Mucosal Immunology最新文献_第2页

Activated eosinophils in early life impair lung development and promote long-term lung damage 生命早期活化的嗜酸性粒细胞会损害肺部发育并促进长期肺损伤。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.06.003

Exaggeration of type 2 immune responses promotes lung inflammation and altered lung development; however, eosinophils, despite expansion in the postnatal lung, have not been specifically assessed in the context of neonatal lung disease. Furthermore, early life factors including prematurity and respiratory infection predispose infants to chronic obstructive pulmonary disease later in life. To assess eosinophils in the developing lung and how they may contribute to chronic lung disease, we generated mice harboring eosinophil-specific deletion of the negative regulatory enzyme SH2 domain-containing inositol 5′ phosphatase-1. This increased the activity and number of pulmonary eosinophils in the developing lung, which was associated with impaired lung development, expansion of activated alveolar macrophages (AMφ), multinucleated giant cell formation, enlargement of airspaces, and fibrosis. Despite regression of eosinophils following completion of lung development, AMφ-dominated inflammation persisted, alongside lung damage. Bone marrow chimera studies showed that SH2 domain-containing inositol 5′ phosphatase-1-deficient eosinophils were not sufficient to drive inflammatory lung disease in adult steady-state mice but once inflammation and damage were present, it could not be resolved. Depletion of eosinophils during alveolarization alleviated pulmonary inflammation and lung pathology, demonstrating an eosinophil-intrinsic effect. These results show that the presence of activated eosinophils during alveolarization aggravates AMφs and promotes sustained inflammation and long-lasting lung pathology.

2型免疫反应的加剧会促进肺部炎症和肺部发育的改变；然而，尽管嗜酸性粒细胞在出生后肺部扩大，但尚未对新生儿肺部疾病进行专门评估。此外，包括早产和呼吸道感染在内的生命早期因素使婴儿日后易患慢性阻塞性肺病。为了评估发育中肺部的嗜酸性粒细胞及其对慢性肺病的影响，我们培育了嗜酸性粒细胞特异性缺失负调控酶 SHIP-1 的小鼠。这增加了发育中肺部嗜酸性粒细胞的活性和数量，导致肺发育受损、活化肺泡巨噬细胞（AMφ）扩张、多核巨细胞形成、气孔扩大和纤维化。尽管嗜酸性粒细胞在肺发育完成后有所减少，但以 AMφ 为主的炎症仍持续存在，同时还伴有肺损伤。骨髓嵌合体研究表明，SHIP-1缺陷的嗜酸性粒细胞不足以驱动成年稳态小鼠的肺部炎症，但炎症和损伤一旦出现，就无法解决。在肺泡化过程中消耗嗜酸性粒细胞可缓解肺部炎症和肺部病理变化，这证明了嗜酸性粒细胞的内在效应。这些结果表明，肺泡化过程中活化的嗜酸性粒细胞会加重 AMφs，并促进持续的炎症和长期的肺部病变。

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引用次数: 0

Dietary protein modulates intestinal dendritic cells to establish mucosal homeostasis 膳食蛋白质调节肠道树突状细胞，建立粘膜稳态。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.06.006

Dietary proteins are taken up by intestinal dendritic cells (DCs), cleaved into peptides, loaded to major histocompatibility complexes, and presented to T cells to generate an immune response. Amino acid (AA)-diets do not have the same effects because AAs cannot bind to major histocompatibility complex to activate T cells. Here, we show that impairment in regulatory T cell generation and loss of tolerance in mice fed a diet lacking whole protein is associated with major transcriptional changes in intestinal DCs including downregulation of genes related to DC maturation, activation and decreased gene expression of immune checkpoint molecules. Moreover, the AA-diet had a profound effect on microbiome composition, including an increase in Akkermansia muciniphilia and Oscillibacter and a decrease in Lactococcus lactis and Bifidobacterium. Although microbiome transfer experiments showed that AA-driven microbiome modulates intestinal DC gene expression, most of the unique transcriptional change in DC was linked to the absence of whole protein in the diet. Our findings highlight the importance of dietary proteins for intestinal DC function and mucosal tolerance.

