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P2RX1-blocked neutrophils induce CD8+ T cell dysfunction and affect the immune escape of gastric cancer cells p2rx1阻断的中性粒细胞诱导CD8+ T细胞功能障碍,影响胃癌细胞的免疫逃逸。
IF 3.7 4区 医学 Q2 CELL BIOLOGY Pub Date : 2025-02-01 DOI: 10.1016/j.cellimm.2024.104901
Yan Zhang , Fenglin Zhang , Zhi Liu , Min Li , Ge Wu , Hui Li

Background

Gastric cancer (GC) is one of the deadly malignancies of the gastrointestinal tract. Research has confirmed the linkage of P2RX1 with immune cell activation and tumor progression. This project focused on the impact of P2RX1 level in neutrophils on the efficacy of immune checkpoint inhibitor (ICI) treatment in GC.

Methods

Blood samples from 23 GC patients eligible for camrelizumab treatment were collected. Flow cytometry was carried out to analyze the proportion of P2RX1 in neutrophils. IHC was utilized to detect the expression level of PD-L1. We also evaluated the chemotaxis ability of neutrophils using a Transwell system, assessed the viability and apoptosis rate of GC cells using CCK-8 and flow cytometry, measured the proportions of CD8+PD-1+ and CD8+GZMB+ cells, determined the expression levels of IL-6, TNFα, IFN-γ, IL-8, IL-12, IL-1β, and GZMB by utilizing enzyme-linked immunosorbent assay (ELISA), and examined the expression levels of P2RX1 and PD-L1 using western blot (WB). By establishing a xenograft mouse model, we studied the impact of P2RX1-blocked neutrophils on the efficacy of ICI treatment in the GC microenvironment.

Results

In GC, clinical analysis revealed increased infiltration of P2RX1-lowly expressed neutrophil subsets and increased expression of PD-L1. In vitro experiments demonstrated that abnormal expression of P2RX1 affected neutrophil function. Furthermore, the blockage or knockdown of P2RX1 in neutrophils modulated CD8+ T cell function, promoting GC progression. In in vivo experiments, the blockage of P2RX1 in neutrophils inhibited the effectiveness of ICI treatment in the GC microenvironment.

