Pub Date : 2024-02-14eCollection Date: 2024-02-01DOI: 10.4110/in.2024.24.e8
Jinyong Choi, Shane Crotty, Youn Soo Choi
Follicular helper T cells (Tfh) play a crucial role in generating high-affinity antibodies (Abs) and establishing immunological memory. Cytokines, among other functional molecules produced by Tfh, are central to germinal center (GC) reactions. This review focuses on the role of cytokines, including IL-21 and IL-4, in regulating B cell responses within the GC, such as differentiation, affinity maturation, and plasma cell development. Additionally, this review explores the impact of other cytokines like CXCL13, IL-10, IL-9, and IL-2 on GC responses and their potential involvement in autoimmune diseases, allergies, and cancer. This review highlights contributions of Tfh-derived cytokines to both protective immunity and immunopathology across a spectrum of diseases. A deeper understanding of Tfh cytokine biology holds promise for insights into biomedical conditions.
滤泡辅助 T 细胞(Tfh)在产生高亲和力抗体(Abs)和建立免疫记忆方面发挥着至关重要的作用。Tfh产生的细胞因子和其他功能分子是生殖中心(GC)反应的核心。本综述重点探讨细胞因子(包括 IL-21 和 IL-4)在调节生殖中心 B 细胞反应(如分化、亲和力成熟和浆细胞发育)中的作用。此外,本综述还探讨了 CXCL13、IL-10、IL-9 和 IL-2 等其他细胞因子对 GC 反应的影响,以及它们在自身免疫性疾病、过敏症和癌症中的潜在作用。本综述强调了 Tfh 派生细胞因子对各种疾病的保护性免疫和免疫病理的贡献。深入了解 Tfh 细胞因子的生物学特性有望深入了解生物医学状况。
{"title":"Cytokines in Follicular Helper T Cell Biology in Physiologic and Pathologic Conditions.","authors":"Jinyong Choi, Shane Crotty, Youn Soo Choi","doi":"10.4110/in.2024.24.e8","DOIUrl":"10.4110/in.2024.24.e8","url":null,"abstract":"<p><p>Follicular helper T cells (Tfh) play a crucial role in generating high-affinity antibodies (Abs) and establishing immunological memory. Cytokines, among other functional molecules produced by Tfh, are central to germinal center (GC) reactions. This review focuses on the role of cytokines, including IL-21 and IL-4, in regulating B cell responses within the GC, such as differentiation, affinity maturation, and plasma cell development. Additionally, this review explores the impact of other cytokines like CXCL13, IL-10, IL-9, and IL-2 on GC responses and their potential involvement in autoimmune diseases, allergies, and cancer. This review highlights contributions of Tfh-derived cytokines to both protective immunity and immunopathology across a spectrum of diseases. A deeper understanding of Tfh cytokine biology holds promise for insights into biomedical conditions.</p>","PeriodicalId":13307,"journal":{"name":"Immune Network","volume":"24 1","pages":"e8"},"PeriodicalIF":4.3,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059230","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}
Pub Date : 2024-02-02eCollection Date: 2024-04-01DOI: 10.4110/in.2024.24.e7
Jung Ah Kim, Sung-Hee Kim, Jeong Jin Kim, Hyuna Noh, Su-Bin Lee, Haengdueng Jeong, Jiseon Kim, Donghun Jeon, Jung Seon Seo, Dain On, Suhyeon Yoon, Sang Gyu Lee, Youn Woo Lee, Hui Jeong Jang, In Ho Park, Jooyeon Oh, Sang-Hyuk Seok, Yu Jin Lee, Seung-Min Hong, Se-Hee An, Joon-Yong Bae, Jung-Ah Choi, Seo Yeon Kim, Young Been Kim, Ji-Yeon Hwang, Hyo-Jung Lee, Hong Bin Kim, Dae Gwin Jeong, Daesub Song, Manki Song, Man-Seong Park, Kang-Seuk Choi, Jun Won Park, Jun-Won Yun, Jeon-Soo Shin, Ho-Young Lee, Ho-Keun Kwon, Jun-Young Seo, Ki Taek Nam, Heon Yung Gee, Je Kyung Seong
Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019. In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×105 plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×102 PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×102 PFU-virus-infected lungs from 2 dpi, but not in 1×105 PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×105 PFU; however, 1×102 PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination.
