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 , Seyed Masood Nabavi , Parisa Shams , Pooya Faranoush , Mehri Salari , 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":"2025-03-01","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}
Pub Date : 2025-03-01Epub Date: 2025-02-27DOI: 10.1016/j.cellimm.2025.104933
Min Wang , Yuxin Hao , Wei He , Hui Jia , Zhaoshuang Zhong , Shuyue Xia
Chronic Obstructive Pulmonary Disease (COPD) is one of the leading causes of death worldwide, and current treatments fail to significantly halt its progression. Exosomes derived from mesenchymal stem cells (MSCs-Exos) have demonstrated promising potential in treating COPD due to their anti-inflammatory and regenerative biological properties. In this study, we investigated the potential anti-inflammatory effects of bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos) in a COPD rat model and the possible mechanisms by which they inhibit airway remodeling, as well as identifying the optimal dosage and administration route. Our results show that nebulized BMSC-Exos significantly improve lung function in COPD rats while reducing pulmonary inflammatory infiltration, bronchial mucus secretion, and collagen deposition. Moreover, BMSC-Exos treatment notably decreased the expression of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1β, and the pro-fibrotic factor TGF-β1 in serum, bronchoalveolar lavage fluid (BALF), and lung tissue. The most pronounced therapeutic effect was observed at a low dose of exosomes. Furthermore, quantitative real-time PCR and immunohistochemical analyses revealed that nebulized BMSC-Exos significantly inhibited airway remodeling and epithelial–mesenchymal transition (EMT) by suppressing the Wnt/β-catenin signaling pathway. In conclusion, these findings indicate that nebulized BMSC-Exos offer a noninvasive therapeutic strategy for COPD by mitigating lung inflammation and airway remodeling through the suppression of abnormal Wnt/β-catenin pathway activation induced by cigarette smoke (CS) and lipopolysaccharide (LPS) in rats.
{"title":"Nebulized mesenchymal stem cell-derived exosomes attenuate airway inflammation in a rat model of chronic obstructive pulmonary disease","authors":"Min Wang , Yuxin Hao , Wei He , Hui Jia , Zhaoshuang Zhong , Shuyue Xia","doi":"10.1016/j.cellimm.2025.104933","DOIUrl":"10.1016/j.cellimm.2025.104933","url":null,"abstract":"<div><div>Chronic Obstructive Pulmonary Disease (COPD) is one of the leading causes of death worldwide, and current treatments fail to significantly halt its progression. Exosomes derived from mesenchymal stem cells (MSCs-Exos) have demonstrated promising potential in treating COPD due to their anti-inflammatory and regenerative biological properties. In this study, we investigated the potential anti-inflammatory effects of bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos) in a COPD rat model and the possible mechanisms by which they inhibit airway remodeling, as well as identifying the optimal dosage and administration route. Our results show that nebulized BMSC-Exos significantly improve lung function in COPD rats while reducing pulmonary inflammatory infiltration, bronchial mucus secretion, and collagen deposition. Moreover, BMSC-Exos treatment notably decreased the expression of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1β, and the pro-fibrotic factor TGF-β1 in serum, bronchoalveolar lavage fluid (BALF), and lung tissue. The most pronounced therapeutic effect was observed at a low dose of exosomes. Furthermore, quantitative real-time PCR and immunohistochemical analyses revealed that nebulized BMSC-Exos significantly inhibited airway remodeling and epithelial–mesenchymal transition (EMT) by suppressing the Wnt/β-catenin signaling pathway. In conclusion, these findings indicate that nebulized BMSC-Exos offer a noninvasive therapeutic strategy for COPD by mitigating lung inflammation and airway remodeling through the suppression of abnormal Wnt/β-catenin pathway activation induced by cigarette smoke (CS) and lipopolysaccharide (LPS) in rats.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"409 ","pages":"Article 104933"},"PeriodicalIF":3.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143509101","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}
Pub Date : 2025-02-01Epub Date: 2024-12-21DOI: 10.1016/j.cellimm.2024.104912
Jyotsana Bakshi, K.P. Mishra
The gastrointestinal (GI) tract is susceptible to damage under high altitude hypoxic conditions, leading to gastrointestinal discomfort and intestinal barrier injury. Sodium butyrate, a short-chain fatty acid present as a metabolite in the gut, has emerged as a promising therapeutic agent due to its ability to act as an immunomodulatory agent and restore intestinal barrier integrity. This study aimed to explore the mechanism by which sodium butyrate exhibits anti inflammatory effect on intestinal epithelial cells. In vitro, Caco-2 epithelial cells and RAW 264.7 macrophages were used to investigate the protective role of sodium butyrate on Lipopolysaccharide (LPS) induced inflammation. Cell viability assays demonstrated that 1 mM (110.86 μg/mL) of sodium butyrate did not exhibit cytotoxicity on cells in vitro. Treatment with sodium butyrate suppressed reactive oxygen species levels and TNF-α production in LPS-stimulated macrophages, indicating its efficacy in mitigating inflammatory responses. Western blot analysis revealed that sodium butyrate attenuated the expression of iNOS in RAW 264.7 macrophage cells. Moreover, sodium butyrate also reversed the LPS induced over expression of HIF-1α, NLRP3, IL-1β as well as NF-kB in Caco-2 epithelial cells and also had a suppressive effect on IL-8 secretion after LPS stimulation. Immunocytochemistry demonstrated that sodium butyrate enhanced tight junction protein occludin expression in Caco-2 cells while also restoring the decreased permeability of the Caco-2 monolayer due to LPS. These results indicate that sodium butyrate may influence immune responses by suppressing inflammatory mediators and improving the integrity of the epithelial barrier. Understanding the intricate interactions between gut metabolites and host immune responses may help in the development of innovative therapeutic strategies to alleviate intestinal inflammation in high altitude environments.