Conclusion

This project validated that the loss of P2RX1 in neutrophils induces CD8+ T cell dysfunction and affects the GC development, indicating that P2RX1 may be an accurate biomarker for predicting ICI response, thus providing a theoretical basis for the clinical application of ICI.
背景:胃癌(GC)是胃肠道中致命的恶性肿瘤之一。研究证实 P2RX1 与免疫细胞活化和肿瘤进展有关。本项目重点研究中性粒细胞中P2RX1水平对免疫检查点抑制剂(ICI)治疗胃癌疗效的影响:方法:收集了23名符合康瑞珠单抗治疗条件的GC患者的血液样本。流式细胞术分析了中性粒细胞中 P2RX1 的比例。利用 IHC 检测 PD-L1 的表达水平。我们还使用 Transwell 系统评估了中性粒细胞的趋化能力,使用 CCK-8 和流式细胞术评估了 GC 细胞的存活率和凋亡率,测量了 CD8+PD-1+ 和 CD8+GZMB+ 细胞的比例、利用酶联免疫吸附试验(ELISA)测定 IL-6、TNFα、IFN-γ、IL-8、IL-12、IL-1β 和 GZMB 的表达水平,并利用 Western 印迹(WB)检测 P2RX1 和 PD-L1 的表达水平。通过建立异种移植小鼠模型,我们研究了 P2RX1 受体阻断的中性粒细胞对 ICI 治疗 GC 微环境疗效的影响:在 GC 中,临床分析显示 P2RX1 低表达的中性粒细胞亚群浸润增加,PD-L1 表达增加。体外实验表明,P2RX1 的异常表达会影响中性粒细胞的功能。此外,阻断或敲除中性粒细胞中的 P2RX1 会调节 CD8+ T 细胞的功能,促进 GC 的进展。在体内实验中,阻断中性粒细胞中的 P2RX1 会抑制 ICI 在 GC 微环境中的治疗效果:该项目验证了中性粒细胞中P2RX1的缺失会诱导CD8+ T细胞功能障碍并影响GC的发展,表明P2RX1可能是预测ICI反应的准确生物标志物,从而为ICI的临床应用提供了理论依据。
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引用次数: 0
Enhanced apoptosis and inflammation allied with autophagic and apoptotic Leishmania amastigotes in the seemingly undamaged ear skin of clinically affected dogs with canine visceral Leishmaniasis 在临床感染犬内脏利什曼病的犬耳皮肤中,与自噬和凋亡利什曼原虫无毛线虫相关的细胞凋亡和炎症增强。
IF 3.7 4区 医学 Q2 CELL BIOLOGY Pub Date : 2025-02-01 DOI: 10.1016/j.cellimm.2024.104909
Barbara Laurice Araújo Verçosa , Maria Imaculada Muniz-Junqueira , Ana Lys Bezerra Barradas Mineiro , Maria Norma Melo , Anilton Cesar Vasconcelos
Programmed cell death plays a relevant role in the pathogenesis of visceral Leishmaniasis. Apoptosis selects suitable parasites, regulating parasite density, whereas autophagy eliminates pathogens. This study aimed to assess the inflammation and apoptosis in inflammatory cells and presents a unique description of the presence of autophagic and apoptotic Leishmania amastigotes in naturally Leishmania-infected dogs. Fragments from seemingly undamaged ear skin of sixteen Leishmania-infected dogs and seven uninfected dogs were evaluated through histomorphometry, ultrastructural, immunohistochemical and transmission electron microscopy (TEM) analyses. Leishmania amastigotes were present on seemingly undamaged ear skin only in clinically affected dogs. Parasite load, morphometrical parameters of inflammation and apoptotic index of inflammatory cells were higher in clinically affected animals and were related to clinical manifestations. Apoptotic index and morphometric parameters of the inflammatory infiltrate in undamaged ear skin were positively correlated with parasite load. Apoptotic and non-apoptotic Leishmania amastigotes were observed within neutrophils and macrophages. Leishmania amastigotes were positive for Bax, a marker for apoptosis, by immunohistochemistry. Morphological characteristics of apoptosis and autophagy in Leishmania amastigotes were observed only in phagocytes of clinically affected dogs. Positive correlations were found between histomorphometry and clinical manifestations. Our results showed that apoptosis and autophagy in Leishmania amastigotes may be related to both the increase in parasite load and apoptotic index in inflammatory cells, and with the intensity of the inflammatory response in clinically affected dogs. Thus, our study suggests that apoptotic and autophagy Leishmania within phagocytes may have facilitate the survival of the parasite and it appears to play an important role in the process of Leishmania infection.
程序性细胞死亡在内脏利什曼病的发病机制中起着相关作用。细胞凋亡选择合适的寄生虫,调节寄生虫密度,而自噬消除病原体。本研究旨在评估炎症细胞的炎症和凋亡,并对自然感染利什曼原虫的狗体内存在自噬和凋亡的利什曼原虫无鞭毛体进行独特的描述。对16只感染利什曼犬和7只未感染利什曼犬的耳部皮肤进行组织形态学、超微结构、免疫组织化学和透射电镜分析。利什曼原虫无鞭毛体只存在于临床感染犬的看似未受损的耳皮肤上。临床感染动物的寄生虫负荷、炎症形态计量参数和炎症细胞凋亡指数均较高,且与临床表现有关。未损伤耳部皮肤炎症浸润的凋亡指数和形态学参数与寄生虫负荷呈正相关。中性粒细胞和巨噬细胞内均可见凋亡和非凋亡利什曼原虫。免疫组化法检测利什曼原虫凋亡标志物Bax阳性。利什曼原虫凋亡和自噬的形态学特征仅在临床感染犬的吞噬细胞中观察到。组织形态学与临床表现呈正相关。我们的研究结果表明,利什曼原虫的凋亡和自噬可能与炎症细胞中寄生虫负荷和凋亡指数的增加有关,并与临床感染犬的炎症反应强度有关。因此,我们的研究表明,吞噬细胞内的凋亡和自噬利什曼原虫可能促进了寄生虫的生存,并在利什曼原虫感染过程中发挥了重要作用。
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引用次数: 0
The effect of tocilizumab treatment for skin fibrosis by inhibiting CD38+ macrophages in systemic sclerosis 托珠单抗通过抑制系统性硬化症中CD38+巨噬细胞治疗皮肤纤维化的作用。
IF 3.7 4区 医学 Q2 CELL BIOLOGY Pub Date : 2025-02-01 DOI: 10.1016/j.cellimm.2024.104914
Hongzhen Chen , Dapeng Yang , Yirui Shi , Haolin Wu , Huiming Zhu , Tingting Jiang , Shu Liu , Dandan Wang

Background

Dermal and pulmonary fibrosis are the main clinical symptoms of systemic scleroderma (SSc), for which there are no effective therapeutic agents. Tocilizumab is thought to improve the symptoms of fibrosis, but the effect of tocilizumab on dermal fibrosis has not been explored. This study aims to investigate the therapeutic effect of tocilizumab on skin fibrosis by inhibiting CD38+ macrophages in the bleomycin-induced SSc mice model.

Methods

The 8-week-old BALB/c mice were randomly divided into three groups: control group (PBS group), model group (BLM group), and tocilizumab group (TCZ group). The mRNA expression of VIMENTIN, TIMP1, and COL1A1 was measured by qPCR. Western blot was used to detect the protein expression of α-SMA, TGF-β, and COL1A1 in skin tissues. The expression of CD38+ macrophages in the BLM-induced fibrosis mouse model was verified by flow cytometry and immunofluorescence.