{"title":"Immune Cells Are Differentially Affected by SARS-CoV-2 Viral Loads in K18-hACE2 Mice.","authors":"Jung Ah Kim, Sung-Hee Kim, Jeong Jin Kim, Hyuna Noh, Su-Bin Lee, Haengdueng Jeong, Jiseon Kim, Donghun Jeon, Jung Seon Seo, Dain On, Suhyeon Yoon, Sang Gyu Lee, Youn Woo Lee, Hui Jeong Jang, In Ho Park, Jooyeon Oh, Sang-Hyuk Seok, Yu Jin Lee, Seung-Min Hong, Se-Hee An, Joon-Yong Bae, Jung-Ah Choi, Seo Yeon Kim, Young Been Kim, Ji-Yeon Hwang, Hyo-Jung Lee, Hong Bin Kim, Dae Gwin Jeong, Daesub Song, Manki Song, Man-Seong Park, Kang-Seuk Choi, Jun Won Park, Jun-Won Yun, Jeon-Soo Shin, Ho-Young Lee, Ho-Keun Kwon, Jun-Young Seo, Ki Taek Nam, Heon Yung Gee, Je Kyung Seong","doi":"10.4110/in.2024.24.e7","DOIUrl":"10.4110/in.2024.24.e7","url":null,"abstract":"<p><p>Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019. In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×10<sup>5</sup> plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×10<sup>2</sup> PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×10<sup>2</sup> PFU-virus-infected lungs from 2 dpi, but not in 1×10<sup>5</sup> PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×10<sup>5</sup> PFU; however, 1×10<sup>2</sup> PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination.</p>","PeriodicalId":13307,"journal":{"name":"Immune Network","volume":"24 2","pages":"e7"},"PeriodicalIF":6.0,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11076298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140900795","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}
Pub Date : 2024-01-31eCollection Date: 2024-02-01DOI: 10.4110/in.2024.24.e6
Hye Young Kim, Dongjin Jeong, Ji Hyung Kim, Doo Hyun Chung
The intricate role of innate type-2 cytokines in immune responses is increasingly acknowledged for its dual nature, encompassing both protective and pathogenic dimensions. Ranging from defense against parasitic infections to contributing to inflammatory diseases like asthma, fibrosis, and obesity, these cytokines intricately engage with various innate immune cells. This review meticulously explores the cellular origins of innate type-2 cytokines and their intricate interactions, shedding light on factors that amplify the innate type-2 response, including TSLP, IL-25, and IL-33. Recent advancements in therapeutic strategies, specifically the utilization of biologics targeting pivotal cytokines (IL-4, IL-5, and IL-13), are discussed, offering insights into both challenges and opportunities. Acknowledging the pivotal role of innate type-2 cytokines in orchestrating immune responses positions them as promising therapeutic targets. The evolving landscape of research and development in this field not only propels immunological knowledge forward but also holds the promise of more effective treatments in the future.