在高海拔缺氧条件下，胃肠道容易受到损伤，导致胃肠道不适和肠屏障损伤。丁酸钠是一种短链脂肪酸，作为肠道代谢物存在，由于其作为免疫调节剂和恢复肠道屏障完整性的能力，已成为一种有前景的治疗剂。本研究旨在探讨丁酸钠对肠上皮细胞抗炎作用的机制。体外实验采用Caco-2上皮细胞和RAW 264.7巨噬细胞研究丁酸钠对脂多糖（LPS）诱导炎症的保护作用。细胞活力实验表明，1 mM （110.86 μg/mL）丁酸钠对体外培养的细胞无杀伤作用。用丁酸钠治疗可抑制lps刺激的巨噬细胞中活性氧水平和TNF-α的产生，表明其减轻炎症反应的功效。Western blot分析显示，丁酸钠能降低巨噬细胞中iNOS的表达。此外，丁酸钠还能逆转LPS诱导的Caco-2上皮细胞中HIF-1α、NLRP3、IL-1β和NF-kB的过表达，并抑制LPS刺激后IL-8的分泌。免疫细胞化学表明，丁酸钠增强Caco-2细胞中紧密连接蛋白occludin的表达，同时也恢复了由于LPS导致的Caco-2单层通透性下降。这些结果表明，丁酸钠可能通过抑制炎症介质和改善上皮屏障的完整性来影响免疫反应。了解肠道代谢物与宿主免疫反应之间复杂的相互作用可能有助于开发创新的治疗策略，以减轻高海拔环境下的肠道炎症。
{"title":"Sodium butyrate prevents lipopolysaccharide induced inflammation and restores the expression of tight junction protein in human epithelial Caco-2 cells","authors":"Jyotsana Bakshi, K.P. Mishra","doi":"10.1016/j.cellimm.2024.104912","DOIUrl":"10.1016/j.cellimm.2024.104912","url":null,"abstract":"<div><div>The gastrointestinal (GI) tract is susceptible to damage under high altitude hypoxic conditions, leading to gastrointestinal discomfort and intestinal barrier injury. Sodium butyrate, a short-chain fatty acid present as a metabolite in the gut, has emerged as a promising therapeutic agent due to its ability to act as an immunomodulatory agent and restore intestinal barrier integrity. This study aimed to explore the mechanism by which sodium butyrate exhibits anti inflammatory effect on intestinal epithelial cells. <em>In vitro,</em> Caco-2 epithelial cells and RAW 264.7 macrophages were used to investigate the protective role of sodium butyrate on Lipopolysaccharide (LPS) induced inflammation. Cell viability assays demonstrated that 1 mM (110.86 μg/mL) of sodium butyrate did not exhibit cytotoxicity on cells <em>in vitro</em>. Treatment with sodium butyrate suppressed reactive oxygen species levels and TNF-α production in LPS-stimulated macrophages, indicating its efficacy in mitigating inflammatory responses. Western blot analysis revealed that sodium butyrate attenuated the expression of iNOS in RAW 264.7 macrophage cells. Moreover, sodium butyrate also reversed the LPS induced over expression of HIF-1α, NLRP3, IL-1β as well as NF-kB in Caco-2 epithelial cells and also had a suppressive effect on IL-8 secretion after LPS stimulation. Immunocytochemistry demonstrated that sodium butyrate enhanced tight junction protein occludin expression in Caco-2 cells while also restoring the decreased permeability of the Caco-2 monolayer due to LPS. These results indicate that sodium butyrate may influence immune responses by suppressing inflammatory mediators and improving the integrity of the epithelial barrier. Understanding the intricate interactions between gut metabolites and host immune responses may help in the development of innovative therapeutic strategies to alleviate intestinal inflammation in high altitude environments.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"408 ","pages":"Article 104912"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892464","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}
Pub Date : 2025-02-01Epub Date: 2024-12-09DOI: 10.1016/j.cellimm.2024.104908
Jinjin Xie , Xin Du , Yuke Li , Chengyu Wu , Rui Li , Mengnan Zhao , Sanjun Shi
Pyroptosis is a programmed cell death (PCD) mainly mediated by the Gasdermin family of proteins, among which Gasdermin E (GSDME) is considered a tumor suppressor gene. GSDME can recruit immune cells to the tumor microenvironment (TME) and promote their effects. Activating and enhancing adaptive immunity through GSDME is a potential solution for anti-tumor therapy. Here we reported that berberine (BBR), a small molecule from traditional Chinese medicine, as a GSDME activator, induced caspase-3 (C-3)/GSDME pathway-mediated pyroptosis through the mitochondrial pathway, improved the immunosuppressive state of the tumor microenvironment, and thus promoted anti-tumor immunity. We determined the induction of pyroptosis of 4 T1 cells by