Results

In comparison to the PBS control group, mice in the BLM group showed skin fibrosis, edema, thickness, and collagen deposition. The percentage of macrophages in the skin, peripheral blood, and spleen was significantly increased in the BLM group, and the percentage of CD38+ macrophages increased in the skin and peripheral blood but decreased in the spleen. After co-cultured with macrophages, L929 fibroblasts differentiated into myofibroblasts, with increased mRNA expression of COL1A1, COL3A, TGF-β, and Fibronectin. Furthermore, after being stimulated by LPS, RAW264.7 cells showed increased expression of IL-6 and CD38. The mRNA levels of COL1A1, COL1A2, COL3A, TGF-β, and Fibronectin in L929 fibroblasts were markedly increased when co-cultured with LPS-stimulated RAW264.7 cells. Tocilizumab treatment reduced dermal thickness and collagen deposition induced by BLM. Furthermore, the percentage of total macrophages and CD38+ macrophages in the skin and peripheral blood significantly decreased after tocilizumab treatment.

Conclusion

This study revealed that tocilizumab improved skin fibrosis in the SSc mice model, which was mediated by inhibiting skin and peripheral CD38+ macrophages.
背景:皮肤和肺纤维化是系统性硬皮病(SSc)的主要临床症状,目前尚无有效的治疗药物。Tocilizumab被认为可以改善纤维化症状,但Tocilizumab对真皮纤维化的影响尚未被探索。本研究旨在探讨tocilizumab通过抑制CD38+巨噬细胞在博莱霉素诱导的SSc小鼠模型中对皮肤纤维化的治疗作用。方法:将8周龄BALB/c小鼠随机分为3组:对照组(PBS组)、模型组(BLM组)、托珠单抗组(TCZ组)。采用qPCR检测VIMENTIN、TIMP1、COL1A1 mRNA的表达。Western blot检测皮肤组织中α-SMA、TGF-β、COL1A1蛋白的表达。用流式细胞术和免疫荧光技术验证CD38+巨噬细胞在blm诱导纤维化小鼠模型中的表达。结果:与PBS对照组比较,BLM组小鼠出现皮肤纤维化、水肿、增厚、胶原沉积。BLM组皮肤、外周血和脾脏中巨噬细胞百分比显著升高,皮肤和外周血中CD38+巨噬细胞百分比升高,脾脏中CD38+巨噬细胞百分比降低。与巨噬细胞共培养后,L929成纤维细胞分化为肌成纤维细胞,COL1A1、COL3A、TGF-β、纤维连接蛋白mRNA表达增加。此外,经LPS刺激后,RAW264.7细胞IL-6和CD38的表达增加。与lps刺激的RAW264.7细胞共培养后,L929成纤维细胞COL1A1、COL1A2、COL3A、TGF-β和纤维连接蛋白mRNA水平显著升高。托珠单抗治疗可减少BLM诱导的真皮厚度和胶原沉积。此外,托珠单抗治疗后,皮肤和外周血中总巨噬细胞和CD38+巨噬细胞的百分比显著降低。结论:本研究揭示tocilizumab改善SSc小鼠模型皮肤纤维化,其机制是通过抑制皮肤和外周血CD38+巨噬细胞介导。
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引用次数: 0
Augmented IFNγ producing ILC1 and IL 17 producing ILC3 in pemphigus vulgaris: Plausible therapeutic target 寻常型天疱疮中IFNγ增强产生ILC1和IL 17产生ILC3:可能的治疗靶点。
IF 3.7 4区 医学 Q2 CELL BIOLOGY Pub Date : 2025-02-01 DOI: 10.1016/j.cellimm.2024.104910
Vishakha Hooda , Sujay Khandpur , Alpana Sharma
Innate Lymphoid cells (ILCs) are innate counterparts of helper T cells. Although low in number, they have proven to play major roles in many autoimmune diseases. In Pemphigus Vulgaris (PV), the gaps in the knowledge of functional role of ILCs remain. To bridge the gap, our study investigated the phenotype along with the functional determinants of ILCs involved in PV immunopathogenesis. Our data suggested augmentation in overall ILC population in circulation of PV patients. Specifically, ILC1 and ILC3 subtypes were significantly increased in peripheral circulation of PV patients compared to healthy controls. We observed no changes in ILC2 population. mRNAs from ILC enriched population showed significant upregulation in transcription factors- ID2, T bet and RORγt and a downregulation in GATA3 and RORα. The mRNA levels of ILC related cytokines- IFNγ and IL17 were significantly upregulated while no change was observed in the levels of IL13, IL 22, AHR. The levels of autoantibodies against desmoglein (Dsg) 3 which is the characteristic of PV pathogenesis were also checked in the serum which confirmed significant upregulation in PV patients. The levels of proinflammatory- IFNγ, IL 17 and IL 15 were elevated and anti-inflammatory cytokines- IL10 was downregulated in the serum of PV patients. The results of this study offer insights into the functional attributes of ILCs and related cytokines, potentially contributing to the development of future therapeutic interventions.
先天淋巴样细胞(ILCs)是辅助T细胞的先天对应物。虽然数量很少,但它们已被证明在许多自身免疫性疾病中发挥重要作用。在寻常型天疱疮(PV)中,ILCs的功能作用知识仍然存在空白。为了弥补这一空白,我们的研究调查了表型以及参与PV免疫发病的ILCs的功能决定因素。我们的数据表明PV患者血液循环中的ILC总体增加。具体而言,与健康对照组相比,PV患者外周循环中的ILC1和ILC3亚型显著增加。我们观察到ILC2人群没有变化。ILC富集群体mrna中转录因子- ID2、tbet和RORγt显著上调,GATA3和RORα显著下调。ILC相关细胞因子IFNγ和IL17 mRNA水平显著上调,IL13、IL 22、AHR mRNA水平未见变化。血清中抗粘粒蛋白(Dsg) 3的自身抗体水平也被检测,这是PV发病机制的特征,证实了PV患者的显著上调。PV患者血清促炎因子- IFNγ、IL 17、IL 15水平升高,抗炎因子- IL10水平下调。这项研究的结果提供了对ilc和相关细胞因子的功能属性的见解,可能有助于未来治疗干预措施的发展。
{"title":"Augmented IFNγ producing ILC1 and IL 17 producing ILC3 in pemphigus vulgaris: Plausible therapeutic target","authors":"Vishakha Hooda ,&nbsp;Sujay Khandpur ,&nbsp;Alpana Sharma","doi":"10.1016/j.cellimm.2024.104910","DOIUrl":"10.1016/j.cellimm.2024.104910","url":null,"abstract":"<div><div>Innate Lymphoid cells (ILCs) are innate counterparts of helper T cells. Although low in number, they have proven to play major roles in many autoimmune diseases. In Pemphigus Vulgaris (PV), the gaps in the knowledge of functional role of ILCs remain. To bridge the gap, our study investigated the phenotype along with the functional determinants of ILCs involved in PV immunopathogenesis. Our data suggested augmentation in overall ILC population in circulation of PV patients. Specifically, ILC1 and ILC3 subtypes were significantly increased in peripheral circulation of PV patients compared to healthy controls. We observed no changes in ILC2 population. mRNAs from ILC enriched population showed significant upregulation in transcription factors- ID2, T bet and RORγt and a downregulation in GATA3 and RORα. The mRNA levels of ILC related cytokines- IFNγ and IL17 were significantly upregulated while no change was observed in the levels of IL13, IL 22, AHR. The levels of autoantibodies against desmoglein (Dsg) 3 which is the characteristic of PV pathogenesis were also checked in the serum which confirmed significant upregulation in PV patients. The levels of proinflammatory- IFNγ, IL 17 and IL 15 were elevated and anti-inflammatory cytokines- IL10 was downregulated in the serum of PV patients. The results of this study offer insights into the functional attributes of ILCs and related cytokines, potentially contributing to the development of future therapeutic interventions.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"408 ","pages":"Article 104910"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The double-edged sword role of natural Killer cells in Parkinson's disease