膳食蛋白质会被肠道树突状细胞（DC）吸收，裂解成肽，装载到主要组织相容性配体（MHC）上，并呈现给 T 细胞以产生免疫反应。氨基酸（AA）饮食没有同样的效果，因为AA不能与MHC结合以激活T细胞。在这里，我们发现，以缺乏全蛋白的饮食喂养的小鼠的 Treg 细胞生成障碍和耐受性丧失与肠道 DC 的主要转录变化有关，包括 DC 成熟、活化和迁移相关基因的下调以及免疫检查点分子基因表达的减少。此外，AA饮食对微生物组的组成也有深远影响，包括Akkermansia muciniphilia和Oscillibacter的增加以及乳酸乳球菌和双歧杆菌的减少。虽然微生物组转移实验表明 AA 驱动的微生物组会调节肠道直肠基因表达，但直肠中大多数独特的转录变化都与膳食中缺乏全蛋白质有关。我们的研究结果凸显了膳食蛋白质对肠道直流电功能和粘膜耐受性的重要性。

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引用次数: 0

Western diet reduces small intestinal intraepithelial lymphocytes via FXR-Interferon pathway 西式饮食通过 FXR- 干扰素途径减少小肠上皮内淋巴细胞。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.07.001

The prevalence of obesity in the United States has continued to increase over the past several decades. Understanding how diet-induced obesity modulates mucosal immunity is of clinical relevance. We previously showed that consumption of a high fat, high sugar “Western” diet (WD) reduces the density and function of small intestinal Paneth cells, a small intestinal epithelial cell type with innate immune function. We hypothesized that obesity could also result in repressed gut adaptive immunity. Using small intestinal intraepithelial lymphocytes (IEL) as a readout, we found that in non-inflammatory bowel disease (IBD) subjects, high body mass index correlated with reduced IEL density. We recapitulated this in wild type (WT) mice fed with WD. A 4-week WD consumption was able to reduce IEL but not splenic, blood, or bone marrow lymphocytes, and the effect was reversible after another 2 weeks of standard diet (SD) washout. Importantly, WD-associated IEL reduction was not dependent on the presence of gut microbiota, as WD-fed germ-free mice also showed IEL reduction. We further found that WD-mediated Farnesoid X Receptor (FXR) activation in the gut triggered IEL reduction, and this was partially mediated by intestinal phagocytes. Activated FXR signaling stimulated phagocytes to secrete type I IFN, and inhibition of either FXR or type I IFN signaling within the phagocytes prevented WD-mediated IEL loss. Therefore, WD consumption represses both innate and adaptive immunity in the gut. These findings have significant clinical implications in the understanding of how diet modulates mucosal immunity.

过去几十年来，美国的肥胖症发病率持续上升。了解饮食引起的肥胖如何调节粘膜免疫具有临床意义。我们以前的研究表明，摄入高脂肪、高糖的 "西式 "饮食（WD）会降低小肠帕奈斯细胞的密度和功能，帕奈斯细胞是一种具有先天性免疫功能的小肠上皮细胞类型。我们假设肥胖也会导致肠道适应性免疫功能受抑制。利用小肠上皮内淋巴细胞（IEL）作为读数，我们发现在非炎症性肠病（IBD）受试者中，高体重指数与 IEL 密度降低相关。我们在喂食 WD 的野生型（WT）小鼠身上重现了这一点。连续 4 周摄入 WD 能够减少 IEL，但不会减少脾脏、血液或骨髓淋巴细胞，而且这种影响在标准饮食（SD）间隔 2 周后是可逆的。重要的是，WD 相关的 IEL 减少并不依赖于肠道微生物群的存在，因为喂食 WD 的无菌小鼠也会出现 IEL 减少。我们进一步发现，WD 介导的肠道类囊体 X 受体（FXR）激活引发了 IEL 减少，而这部分是由肠道吞噬细胞介导的。激活的 FXR 信号刺激吞噬细胞分泌 I 型 IFN，抑制吞噬细胞内的 FXR 或 I 型 IFN 信号可防止 WD 介导的 IEL 损失。因此，摄入 WD 会抑制肠道内的先天性免疫和适应性免疫。这些发现对于了解饮食如何调节粘膜免疫具有重要的临床意义。