BBR through various experiments, and investigated the immune activation effect of BBR by co-culture in vitro, which induced DCs maturation and macrophage polarization. Zebrafish embryo toxicity experiments were used to evaluate the in vivo safety of berberine. Furthermore, the in vivo antitumor and immune activation effects of BBR were investigated using 4 T1 orthotopic model mice, and the results showed that BBR could eliminate orthotopic tumor cells by activating local and systemic immunity. Moreover, we observed that BBR significantly inhibited breast cancer lung metastasis. In summary, our results showd the role of BBR as a GSDME activator stimulated both local and systemic antitumor immune responses by inducing pyroptosis, effectively preventing tumor development and metastasis.
焦亡是一种主要由Gasdermin家族蛋白介导的程序性细胞死亡（PCD），其中Gasdermin E （GSDME）被认为是一种肿瘤抑制基因。GSDME可以将免疫细胞招募到肿瘤微环境（tumor microenvironment， TME）并促进其作用。通过GSDME激活和增强适应性免疫是抗肿瘤治疗的潜在解决方案。本文报道了中药小分子小檗碱（berberine， BBR）作为GSDME激活剂，通过线粒体途径诱导caspase-3 (C-3)/GSDME途径介导的焦亡，改善肿瘤微环境的免疫抑制状态，从而促进抗肿瘤免疫。我们通过各种实验确定BBR对4个T1细胞的诱导凋亡作用，并通过体外共培养研究BBR诱导DCs成熟和巨噬细胞极化的免疫激活作用。采用斑马鱼胚胎毒性实验评价小檗碱的体内安全性。利用4只T1原位模型小鼠研究了BBR的体内抗肿瘤和免疫激活作用，结果表明BBR可以通过激活局部和全身免疫来消除原位肿瘤细胞。此外，我们观察到BBR显著抑制乳腺癌肺转移。综上所述，我们的研究结果表明，BBR作为GSDME激活剂通过诱导焦亡刺激局部和全身的抗肿瘤免疫反应，有效地阻止肿瘤的发展和转移。
{"title":"Berberine shaping the tumor immune landscape via pyroptosis","authors":"Jinjin Xie , Xin Du , Yuke Li , Chengyu Wu , Rui Li , Mengnan Zhao , Sanjun Shi","doi":"10.1016/j.cellimm.2024.104908","DOIUrl":"10.1016/j.cellimm.2024.104908","url":null,"abstract":"<div><div>Pyroptosis is a programmed cell death (PCD) mainly mediated by the Gasdermin family of proteins, among which Gasdermin E (GSDME) is considered a tumor suppressor gene. GSDME can recruit immune cells to the tumor microenvironment (TME) and promote their effects. Activating and enhancing adaptive immunity through GSDME is a potential solution for anti-tumor therapy. Here we reported that berberine (BBR), a small molecule from traditional Chinese medicine, as a GSDME activator, induced caspase-3 (C-3)/GSDME pathway-mediated pyroptosis through the mitochondrial pathway, improved the immunosuppressive state of the tumor microenvironment, and thus promoted anti-tumor immunity. We determined the induction of pyroptosis of 4 T1 cells by BBR through various experiments, and investigated the immune activation effect of BBR by co-culture <em>in vitro</em>, which induced DCs maturation and macrophage polarization. Zebrafish embryo toxicity experiments were used to evaluate the <em>in vivo</em> safety of berberine. Furthermore, the <em>in vivo</em> antitumor and immune activation effects of BBR were investigated using 4 T1 orthotopic model mice, and the results showed that BBR could eliminate orthotopic tumor cells by activating local and systemic immunity. Moreover, we observed that BBR significantly inhibited breast cancer lung metastasis. In summary, our results showd the role of BBR as a GSDME activator stimulated both local and systemic antitumor immune responses by inducing pyroptosis, effectively preventing tumor development and metastasis.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"408 ","pages":"Article 104908"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863322","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}
Pub Date : 2025-02-01Epub Date: 2025-01-04DOI: 10.1016/j.cellimm.2025.104916
R. Dovhyi , A. Dvukhriadkina , K. Ostrovska , M. Rudyk , Irina Verhovcova , Kristine Vaivode , D. Pjanova , L. Ostapchenko , L. Skivka