IF 3.7 4区 医学 Q2 CELL BIOLOGY Pub Date : 2025-01-23 DOI: 10.1016/j.cellimm.2025.104928
Delbar Daneshjou , Seyed Masood Nabavi , Parisa Shams , Pooya Faranoush , Mehri Salari , Marzieh Ebrahimi
Neurological disorders are the leading cause of disability worldwide, with Parkinson's disease (PD) emerging as a rapidly growing neurological condition on a global scale. Although treatments exist to alleviate symptoms and maintain patients' quality of life, PD remains incurable. According to some recent studies, natural killer (NK) cells may play a role in clearing alpha-synuclein aggregates, which are the main component of Lewy bodies that cause neuronal degeneration in Parkinson's disease. NK cells may also have an adverse impact on this condition by modulating inflammation and antigen-presenting cell function. Modifying NK cells derived from diverse sources, such as umbilical cord blood, presents a promising avenue for immunotherapy in PD patients, particularly during the early stages of the condition. Consequently, further research is essential to elucidate the mechanisms by which NK cells operate in Parkinson's patients and to assess their viability as potential biomarkers or therapeutic targets.
{"title":"The double-edged sword role of natural Killer cells in Parkinson's disease","authors":"Delbar Daneshjou ,&nbsp;Seyed Masood Nabavi ,&nbsp;Parisa Shams ,&nbsp;Pooya Faranoush ,&nbsp;Mehri Salari ,&nbsp;Marzieh Ebrahimi","doi":"10.1016/j.cellimm.2025.104928","DOIUrl":"10.1016/j.cellimm.2025.104928","url":null,"abstract":"<div><div>Neurological disorders are the leading cause of disability worldwide, with Parkinson's disease (PD) emerging as a rapidly growing neurological condition on a global scale. Although treatments exist to alleviate symptoms and maintain patients' quality of life, PD remains incurable. According to some recent studies, natural killer (NK) cells may play a role in clearing alpha-synuclein aggregates, which are the main component of Lewy bodies that cause neuronal degeneration in Parkinson's disease. NK cells may also have an adverse impact on this condition by modulating inflammation and antigen-presenting cell function. Modifying NK cells derived from diverse sources, such as umbilical cord blood, presents a promising avenue for immunotherapy in PD patients, particularly during the early stages of the condition. Consequently, further research is essential to elucidate the mechanisms by which NK cells operate in Parkinson's patients and to assess their viability as potential biomarkers or therapeutic targets.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"409 ","pages":"Article 104928"},"PeriodicalIF":3.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Effect of high-fat diet on IgA+ cells and BAFF/APRIL in small intestinal villous lamina propria of mice
IF 3.7 4区 医学 Q2 CELL BIOLOGY Pub Date : 2025-01-21 DOI: 10.1016/j.cellimm.2024.104911
Yuta Sakamoto , Masatoshi Niwa , Ken Muramatsu , Satoshi Shimo
Obesity exacerbates susceptibility to infectious diseases. We investigated the effects of a high-fat diet (HFD) on intestinal immunity, particularly immunoglobulin (Ig)A-producing cells, B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL) localization. Mice (4- to 20-weeks old) were fed HFD or standard chow diet, and their jejunum and ileum were fixed using the in vivo cryotechnique. Immunohistochemistry was performed for IgA, BAFF, and APRIL. In the HFD group, IgA+, IgA+CD22+ (p < 0.001), and IgA+CD138 (p = 0.007) cell counts were diminished in the middle sections of the lamina propria of jejunal villi, and BAFF levels were significantly reduced in jejunal villi. The HFD effects on IgA+ cell distribution seem to be confined to jejunal villi, hinting at localized vulnerabilities in intestinal immunity during obesity. Moreover, in the HFD group, IgA+ B-cell counts were reduced in the middle jejunum, indicating inhibition of the IgA+ B-cells through a T-cell-independent pathway.
{"title":"Effect of high-fat diet on IgA+ cells and BAFF/APRIL in small intestinal villous lamina propria of mice","authors":"Yuta Sakamoto ,&nbsp;Masatoshi Niwa ,&nbsp;Ken Muramatsu ,&nbsp;Satoshi Shimo","doi":"10.1016/j.cellimm.2024.104911","DOIUrl":"10.1016/j.cellimm.2024.104911","url":null,"abstract":"<div><div>Obesity exacerbates susceptibility to infectious diseases. We investigated the effects of a high-fat diet (HFD) on intestinal immunity, particularly immunoglobulin (Ig)A-producing cells, B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL) localization. Mice (4- to 20-weeks old) were fed HFD or standard chow diet, and their jejunum and ileum were fixed using the <em>in vivo</em> cryotechnique. Immunohistochemistry was performed for IgA, BAFF, and APRIL. In the HFD group, IgA<sup>+</sup>, IgA<sup>+</sup>CD22<sup>+</sup> (<em>p</em> &lt; 0.001), and IgA<sup>+</sup>CD138<sup>−</sup> (<em>p</em> = 0.007) cell counts were diminished in the middle sections of the lamina propria of jejunal villi, and BAFF levels were significantly reduced in jejunal villi. The HFD effects on IgA<sup>+</sup> cell distribution seem to be confined to jejunal villi, hinting at localized vulnerabilities in intestinal immunity during obesity. Moreover, in the HFD group, IgA<sup>+</sup> B-cell counts were reduced in the middle jejunum, indicating inhibition of the IgA<sup>+</sup> B-cells through a T-cell-independent pathway.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"409 ","pages":"Article 104911"},"PeriodicalIF":3.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
IL-17 family members exert an autocrine pro-inflammatory loop in CF respiratory epithelial cells ex vivo IL-17家族成员体外在CF呼吸上皮细胞中发挥自分泌促炎回路。
IF 3.7 4区 医学 Q2 CELL BIOLOGY Pub Date : 2025-01-17 DOI: 10.1016/j.cellimm.2025.104926
Caterina Allegretta , Enza Montemitro , Fabiana Ciciriello , Maria Teresa Altieri , Giuseppe Sabbioni , Giulia Breveglieri , Monica Borgatti , Giulio Cabrini , Onofrio Laselva