{"title":"Innate Type-2 Cytokines: From Immune Regulation to Therapeutic Targets.","authors":"Hye Young Kim, Dongjin Jeong, Ji Hyung Kim, Doo Hyun Chung","doi":"10.4110/in.2024.24.e6","DOIUrl":"10.4110/in.2024.24.e6","url":null,"abstract":"<p><p>The intricate role of innate type-2 cytokines in immune responses is increasingly acknowledged for its dual nature, encompassing both protective and pathogenic dimensions. Ranging from defense against parasitic infections to contributing to inflammatory diseases like asthma, fibrosis, and obesity, these cytokines intricately engage with various innate immune cells. This review meticulously explores the cellular origins of innate type-2 cytokines and their intricate interactions, shedding light on factors that amplify the innate type-2 response, including TSLP, IL-25, and IL-33. Recent advancements in therapeutic strategies, specifically the utilization of biologics targeting pivotal cytokines (IL-4, IL-5, and IL-13), are discussed, offering insights into both challenges and opportunities. Acknowledging the pivotal role of innate type-2 cytokines in orchestrating immune responses positions them as promising therapeutic targets. The evolving landscape of research and development in this field not only propels immunological knowledge forward but also holds the promise of more effective treatments in the future.</p>","PeriodicalId":13307,"journal":{"name":"Immune Network","volume":"24 1","pages":"e6"},"PeriodicalIF":6.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059235","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}
Pub Date : 2024-01-26eCollection Date: 2024-02-01DOI: 10.4110/in.2024.24.e5
Jonathan Sprent, Onur Boyman
The key role of T cells in cancer immunotherapy is well established and is highlighted by the remarkable capacity of Ab-mediated checkpoint blockade to overcome T-cell exhaustion and amplify anti-tumor responses. However, total or partial tumor remission following checkpoint blockade is still limited to only a few types of tumors. Hence, concerted attempts are being made to devise new methods for improving tumor immunity. Currently, much attention is being focused on therapy with IL-2. This cytokine is a powerful growth factor for T cells and optimises their effector functions. When used at therapeutic doses for cancer treatment, however, IL-2 is highly toxic. Nevertheless, recent work has shown that modifying the structure or presentation of IL-2 can reduce toxicity and lead to effective anti-tumor responses in synergy with checkpoint blockade. Here, we review the complex interaction of IL-2 with T cells: first during normal homeostasis, then during responses to pathogens, and finally in anti-tumor responses.
T 细胞在癌症免疫疗法中的关键作用已得到充分证实,Ab 介导的检查点阻断疗法在克服 T 细胞衰竭和增强抗肿瘤反应方面的显著能力也凸显了这一点。然而,检查点阻断后肿瘤的完全或部分缓解仍仅限于少数类型的肿瘤。因此,人们正齐心协力,试图设计出改善肿瘤免疫的新方法。目前,IL-2疗法备受关注。这种细胞因子是一种强大的 T 细胞生长因子,能优化 T 细胞的效应功能。然而,当以治疗剂量用于癌症治疗时,IL-2 具有很强的毒性。然而,最近的研究表明,改变 IL-2 的结构或表达方式可以降低毒性,并与检查点阻断协同作用,产生有效的抗肿瘤反应。在此,我们回顾了 IL-2 与 T 细胞的复杂相互作用:首先是在正常稳态过程中,然后是在对病原体的反应过程中,最后是在抗肿瘤反应过程中。
{"title":"Optimising IL-2 for Cancer Immunotherapy.","authors":"Jonathan Sprent, Onur Boyman","doi":"10.4110/in.2024.24.e5","DOIUrl":"10.4110/in.2024.24.e5","url":null,"abstract":"<p><p>The key role of T cells in cancer immunotherapy is well established and is highlighted by the remarkable capacity of Ab-mediated checkpoint blockade to overcome T-cell exhaustion and amplify anti-tumor responses. However, total or partial tumor remission following checkpoint blockade is still limited to only a few types of tumors. Hence, concerted attempts are being made to devise new methods for improving tumor immunity. Currently, much attention is being focused on therapy with IL-2. This cytokine is a powerful growth factor for T cells and optimises their effector functions. When used at therapeutic doses for cancer treatment, however, IL-2 is highly toxic. Nevertheless, recent work has shown that modifying the structure or presentation of IL-2 can reduce toxicity and lead to effective anti-tumor responses in synergy with checkpoint blockade. Here, we review the complex interaction of IL-2 with T cells: first during normal homeostasis, then during responses to pathogens, and finally in anti-tumor responses.</p>","PeriodicalId":13307,"journal":{"name":"Immune Network","volume":"24 1","pages":"e5"},"PeriodicalIF":4.3,"publicationDate":"2024-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059237","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}
Pub Date : 2024-01-26eCollection Date: 2024-02-01DOI: 10.4110/in.2024.24.e4
Jae-Min Yuk, Jin Kyung Kim, In Soo Kim, Eun-Kyeong Jo
TNF, a pleiotropic proinflammatory cytokine, is important for protective immunity and immunopathology during Mycobacterium tuberculosis (Mtb) infection, which causes tuberculosis (TB) in humans. TNF is produced primarily by phagocytes in the lungs during the early stages of Mtb infection and performs diverse physiological and pathological functions by binding to its receptors in a context-dependent manner. TNF is essential for granuloma formation, chronic infection prevention, and macrophage recruitment to and activation at the site of infection. In animal models, TNF, in cooperation with chemokines, contributes to the initiation, maintenance, and clearance of mycobacteria in granulomas. Although anti-TNF therapy is effective against immune diseases such as rheumatoid arthritis, it carries the risk of reactivating TB. Furthermore, TNF-associated inflammation contributes to cachexia in patients with TB. This review focuses on the multifaceted role of TNF in the pathogenesis and prevention of TB and underscores the importance of investigating the functions of TNF and its receptors in the establishment of protective immunity against and in the pathology of TB. Such investigations will facilitate the development of therapeutic strategies that target TNF signaling, which makes beneficial and detrimental contributions to the pathogenesis of TB.