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引用次数: 0

Type I IFN signaling in the absence of IRGM1 promotes M. tuberculosis replication in immune cells by suppressing T cell responses 在 IRGM1 缺失的情况下，I 型 IFN 信号通过抑制 T 细胞反应促进结核杆菌在免疫细胞中的复制。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.07.002

Sumanta K. Naik, Michael E. McNehlan, Yassin Mreyoud, Rachel L. Kinsella, Asya Smirnov, Chanchal Sur Chowdhury, Samuel R. McKee, Neha Dubey, Reilly Woodson, Darren Kreamalmeyer, Christina L. Stallings

Polymorphisms in the IRGM gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of Irgm, Irgm1, is also essential for controlling Mycobacterium tuberculosis (Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells. However, what IRGM1-mediated pathway is necessary to control Mtb infection in vivo and the mechanistic basis for this control remains unknown. We dissected the contribution of IRGM1 to immune control of Mtb pathogenesis in vivo and found that Irgm1 deletion leads to higher levels of IRGM3-dependent type I interferon signaling. The increased type I interferon signaling precludes T cell expansion during Mtb infection. The absence of Mtb-specific T cell expansion in Irgm1^−/− mice results in uncontrolled Mtb infection in neutrophils and alveolar macrophages, which directly contributes to susceptibility to infection. Together, our studies reveal that IRGM1 is required to promote T cell-mediated control of Mtb infection in neutrophils, which is essential for the survival of Mtb-infected mice. These studies also uncover new ways type I interferon signaling can impact T_H1 immune responses.

IRGM基因的多态性与人类对结核病的易感性有关。Irgm的小鼠直向同源物Irgm1也是控制小鼠结核分枝杆菌（Mtb）感染的关键。与IRGM1活性相关的多个过程可能会影响宿主对Mtb感染的反应，包括在自噬介导的病原体清除和活化T细胞扩增中的作用。然而，IRGM1 介导的哪种途径是控制体内 Mtb 感染所必需的，以及这种控制的机理基础仍然未知。我们剖析了IRGM1对体内Mtb发病的免疫控制的贡献，发现Irgm1缺失会导致IRGM3依赖的I型干扰素信号水平升高。I型干扰素信号的增加阻止了T细胞在Mtb感染期间的扩增。Irgm1-/-小鼠缺乏Mtb特异性T细胞扩增，导致中性粒细胞和肺泡巨噬细胞中的Mtb感染失控，从而直接导致感染易感性。总之，我们的研究揭示了IRGM1是促进T细胞介导的中性粒细胞Mtb感染控制所必需的，这对Mtb感染小鼠的存活至关重要。这些研究还发现了 I 型干扰素信号转导影响 TH1 免疫反应的新途径。

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引用次数: 0

Translocating bacteria in SIV infection are not stochastic and preferentially express cytosine methyltransferases SIV 感染中的转运细菌并非随机，而是优先表达胞嘧啶甲基转移酶。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.07.008

Jacob K. Flynn , Alexandra M. Ortiz , Ivan Vujkovic-Cvijin , Hugh C. Welles , Jennifer Simpson , Fabiola M. Castello Casta , Debra S. Yee , Andrew R. Rahmberg , Kelsie L. Brooks , Marlon De Leon , Samantha Knodel , Kenzie Birse , Laura Noel-Romas , Anshu Deewan , Yasmine Belkaid , Adam Burgener , Jason M. Brenchley

Microbial translocation is a significant contributor to chronic inflammation in people living with HIV (PLWH) and is associated with increased mortality and morbidity in individuals treated for long periods with antiretrovirals. The use of therapeutics to treat microbial translocation has yielded mixed effects, in part, because the species and mechanisms contributing to translocation in HIV remain incompletely characterized. To characterize translocating bacteria, we cultured translocators from chronically SIV-infected rhesus macaques. Proteomic profiling of these bacteria identified cytosine-specific methyltransferases as a common feature and therefore, a potential driver of translocation. Treatment of translocating bacteria with the cytosine methyltransferase inhibitor decitabine significantly impaired growth for several species in vitro. In rhesus macaques, oral treatment with decitabine led to some transient decreases in translocator taxa in the gut microbiome. These data provide mechanistic insight into bacterial translocation in lentiviral infection and explore a novel therapeutic intervention that may improve the prognosis of PLWH.