Background

Lungs of people with Cystic Fibrosis (pwCF) are characterized by chronic inflammation and infection with P. aeruginosa. High levels of IL-17 A and F have been observed in sputum of pwCF and the interleukin-17(IL-17) family (A-to-F) has been suggested to play a key role in CF pulmonary disease.

Methods

We measured mRNA levels of IL-17 receptors (IL-17R) by RT-qPCR in CF bronchial epithelial (CFBE) cultured cells upon infection with P. aeruginosa PAO1 strain or clinical exoproducts (EXO) isolated from pwCF. We measured IL-17 mRNA expression by RT-qPCR and the release of cytokines by ELISA and Bioplex from CF primary nasal epithelial (HNE) cultured cells.

Results

Infection of CFBE cells with PAO1 or EXO isolated from 15 pwCF significantly increased mRNA expression of all IL-17R, except IL-17RD. Infection of HNE cells with EXO isolated from the correspondent donor significantly increased the mRNA levels of all the IL-17 cytokines and receptors, except for IL-17D and IL-17RD, and the release of the cytokines IL-17 A, IL-17B, IL-17C, IL-17E and IL-17F. HNE exposed to IL-17 A and F were induced to release pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), neutrophil chemokines (IL-8, G-CSF) and cytokines known to be involved in chloride and bicarbonate secretion, together with mucin upregulation (IL-4, IL-13).