{"title":"TNF in Human Tuberculosis: A Double-Edged Sword.","authors":"Jae-Min Yuk, Jin Kyung Kim, In Soo Kim, Eun-Kyeong Jo","doi":"10.4110/in.2024.24.e4","DOIUrl":"10.4110/in.2024.24.e4","url":null,"abstract":"<p><p>TNF, a pleiotropic proinflammatory cytokine, is important for protective immunity and immunopathology during <i>Mycobacterium tuberculosis</i> (Mtb) infection, which causes tuberculosis (TB) in humans. TNF is produced primarily by phagocytes in the lungs during the early stages of Mtb infection and performs diverse physiological and pathological functions by binding to its receptors in a context-dependent manner. TNF is essential for granuloma formation, chronic infection prevention, and macrophage recruitment to and activation at the site of infection. In animal models, TNF, in cooperation with chemokines, contributes to the initiation, maintenance, and clearance of mycobacteria in granulomas. Although anti-TNF therapy is effective against immune diseases such as rheumatoid arthritis, it carries the risk of reactivating TB. Furthermore, TNF-associated inflammation contributes to cachexia in patients with TB. This review focuses on the multifaceted role of TNF in the pathogenesis and prevention of TB and underscores the importance of investigating the functions of TNF and its receptors in the establishment of protective immunity against and in the pathology of TB. Such investigations will facilitate the development of therapeutic strategies that target TNF signaling, which makes beneficial and detrimental contributions to the pathogenesis of TB.</p>","PeriodicalId":13307,"journal":{"name":"Immune Network","volume":"24 1","pages":"e4"},"PeriodicalIF":6.0,"publicationDate":"2024-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059238","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}
Pub Date : 2024-01-19eCollection Date: 2024-02-01DOI: 10.4110/in.2024.24.e2
Choong-Hyun Koh, Byung-Seok Kim, Chang-Yuil Kang, Yeonseok Chung, Hyungseok Seo
Studies over the last 2 decades have identified IL-17 and IL-21 as key cytokines in the modulation of a wide range of immune responses. IL-17 serves as a critical defender against bacterial and fungal pathogens, while maintaining symbiotic relationships with commensal microbiota. However, alterations in its levels can lead to chronic inflammation and autoimmunity. IL-21, on the other hand, bridges the adaptive and innate immune responses, and its imbalance is implicated in autoimmune diseases and cancer, highlighting its important role in both health and disease. Delving into the intricacies of these cytokines not only opens new avenues for understanding the immune system, but also promises innovative advances in the development of therapeutic strategies for numerous diseases. In this review, we will discuss an updated view of the immunobiology and therapeutic potential of IL-17 and IL-21.