Bacteriophage-derived dsRNA (bp-dsRNA), also known as Larifan, is a poly-functional and wide-spectrum antiviral medication with potent interferonogenic activity. In the lungs of golden Syrian hamsters infected with SARS-CoV-2, Larifan substantially reduces viral load and decreases infection-induced pathological lesion severity. Alveolar macrophages (AM) are key sentinel cells in the lung, which play an important role in antiviral innate immune responses and, at the same time, can trigger infection-associated hyper-inflammatory response. This study revealed that treatment with bp-dsRNA (Larifan) in vitro modulates the functional profile of AM from intact Balb/c and C57Bl/6 mice. The pattern of the drug response depends on the animal strain, age and sex. AM from Balb/c mice generated a weaker response to the preparation as compared to cells from C57Bl/6 mice. Most emphatic responses to the treatment with bf-dsRNA (Larifan) were registered in AM from old males of both BALB/c and C57BL/6 strains with the strongest in the latter. AM from old C57BL/6 females were less likely to be influenced by the preparation. In most cases, exposure to bf-dsRNA (Larifan) increased AM phagocytic activity and was more often accompanied by the stimulation of intracellular reactive oxygen species generation, than by its decrease. In most animal groups, treatment with bf-dsRNA (Larifan) did not affect significantly CD206 expression and down-regulated CD80 expression in AM. Taken together, our findings suggest that bf-dsRNA (Larifan) not so much stimulates the bivalent phenotype of AM, as restrains their hyper-inflammatory responses through the control of antigen-presentation while preserving functional signatures typical of patrolling tissue-resident macrophages.
{"title":"Bacteriophage derived dsRNA induces polarized activation of alveolar macrophages from Balb/c and C57Bl/6 mice in vitro in sex- and age-dependent manner","authors":"R. Dovhyi , A. Dvukhriadkina , K. Ostrovska , M. Rudyk , Irina Verhovcova , Kristine Vaivode , D. Pjanova , L. Ostapchenko , L. Skivka","doi":"10.1016/j.cellimm.2025.104916","DOIUrl":"10.1016/j.cellimm.2025.104916","url":null,"abstract":"<div><div>Bacteriophage-derived dsRNA (bp-dsRNA), also known as Larifan, is a poly-functional and wide-spectrum antiviral medication with potent interferonogenic activity. In the lungs of golden Syrian hamsters infected with SARS-CoV-2, Larifan substantially reduces viral load and decreases infection-induced pathological lesion severity. Alveolar macrophages (AM) are key sentinel cells in the lung, which play an important role in antiviral innate immune responses and, at the same time, can trigger infection-associated hyper-inflammatory response. This study revealed that treatment with bp-dsRNA (Larifan) <em>in vitro</em> modulates the functional profile of AM from intact Balb/c and C57Bl/6 mice. The pattern of the drug response depends on the animal strain, age and sex. AM from Balb/c mice generated a weaker response to the preparation as compared to cells from C57Bl/6 mice. Most emphatic responses to the treatment with bf-dsRNA (Larifan) were registered in AM from old males of both BALB/c and C57BL/6 strains with the strongest in the latter. AM from old C57BL/6 females were less likely to be influenced by the preparation. In most cases, exposure to bf-dsRNA (Larifan) increased AM phagocytic activity and was more often accompanied by the stimulation of intracellular reactive oxygen species generation, than by its decrease. In most animal groups, treatment with bf-dsRNA (Larifan) did not affect significantly CD206 expression and down-regulated CD80 expression in AM. Taken together, our findings suggest that bf-dsRNA (Larifan) not so much stimulates the bivalent phenotype of AM, as restrains their hyper-inflammatory responses through the control of antigen-presentation while preserving functional signatures typical of patrolling tissue-resident macrophages.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"408 ","pages":"Article 104916"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945543","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}
Pub Date : 2025-02-01Epub Date: 2024-12-15DOI: 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.