Conclusion

These results highlight a wider expression of IL-17 family member in respiratory epithelial cells, which can play a role as an autocrine inflammatory amplification loop in CF airways. These in-vitro studies using patient-derived cultures underline the relevant role of IL-17 family members in CF pulmonary immune response.
背景:囊性纤维化(pwCF)患者的肺部以慢性炎症和铜绿假单胞菌感染为特征。在pwCF患者的痰中观察到高水平的il - 17a和F,白细胞介素-17(IL-17)家族(A-to-F)被认为在CF肺部疾病中起关键作用。方法:采用RT-qPCR方法检测铜绿假单胞菌PAO1菌株或pwCF临床外产物(EXO)感染CF支气管上皮(CFBE)细胞后IL-17受体(IL-17R) mRNA水平。采用RT-qPCR检测CF原代鼻上皮(HNE)培养细胞IL-17 mRNA的表达,ELISA和Bioplex检测细胞因子的释放。结果:15 pwCF中分离的PAO1或EXO感染CFBE细胞后,除IL-17RD外,其余IL-17R mRNA表达均显著升高。从相应供体分离的EXO感染HNE细胞后,除IL-17D和IL-17RD外,所有IL-17细胞因子和受体的mRNA水平均显著升高,细胞因子il - 17a、IL-17B、IL-17C、IL-17E和IL-17F的释放均显著升高。暴露于il - 17a和F的HNE被诱导释放促炎细胞因子(IL-1β, IL-6, TNF-α),中性粒细胞趋化因子(IL-8, G-CSF)和已知参与氯化物和碳酸氢盐分泌的细胞因子,以及粘蛋白上调(IL-4, IL-13)。结论:这些结果提示IL-17家族成员在呼吸上皮细胞中广泛表达,可在CF气道中发挥自分泌炎症扩增环的作用。这些使用患者源性培养的体外研究强调了IL-17家族成员在CF肺免疫应答中的相关作用。
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引用次数: 0
The distinct characteristic of two peritoneal macrophage subsets in a mouse model of hepatocellular carcinoma presents a novel therapeutic strategy 两种腹膜巨噬细胞亚群在肝癌小鼠模型中的独特特征提出了一种新的治疗策略。
IF 3.7 4区 医学 Q2 CELL BIOLOGY Pub Date : 2025-01-17 DOI: 10.1016/j.cellimm.2025.104917
Wan-Li Yang , Chao Yang , Nan Pang , Rui-Hua Yu , Kui-Yuan Tong , Feng Jiang
The peritoneal cavity (PerC) is a discrete anatomical compartment housing diverse peritoneal macrophage subpopulations. Nonetheless, there exists a paucity of knowledge concerning the distinct functions of these subpopulations in the context of hepatocellular carcinoma (HCC) and their evolution throughout tumor advancement. This investigation seeks to analyze the characteristics of two principal peritoneal macrophage subpopulations, specifically large peritoneal macrophage (LPM) and small peritoneal macrophage (SPM), in the context of HCC. The results of our research indicate a significant decrease in the proportion of LPM during the progression of HCC, accompanied by an increase in the quantity of SPM. Furthermore, SPM found in ascites exhibited a macrophage phenotype that supports tumor growth in HCC. Importantly, the dynamic decrease of LPM in murine models following lipopolysaccharide (LPS) stimulation led to a decrease in survival rate, highlighting the critical role of the altered LPM to SPM ratio in HCC survival. By employing clodronate liposomes (CL) to deplete peritoneal macrophage in murine models, followed by the adoptive transfer of LPM, we effectively prolonged the survival of HCC and attenuated tumor progression. Our results suggest that a decrease in the LPM to SPM ratio correlates with increased mortality in the HCC model. On the contrary, the maintenance of a high ratio of LPM to SPM has shown a positive effect on HCC survival. These findings have enhanced our understanding of the complex interaction between different subpopulations of peritoneal macrophage in the development of HCC. Furthermore, these results have important implications for the development of novel therapeutic strategies.
腹膜腔(PerC)是一个离散的解剖室,容纳不同的腹膜巨噬细胞亚群。然而,关于这些亚群在肝细胞癌(HCC)中的独特功能及其在肿瘤进展过程中的演变,目前还缺乏相关知识。本研究旨在分析HCC背景下两种主要腹膜巨噬细胞亚群的特征,特别是大腹膜巨噬细胞(LPM)和小腹膜巨噬细胞(SPM)。我们的研究结果表明,在HCC的进展过程中,LPM的比例明显下降,同时伴有SPM的数量增加。此外,在腹水中发现的SPM表现出支持HCC肿瘤生长的巨噬细胞表型。重要的是,脂多糖(LPS)刺激后小鼠模型中LPM的动态下降导致存活率下降,突出了LPM与SPM比值的改变在HCC存活中的关键作用。通过使用氯膦酸脂质体(CL)在小鼠模型中消耗腹膜巨噬细胞,然后过继转移LPM,我们有效地延长了HCC的生存期并减缓了肿瘤的进展。我们的研究结果表明,在HCC模型中,LPM与SPM之比的降低与死亡率的增加相关。相反,维持较高的LPM / SPM比例对HCC存活有积极作用。这些发现增强了我们对不同亚群腹膜巨噬细胞在HCC发展中的复杂相互作用的理解。此外,这些结果对开发新的治疗策略具有重要意义。
{"title":"The distinct characteristic of two peritoneal macrophage subsets in a mouse model of hepatocellular carcinoma presents a novel therapeutic strategy","authors":"Wan-Li Yang ,&nbsp;Chao Yang ,&nbsp;Nan Pang ,&nbsp;Rui-Hua Yu ,&nbsp;Kui-Yuan Tong ,&nbsp;Feng Jiang","doi":"10.1016/j.cellimm.2025.104917","DOIUrl":"10.1016/j.cellimm.2025.104917","url":null,"abstract":"<div><div>The peritoneal cavity (PerC) is a discrete anatomical compartment housing diverse peritoneal macrophage subpopulations. Nonetheless, there exists a paucity of knowledge concerning the distinct functions of these subpopulations in the context of hepatocellular carcinoma (HCC) and their evolution throughout tumor advancement. This investigation seeks to analyze the characteristics of two principal peritoneal macrophage subpopulations, specifically large peritoneal macrophage (LPM) and small peritoneal macrophage (SPM), in the context of HCC. The results of our research indicate a significant decrease in the proportion of LPM during the progression of HCC, accompanied