tyr 挑战有抵抗力,但对葡聚糖硫酸钠(DSS)诱导的结肠炎的易感性增加。从机理上讲,缺乏 Igsf6 会增强 IRE1α/XBP1s 通路、炎症反应和 ROS 的产生,从而导致肠道巨噬细胞的杀菌活性增强。抑制 ROS 或 IRE1α-XBP1 通路会降低 Igsf6 缺乏在杀菌能力方面的优势。总之,我们的研究结果让我们深入了解了 IgSF6 在肠巨噬细胞中调节 ER 应激反应和维持肠道稳态的作用。
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引用次数: 0
TRPV1+ sensory nerves suppress conjunctival inflammation via SST-SSTR5 signaling in murine allergic conjunctivitis TRPV1+感觉神经通过 SST-SSTR5 信号传导抑制小鼠过敏性结膜炎的结膜炎症
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-04-01 DOI: 10.1016/j.mucimm.2024.02.001
Ruoxun Yu , Sijing Liu , Yan Li , Liyuan Lu , Shuoya Huang , Xinwei Chen , Yunxia Xue , Ting Fu , Jun Liu , Zhijie Li

Allergic conjunctivitis (AC), an allergen-induced ocular inflammatory disease, primarily involves mast cells (MCs) and eosinophils. The role of neuroimmune mechanisms in AC, however, remains to be elucidated. We investigated the effects of transient receptor potential vanilloid 1 (TRPV1)-positive sensory nerve ablation (using resiniferatoxin) and TRPV1 blockade (using Acetamide, N-[4-[[6-[4-(trifluoromethyl)phenyl]-4-pyrimidinyl]oxy]-2-benzothiazolyl] (AMG-517)) on ovalbumin-induced conjunctival allergic inflammation in mice. The results showed an exacerbation of allergic inflammation as evidenced by increased inflammatory gene expression, MC degranulation, tumor necrosis factor-α production by MCs, eosinophil infiltration and activation, and C-C motif chemokine 11 (CCL11) (eotaxin-1) expression in fibroblasts. Subsequent findings demonstrated that TRPV1+ sensory nerves secrete somatostatin (SST), which binds to SST receptor 5 (SSTR5) on MCs and conjunctival fibroblasts. SST effectively inhibited tumor necrosis factor-α production in MCs and CCL11 expression in fibroblasts, thereby reducing eosinophil infiltration and alleviating AC symptoms, including eyelid swelling, lacrimation, conjunctival chemosis, and redness. These findings suggest that targeting TRPV1+ sensory nerve-mediated SST-SSTR5 signaling could be a promising therapeutic strategy for AC, offering insights into neuroimmune mechanisms and potential targeted treatments.

过敏性结膜炎(AC)是一种过敏原诱发的眼部炎症性疾病,主要涉及肥大细胞(MC)和嗜酸性粒细胞。然而,神经免疫机制在 AC 中的作用仍有待阐明。我们研究了瞬时受体电位类香草素 1(TRPV1)阳性感觉神经消融(使用树脂松脂素)和 TRPV1 阻断(使用 AMG-517)对卵清蛋白诱导的小鼠结膜过敏性炎症的影响。结果显示,过敏性炎症加剧,表现为炎症基因表达、MC 脱颗粒、MC 产生 TNF-α、嗜酸性粒细胞浸润和活化以及成纤维细胞中 CCL11(eotaxin-1)表达增加。随后的研究结果表明,TRPV1+感觉神经会分泌体生长抑素(SST),它能与 MCs 和结膜成纤维细胞上的体生长抑素受体 5(SSTR5)结合。SST 能有效抑制 MCs 中 TNF-α 的产生和成纤维细胞中 CCL11 的表达,从而减少嗜酸性粒细胞的浸润,缓解 AC 症状,包括眼睑肿胀、流泪、结膜化脓和发红。这些研究结果表明,针对TRPV1+感觉神经介导的SST-SSTR5信号传导可能是一种很有前景的AC治疗策略,为神经免疫机制和潜在的靶向治疗提供了启示。
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引用次数: 0
Immunity to pathogenic mucosal C. albicans infections mediated by oral megakaryocytes activated by IL-17 and candidalysin 由 IL-17 和念珠菌素激活的口腔巨核细胞介导的致病性粘膜白僵菌感染免疫。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-04-01 DOI: 10.1016/j.mucimm.2024.01.003
Dylan Launder , John T. Dillon , Leah M. Wuescher , Trevor Glanz , Nora Abdul-Aziz , Elise Mein-Chiain Yi , Julian R. Naglik , Randall G. Worth , Heather R. Conti

The fungus Candida albicans can cause mucosal infections including oropharyngeal candidiasis (OPC) in immunocompromised patients. In humans, an increased risk of fungal infections correlates with thrombocytopenia. However, our understanding of platelets and megakaryocytes (Mks) in mucosal fungal infections is almost entirely unknown. When megakaryocyte- and platelet-depleted mice were infected with OPC, the tongue showed higher fungal burden, due to decreased neutrophil accumulation. Protection depended on a distinct population of oral-resident Mks. Interleukin-17, important in antifungal immunity, was required since mice lacking the IL-17 receptor had decreased circulating platelets and their oral Mks did not expand during OPC. The secretion of the peptide toxin candidalysin activated human Mks to release platelets with antifungal capacity. Infection with a candidalysin-deficient strain resulted in decreased expansion of tongue Mks during OPC. This is the first time that a distinct megakaryocyte population was identified in the oral mucosa which is critical for immunity against fungal infection.

真菌白色念珠菌可引起粘膜感染,包括免疫力低下患者的口咽念珠菌病(OPC)。在人体中,真菌感染风险的增加与血小板减少有关。然而,我们对血小板和巨核细胞在粘膜真菌感染中的作用几乎一无所知。当巨核细胞和血小板缺失的小鼠感染 OPC 时,由于中性粒细胞聚集减少,舌头显示出更高的真菌负荷。保护作用取决于口腔巨核细胞的独特群体。白细胞介素-17在抗真菌免疫中非常重要,而缺乏白细胞介素-17受体的小鼠循环血小板减少,口腔巨核细胞在OPC期间也不会增大,因此需要白细胞介素-17。多肽毒素念珠菌素的分泌激活了人类巨核细胞,使其释放出具有抗真菌能力的血小板。感染念珠菌素缺陷菌株会导致舌巨核细胞在 OPC 期间扩张减少。这是首次在口腔粘膜中发现对真菌感染免疫至关重要的独特巨核细胞群。
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引用次数: 0
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Mucosal Immunology
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