微生物易位是导致艾滋病病毒感染者（PLWH）慢性炎症的一个重要因素，并与长期接受抗逆转录病毒药物治疗者的死亡率和发病率增加有关。使用治疗药物治疗微生物易位的效果不一，部分原因是导致艾滋病病毒易位的菌种和机制尚未完全定性。为了确定转运细菌的特征，我们从长期感染 SIV 的猕猴身上培养出了转运细菌。对这些细菌的蛋白质组分析发现，胞嘧啶特异性甲基转移酶是它们的共同特征，因此也是易位的潜在驱动因素。用胞嘧啶甲基转移酶抑制剂地西他滨处理易位细菌，可显著抑制几种细菌在体外的生长。在猕猴体内，地西他滨口服治疗会导致肠道微生物群中的易位分类群短暂减少。这些数据提供了慢病毒感染中细菌易位的机理，并探索了一种可能改善 PLWH 预后的新型治疗干预方法。

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引用次数: 0

Viral-vectored boosting of OmcB- or CPAF-specific T-cell responses fail to enhance protection from Chlamydia muridarum in infection-immune mice and elicits a non-protective CD8-dominant response in naïve mice 病毒载体增强的 OmcB 或 CPAF 特异性 T 细胞反应不能增强感染免疫小鼠对鼠衣原体的保护能力，并在幼稚小鼠中引起无保护作用的 CD8 优势反应。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.06.012

A vaccine is needed to combat the Chlamydia epidemic. Replication-deficient viral vectors are safe and induce antigen-specific T-cell memory. We tested the ability of intramuscular immunization with modified vaccinia Ankara (MVA) virus or chimpanzee adenovirus (ChAd) expressing chlamydial outer membrane protein (OmcB) or the secreted protein, chlamydial protease-like activating factor (CPAF), to enhance T-cell immunity and protection in mice previously infected with plasmid-deficient Chlamydia muridarum CM972 and elicit protection in naïve mice. MVA.OmcB or MVA.CPAF increased antigen-specific T cells in CM972-immune mice ∼150 and 50-fold, respectively, but failed to improve bacterial clearance. ChAd.OmcB/MVA.OmcB prime-boost immunization of naïve mice elicited a cluster of differentiation (CD) 8-dominant T-cell response dominated by cluster of differentiation (CD)8 T cells that failed to protect. ChAd.CPAF/ChAd.CPAF prime-boost also induced a CD8-dominant response with a marginal reduction in burden. Challenge of ChAd.CPAF-immunized mice genetically deficient in CD4 or CD8 T cells showed that protection was entirely CD4-dependent. CD4-deficient mice had prolonged infection, whereas CD8-deficient mice had higher frequencies of CPAF-specific CD4 T cells, earlier clearance, and reduced burden than wild-type controls. These data reinforce the essential nature of the CD4 T-cell response in protection from chlamydial genital infection in mice and the need for vaccine platforms that drive CD4-dominant responses.