by an increase in the quantity of SPM. Furthermore, SPM found in ascites exhibited a macrophage phenotype that supports tumor growth in HCC. Importantly, the dynamic decrease of LPM in murine models following lipopolysaccharide (LPS) stimulation led to a decrease in survival rate, highlighting the critical role of the altered LPM to SPM ratio in HCC survival. By employing clodronate liposomes (CL) to deplete peritoneal macrophage in murine models, followed by the adoptive transfer of LPM, we effectively prolonged the survival of HCC and attenuated tumor progression. Our results suggest that a decrease in the LPM to SPM ratio correlates with increased mortality in the HCC model. On the contrary, the maintenance of a high ratio of LPM to SPM has shown a positive effect on HCC survival. These findings have enhanced our understanding of the complex interaction between different subpopulations of peritoneal macrophage in the development of HCC. Furthermore, these results have important implications for the development of novel therapeutic strategies.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"409 ","pages":"Article 104917"},"PeriodicalIF":3.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Arctiin suppress Th17 cells response and ameliorates experimental autoimmune uveitis through JAK/STAT signaling
IF 3.7 4区 医学 Q2 CELL BIOLOGY Pub Date : 2025-01-16 DOI: 10.1016/j.cellimm.2025.104927
Xiao'e Fan , Manhong Xu , Zhengmin Wang , Xiaoyan Sun , Yan Fan , Jiaqi Chen , Junpeng Hao , Ranran Wang , Wei Jia
Conventional treatments for autoimmune uveitis, such as corticosteroids and systemic immunosuppressants, often result in adverse side effects, prompting the need for therapies targeting specific molecular pathways. This study investigates the effects of Arctiin, known for its diverse biological properties, on experimental autoimmune uveitis (EAU) through its action on Th17 cells and the JAK/STAT signaling pathway. Our findings reveal that Arctiin significantly alleviates EAU by reducing clinical scores, inflammatory cell infiltration, and levels of inflammatory cytokines like IL-17 and TNF-α in the eye. Arctiin achieves this by activating adiponectin receptor 1 (AdipoR1), which modulates the JAK/STAT pathway, thereby inhibiting Th17 cell differentiation and cytokine secretion. Additionally, Arctiin effectively suppresses IRBP-specific Th17 cell activation in cervical lymph nodes, further mitigating retinal inflammation and tissue damage. These results underscore Arctiin's potential as a therapeutic agent for uveitis and other autoimmune inflammatory disorders through the modulation of the AdipoR1/JAK/STAT pathway in Th17 cells.
{"title":"Arctiin suppress Th17 cells response and ameliorates experimental autoimmune uveitis through JAK/STAT signaling","authors":"Xiao'e Fan ,&nbsp;Manhong Xu ,&nbsp;Zhengmin Wang ,&nbsp;Xiaoyan Sun ,&nbsp;Yan Fan ,&nbsp;Jiaqi Chen ,&nbsp;Junpeng Hao ,&nbsp;Ranran Wang ,&nbsp;Wei Jia","doi":"10.1016/j.cellimm.2025.104927","DOIUrl":"10.1016/j.cellimm.2025.104927","url":null,"abstract":"<div><div>Conventional treatments for autoimmune uveitis, such as corticosteroids and systemic immunosuppressants, often result in adverse side effects, prompting the need for therapies targeting specific molecular pathways. This study investigates the effects of Arctiin, known for its diverse biological properties, on experimental autoimmune uveitis (EAU) through its action on Th17 cells and the JAK/STAT signaling pathway. Our findings reveal that Arctiin significantly alleviates EAU by reducing clinical scores, inflammatory cell infiltration, and levels of inflammatory cytokines like IL-17 and TNF-α in the eye. Arctiin achieves this by activating adiponectin receptor 1 (AdipoR1), which modulates the JAK/STAT pathway, thereby inhibiting Th17 cell differentiation and cytokine secretion. Additionally, Arctiin effectively suppresses IRBP-specific Th17 cell activation in cervical lymph nodes, further mitigating retinal inflammation and tissue damage. These results underscore Arctiin's potential as a therapeutic agent for uveitis and other autoimmune inflammatory disorders through the modulation of the AdipoR1/JAK/STAT pathway in Th17 cells.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"409 ","pages":"Article 104927"},"PeriodicalIF":3.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Deciphering the role of TMEM164 in autophagy-mediated ferroptosis and immune modulation in non-small cell lung cancer 解读TMEM164在非小细胞肺癌自噬介导的铁凋亡和免疫调节中的作用。
IF 3.7 4区 医学 Q2 CELL BIOLOGY Pub Date : 2025-01-10 DOI: 10.1016/j.cellimm.2024.104915
Tahani Ahmad ALMatrafi