{"title":"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","authors":"Barbara Laurice Araújo Verçosa , Maria Imaculada Muniz-Junqueira , Ana Lys Bezerra Barradas Mineiro , Maria Norma Melo , Anilton Cesar Vasconcelos","doi":"10.1016/j.cellimm.2024.104909","DOIUrl":"10.1016/j.cellimm.2024.104909","url":null,"abstract":"<div><div>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 <em>Leishmania</em> amastigotes in naturally <em>Leishmania-</em>infected dogs. Fragments from seemingly undamaged ear skin of sixteen <em>Leishmania</em>-infected dogs and seven uninfected dogs were evaluated through histomorphometry, ultrastructural, immunohistochemical and transmission electron microscopy (TEM) analyses. <em>Leishmania</em> 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 <em>Leishmania</em> amastigotes were observed within neutrophils and macrophages. <em>Leishmania</em> amastigotes were positive for Bax, a marker for apoptosis, by immunohistochemistry. Morphological characteristics of apoptosis and autophagy in <em>Leishmania</em> 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 <em>Leishmania</em> 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 <em>Leishmania</em> within phagocytes may have facilitate the survival of the parasite and it appears to play an important role in the process of <em>Leishmania</em> infection.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"408 ","pages":"Article 104909"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863424","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}
Pub Date : 2025-02-01Epub Date: 2024-12-04DOI: 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.
{"title":"P2RX1-blocked neutrophils induce CD8+ T cell dysfunction and affect the immune escape of gastric cancer cells","authors":"Yan Zhang , Fenglin Zhang , Zhi Liu , Min Li , Ge Wu , Hui Li","doi":"10.1016/j.cellimm.2024.104901","DOIUrl":"10.1016/j.cellimm.2024.104901","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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<sup>+</sup>PD-1<sup>+</sup> and CD8<sup>+</sup>GZMB<sup>+</sup> 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.</div></div><div><h3>Results</h3><div>In GC, clinical analysis revealed increased infiltration of P2RX1-lowly expressed neutrophil subsets and increased expression of PD-L1. <em>In vitro</em> experiments demonstrated that abnormal expression of P2RX1 affected neutrophil function. Furthermore, the blockage or knockdown of P2RX1 in neutrophils modulated CD8<sup>+</sup> T cell function, promoting GC progression. In <em>in vivo</em> experiments, the blockage of P2RX1 in neutrophils inhibited the effectiveness of ICI treatment in the GC microenvironment.</div></div><div><h3>Conclusion</h3><div>This project validated that the loss of P2RX1 in neutrophils induces CD8<sup>+</sup> 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.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"408 ","pages":"Article 104901"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827181","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}
Pub Date : 2025-02-01Epub Date: 2024-12-31DOI: 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.
{"title":"The effect of tocilizumab treatment for skin fibrosis by inhibiting CD38+ macrophages in systemic sclerosis","authors":"Hongzhen Chen , Dapeng Yang , Yirui Shi , Haolin Wu , Huiming Zhu , Tingting Jiang , Shu Liu , Dandan Wang","doi":"10.1016/j.cellimm.2024.104914","DOIUrl":"10.1016/j.cellimm.2024.104914","url":null,"abstract":"<div><h3>Background</h3><div>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<sup>+</sup> macrophages in the bleomycin-induced SSc mice model.</div></div><div><h3>Methods</h3><div>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<sup>+</sup> macrophages in the BLM-induced fibrosis mouse model was verified by flow cytometry and immunofluorescence.</div></div><div><h3>Results</h3><div>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<sup>+</sup> 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<sup>+</sup> macrophages in the skin and peripheral blood significantly decreased after tocilizumab treatment.</div></div><div><h3>Conclusion</h3><div>This study revealed that tocilizumab improved skin fibrosis in the SSc mice model, which was mediated by inhibiting skin and peripheral CD38<sup>+</sup> macrophages.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"408 ","pages":"Article 104914"},"PeriodicalIF":3.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945542","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}
Pub Date : 2025-02-01Epub Date: 2024-12-18DOI: 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.
{"title":"Augmented IFNγ producing ILC1 and IL 17 producing ILC3 in pemphigus vulgaris: Plausible therapeutic target","authors":"Vishakha Hooda , Sujay Khandpur , 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}
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