需要一种疫苗来防治衣原体流行病。复制缺陷病毒载体既安全又能诱导抗原特异性 T 细胞记忆。我们测试了用表达衣原体外膜蛋白OmcB或分泌蛋白CPAF的改良安卡拉疫苗病毒（MVA）或黑猩猩腺病毒（ChAd）进行肌肉注射免疫，增强小鼠T细胞免疫力和保护力的能力，这些小鼠以前感染过质粒缺陷的鼠衣原体CM972，并在天真小鼠中产生保护作用。MVA.OmcB 或 MVA.CPAF 可使 CM972-免疫小鼠的抗原特异性 T 细胞分别增加 150 倍和 50 倍，但未能提高细菌清除率。ChAd.OmcB/MVA.OmcB对幼稚小鼠的原代增强免疫引起了CD8占优势的T细胞反应，但未能起到保护作用。ChAd.CPAF/ChAd.CPAF原代增强免疫也能诱导CD8优势反应，但负担略有减少。对基因上缺乏 CD4 或 CD8 T 细胞的 ChAd.CPAF 免疫小鼠的挑战表明，保护作用完全依赖于 CD4。与野生型对照组相比，CD4缺陷小鼠的感染时间延长，而CD8缺陷小鼠的CPAF特异性CD4 T细胞频率更高，清除时间更早，负担更轻。这些数据进一步证实了 CD4 T 细胞应答在保护小鼠免受衣原体生殖器感染中的重要作用，同时也证明了开发 CD4 主导应答的疫苗平台的必要性。

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引用次数: 0

Distinct olfactory mucosal macrophage populations mediate neuronal maintenance and pathogen defense 不同的嗅粘膜巨噬细胞群介导神经元维护和病原体防御

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.07.009

Sebastian A. Wellford , Ching-Wen Chen , Marko Vukovic , Kristen A. Batich , Elliot Lin , Alex K. Shalek , Jose Ordovas-Montanes , Annie Park Moseman , E. Ashley Moseman

The olfactory mucosa is important for both the sense of smell and as a mucosal immune barrier to the upper airway and brain. However, little is known about how the immune system mediates the conflicting goals of neuronal maintenance and inflammation in this tissue. A number of immune cell populations reside within the olfactory mucosa and yet we have little understanding of how these resident olfactory immune cells functionally interact with the chemosensory environment. Identifying these interactions will allow therapeutic manipulations that treat disorders such as post-viral olfactory dysfunction. Macrophages are the most prevalent immune cell type in the uninflamed olfactory mucosa and here, we identify two distinct tissue macrophage populations in murine olfactory mucosa. P2ry12^hi macrophages are transcriptionally specialized for neuron interactions, closely associated with olfactory neuron cell bodies, long-term tissue residents, and functionally specialized to phagocytose cells and debris, including olfactory neurons. Conversely, MHC Class II^hi macrophages are transcriptionally dedicated to cytokine production and antigen presentation, localized primarily within the olfactory lamina propria, more rapidly replaced by blood monocytes, and rapidly produce chemokines in response to viral infection. We further show that these macrophage signatures are present in human olfactory biopsies, and P2ry12-like olfactory macrophages are reduced in patients with long-term smell loss following COVID-19. Together, these data show that two olfactory macrophage populations regulate neurons and initiate the immune response, contributing to our understanding of both olfactory immunity and tissue-resident macrophage biology.

嗅觉粘膜对于嗅觉以及作为上呼吸道和大脑的粘膜免疫屏障都非常重要。然而，人们对免疫系统如何在该组织中介导神经元维护和炎症这两个相互冲突的目标知之甚少。嗅觉粘膜内驻留着许多免疫细胞群，但我们对这些驻留的嗅觉免疫细胞如何与化感环境发生功能性相互作用却知之甚少。确定这些相互作用将有助于治疗操作，从而治疗病毒后嗅觉功能障碍等疾病。巨噬细胞是未发炎的嗅觉粘膜中最常见的免疫细胞类型，在这里，我们确定了小鼠嗅觉粘膜中两种不同的组织巨噬细胞群。P2ry12hi 巨噬细胞在转录上专门与神经元相互作用，与嗅神经元细胞体密切相关，是长期的组织居民，在功能上专门吞噬细胞和碎片，包括嗅神经元。相反，MHC IIhi 类巨噬细胞转录专用于细胞因子的产生和抗原呈递，主要定位于嗅固有层，更快地被血液单核细胞取代，并在病毒感染时迅速产生趋化因子。我们进一步发现，这些巨噬细胞特征存在于人类的嗅觉活检组织中，而且在 COIVD-19 后长期嗅觉丧失的患者中，P2ry12 样嗅觉巨噬细胞减少。这些数据共同表明，两种嗅觉巨噬细胞群能调节神经元并启动免疫反应，有助于我们了解嗅觉免疫和组织驻留巨噬细胞生物学。