Background

Non-small cell lung cancer (NSCLC) remains one of the most prevalent and deadly malignancies. Despite advancements in molecular therapies and diagnostic methods, the 5-year survival rate for lung adenocarcinoma patients remains unacceptably low, highlighting the urgent need for novel therapeutic strategies. Ferroptosis, a distinct form of regulated cell death, has emerged as a promising target in cancer treatment. This study investigates the role of TMEM164, a membrane protein, in promoting ferroptosis and modulating anti-tumor immunity in NSCLC, aiming to elucidate its therapeutic potential.

Methods

Using publicly available datasets, we performed bioinformatics analyses to identify TMEM164-regulated genes involved in ferroptosis. In addition, in vitro and in vivo assays were conducted to assess the impact of TMEM164 on cellular functions in NSCLC.

Results

Functional assays demonstrated that TMEM164 overexpression significantly inhibited invasion, migration, and cell proliferation in both in vitro and in vivo models. TMEM164 was also found to induce ferroptosis in NSCLC cells by promoting autophagy. Specifically, we identified a mechanism whereby TMEM164 mediates ATG5-dependent autophagosome formation, leading to the degradation of ferritin, GPX4, and lipid droplets. This degradation facilitated iron accumulation and lipid peroxidation, which triggered iron-dependent cell death. Notably, co-administration of TMEM164 upregulation and anti-PD-1 antibodies exhibited synergistic anti-tumor effects in a mouse model.

Conclusion

These findings suggest that targeting TMEM164 to enhance ferroptosis and stimulate anti-tumor immunity may inhibit NSCLC progression. Consequently, TMEM164 holds promise as a new therapeutic target for NSCLC treatment.
背景:非小细胞肺癌(NSCLC)仍然是最常见和最致命的恶性肿瘤之一。尽管分子治疗和诊断方法取得了进步,但肺腺癌患者的5年生存率仍然低得令人无法接受,这表明迫切需要新的治疗策略。铁下垂是一种不同形式的受调节细胞死亡,已成为癌症治疗的一个有希望的目标。本研究探讨了膜蛋白TMEM164在非小细胞肺癌中促进铁凋亡和调节抗肿瘤免疫的作用,旨在阐明其治疗潜力。方法:利用公开的数据集,我们进行了生物信息学分析,以确定与铁下垂有关的tmem164调节基因。此外,我们还通过体外和体内实验来评估TMEM164对NSCLC细胞功能的影响。结果:功能分析表明,在体外和体内模型中,TMEM164过表达显著抑制了细胞的侵袭、迁移和增殖。TMEM164还被发现通过促进自噬诱导非小细胞肺癌细胞铁下垂。具体来说,我们确定了TMEM164介导atg5依赖性自噬体形成的机制,导致铁蛋白、GPX4和脂滴的降解。这种降解促进了铁的积累和脂质过氧化,从而引发铁依赖性细胞死亡。值得注意的是,在小鼠模型中,TMEM164上调和抗pd -1抗体共同施用显示出协同抗肿瘤作用。结论:以TMEM164为靶点,增强铁下垂,刺激抗肿瘤免疫,可抑制NSCLC的进展。因此,TMEM164有望成为NSCLC治疗的新靶点。
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引用次数: 0
期刊
Cellular immunology
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