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引用次数: 0

CD38 and extracellular NAD+ regulate the development and maintenance of Hp vaccine‐induced CD4+ TRM in the gastric epithelium CD38 和细胞外 NAD+ 可调节胃上皮细胞中由 Hp 疫苗诱导的 CD4+ TRM 的发育和维持。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.06.011

Tissue-resident memory T cells (T_RM) can be induced by infection and vaccination, and play a key role in maintaining long-term protective immunity against mucosal pathogens. Our studies explored the key factors and mechanisms affecting the differentiation, maturation, and stable residence of gastric epithelial CD4⁺ T_RM induced by Helicobacter pylori (Hp) vaccine and optimized Hp vaccination to promote the generation and residence of T_RM. Cluster of differentiation (CD)38 regulated mitochondrial activity and enhanced transforming growth factor-β signal transduction to promote the differentiation and residence of gastric epithelial CD4⁺ T_RM by mediating the expression of CD105. Extracellular nucleotides influenced the long-term maintenance of T_RM in gastric epithelium by the P2X7 receptor (P2RX7). Vitamin D3 and Gram-positive enhancer matrix (GEM) particles as immune adjuvants combined with Hp vaccination promoted the production of CD69⁺CD103⁺CD4⁺ T_RM.

组织驻留记忆T细胞（TRM）可由感染和疫苗接种诱导，并在维持针对粘膜病原体的长期保护性免疫中发挥关键作用。我们的研究探讨了影响幽门螺杆菌（Hp）疫苗诱导的胃上皮CD4+TRM分化、成熟和稳定驻留的关键因素和机制，并优化了Hp疫苗接种，以促进TRM的产生和驻留。CD38通过介导CD105的表达，调节线粒体活性并增强TGF-β信号转导，从而促进胃上皮CD4+TRM的分化和驻留。细胞外核苷酸通过P2RX7影响TRM在胃上皮的长期维持。维生素D3和革兰氏阳性增强基质颗粒（GEMs）作为免疫佐剂与Hp疫苗接种结合可促进CD69+CD103+CD4+TRM的产生。

引用次数: 0

Opposing roles of resident and infiltrating immune cells in the defense against Legionella longbeachae via IL-18R/IFN-γ/ROS axis in mice 常驻和浸润免疫细胞通过 IL-18R/IFN-γ/ROS 轴在小鼠体内防御长须鲸军团菌的过程中发挥相反的作用。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.05.001

The immune response against Legionella longbeachae, a causative agent of the often-fatal Legionnaires’ pneumonia, is poorly understood. Here, we investigated the specific roles of tissue-resident alveolar macrophages (AMs) and infiltrating phagocytes during infection with this pathogen. AMs were the predominant cell type that internalized bacteria 1 day after infection. A total of 3 and 5 days after infection, AM numbers were greatly reduced, whereas there was an influx of neutrophils and, later, monocyte-derived cells (MCs) into lung tissue. AMs carried greater numbers of viable L. longbeachae than neutrophils and MCs, which correlated with a higher capacity of L. longbeachae to translocate bacterial effector proteins required for bacterial replication into the AM cytosol. Cell ablation experiments demonstrated that AM promoted infection, whereas neutrophils and MC were required for efficient bacterial clearance. Interleukin (IL)-18 was important for interferon-γ production by IL-18R⁺ natural killer cells and T cells, which, in turn, stimulated reactive oxygen species–mediated bactericidal activity in neutrophils, resulting in the restriction of L. longbeachae infection. Ciliated bronchiolar epithelial cells also expressed IL-18R but did not play a role in IL-18–mediated L. longbeachae clearance. Our results have identified opposing innate functions of tissue-resident and infiltrating immune cells during L. longbeachae infection that may be manipulated to improve protective responses.

长须鲸军团菌是经常导致死亡的军团菌肺炎的致病菌，人们对这种病菌的免疫反应知之甚少。在这里，我们研究了组织驻留的肺泡巨噬细胞（AM）和浸润吞噬细胞在感染这种病原体时的特殊作用。AM是感染一天后内化细菌的主要细胞类型。感染 3 天和 5 天后，AM 的数量大大减少，而中性粒细胞和随后的单核细胞衍生细胞（MC）则大量涌入肺组织。与中性粒细胞和单核细胞相比，AM携带的存活长须杆菌数量更多，这与长须杆菌将细菌复制所需的细菌效应蛋白转运到AM细胞膜的能力更强有关。细胞消融实验表明，AM 能促进感染，而中性粒细胞和 MC 则是有效清除细菌的必要条件。IL-18对IL-18R+ NK细胞和T细胞产生IFN-γ非常重要，这反过来又刺激了中性粒细胞中ROS介导的杀菌活性，从而限制了L.longbeachae的感染。纤毛支气管上皮细胞也表达 IL-18R，但在 IL-18 介导的 L.longbeachae 清除过程中并未发挥作用。我们的研究结果发现，在L.longbeachae感染过程中，组织驻留免疫细胞和浸润免疫细胞的先天功能是相反的，可以通过调节这些功能来改善保护性反应。

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引用次数: 0

IL-23 exerts dominant pathogenic functions in Crohn’s disease-ileitis IL-23在克罗恩病-静脉炎中发挥主导致病功能

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.05.008

Crohn’s disease (CD), a main form of Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder, mainly affecting the ileum. Interleukin (IL)-12 and IL-23 are both targeted by Ustekinumab, a commonly used monoclonal antibody for IBD treatment. However, their specific roles in ileitis have not been extensively explored. Here, we utilized the Tnf^ΔΑRE model of CD-ileitis to probe the functions of IL-12 and IL-23 by employing genetically deficient mice for their respective subunits. Our findings highlight that IL-23, rather than IL-12, plays a pivotal role in the progression of ileitis. IL-23 deficiency resulted in reduced immune cell infiltration in the ileum, and decreased expression of effector cytokines downstream of IL-23 signaling. Interestingly, expanding CD14⁺ neutrophils were highly expressing Il23a in the inflamed ileum. Furthermore, the deletion of IL-12 conferred modest additional protection only in the absence of IL-23, suggesting potential compensatory mechanisms between these cytokines. Furthermore, our study suggests that IL-23 may function independently of IL-17, as Il17a deletion exacerbated murine ileitis, consistent with clinical studies in human CD patients using anti–IL-17 inhibitors. This research underscores the significance of targeting IL-23 in CD-ileitis, while the concurrent targeting of both IL-12 and IL-23 should be also considered as an advantageous therapeutic approach.

克罗恩病（CD）是炎症性肠病（IBD）的一种主要形式，是一种慢性炎症性疾病，主要影响回肠。IL-12和IL-23都是治疗IBD的常用单克隆抗体Ustekinumab的靶点。然而，它们在回肠炎中的具体作用尚未得到广泛探讨。在此，我们利用TnfΔΑRE CD回肠炎模型，通过基因缺陷小鼠来探究IL-12和IL-23各自亚单位的功能。我们的研究结果表明，IL-23而非IL-12在回肠炎的发展过程中起着关键作用。IL-23 基因缺陷导致回肠中免疫细胞浸润减少，IL-23 信号下游效应细胞因子表达降低。有趣的是，扩大的 CD14+ 中性粒细胞在发炎的回肠中高度表达 IL-23。此外，只有在没有IL-23的情况下，IL-12的缺失才会带来适度的额外保护，这表明这些细胞因子之间存在潜在的补偿机制。此外，我们的研究还表明，IL-23 的功能可能独立于 IL-17 ，因为 IL-17 的缺失会加重小鼠回肠炎，这与使用抗 IL-17 抑制剂对人类 CD 患者进行的临床研究一致。这项研究强调了靶向 IL-23 在 CD 回肠炎中的重要性，同时靶向 IL-12 和 IL-23 也应被视为一种有利的治疗方法。

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引用次数: 0