{"title":"IL-17 and IL-21: Their Immunobiology and Therapeutic Potentials.","authors":"Choong-Hyun Koh, Byung-Seok Kim, Chang-Yuil Kang, Yeonseok Chung, Hyungseok Seo","doi":"10.4110/in.2024.24.e2","DOIUrl":"10.4110/in.2024.24.e2","url":null,"abstract":"<p><p>Studies over the last 2 decades have identified IL-17 and IL-21 as key cytokines in the modulation of a wide range of immune responses. IL-17 serves as a critical defender against bacterial and fungal pathogens, while maintaining symbiotic relationships with commensal microbiota. However, alterations in its levels can lead to chronic inflammation and autoimmunity. IL-21, on the other hand, bridges the adaptive and innate immune responses, and its imbalance is implicated in autoimmune diseases and cancer, highlighting its important role in both health and disease. Delving into the intricacies of these cytokines not only opens new avenues for understanding the immune system, but also promises innovative advances in the development of therapeutic strategies for numerous diseases. In this review, we will discuss an updated view of the immunobiology and therapeutic potential of IL-17 and IL-21.</p>","PeriodicalId":13307,"journal":{"name":"Immune Network","volume":"24 1","pages":"e2"},"PeriodicalIF":6.0,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059234","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}
Cigarette smoke extract (CSE)-treated mouse airway epithelial cells (MAECs)-derived exosomes accelerate the progression of chronic obstructive pulmonary disease (COPD) by upregulating triggering receptor expressed on myeloid cells 1 (TREM-1); however, the specific mechanism remains unclear. We aimed to explore the potential mechanisms of CSE-treated MAECs-derived exosomes on M1 macrophage polarization and pyroptosis in COPD. In vitro, exosomes were extracted from CSE-treated MAECs, followed by co-culture with macrophages. In vivo, mice exposed to cigarette smoke (CS) to induce COPD, followed by injection or/and intranasal instillation with oe-TREM-1 lentivirus. Lung function and pathological changes were evaluated. CD68+ cell number and the levels of iNOS, TNF-α, IL-1β (M1 macrophage marker), and pyroptosis-related proteins (NOD-like receptor family pyrin domain containing 3, apoptosis-associated speck-like protein containing a caspase-1 recruitment domain, caspase-1, cleaved-caspase-1, gasdermin D [GSDMD], and GSDMD-N) were examined. The expression of maternally expressed gene 3 (MEG3), spleen focus forming virus proviral integration oncogene (SPI1), methyltransferase 3 (METTL3), and TREM-1 was detected and the binding relationships among them were verified. MEG3 increased N6-methyladenosine methylation of TREM-1 by recruiting SPI1 to activate METTL3. Overexpression of TREM-1 or METTL3 negated the alleviative effects of MEG3 inhibition on M1 polarization and pyroptosis. In mice exposed to CS, EXO-CSE further aggravated lung injury, M1 polarization, and pyroptosis, which were reversed by MEG3 inhibition. TREM-1 overexpression negated the palliative effects of MEG3 inhibition on COPD mouse lung injury. Collectively, CSE-treated MAECs-derived exosomal long non-coding RNA MEG3 may expedite M1 macrophage polarization and pyroptosis in COPD via the SPI1/METTL3/TREM-1 axis.
{"title":"Cigarette Smoke Extract-Treated Mouse Airway Epithelial Cells-Derived Exosomal LncRNA MEG3 Promotes M1 Macrophage Polarization and Pyroptosis in Chronic Obstructive Pulmonary Disease by Upregulating TREM-1 via m<sup>6</sup>A Methylation.","authors":"Lijing Wang, Qiao Yu, Jian Xiao, Qiong Chen, Min Fang, Hongjun Zhao","doi":"10.4110/in.2024.24.e3","DOIUrl":"10.4110/in.2024.24.e3","url":null,"abstract":"<p><p>Cigarette smoke extract (CSE)-treated mouse airway epithelial cells (MAECs)-derived exosomes accelerate the progression of chronic obstructive pulmonary disease (COPD) by upregulating triggering receptor expressed on myeloid cells 1 (TREM-1); however, the specific mechanism remains unclear. We aimed to explore the potential mechanisms of CSE-treated MAECs-derived exosomes on M1 macrophage polarization and pyroptosis in COPD. <i>In vitro</i>, exosomes were extracted from CSE-treated MAECs, followed by co-culture with macrophages. <i>In vivo</i>, mice exposed to cigarette smoke (CS) to induce COPD, followed by injection or/and intranasal instillation with oe-TREM-1 lentivirus. Lung function and pathological changes were evaluated. CD68<sup>+</sup> cell number and the levels of iNOS, TNF-α, IL-1β (M1 macrophage marker), and pyroptosis-related proteins (NOD-like receptor family pyrin domain containing 3, apoptosis-associated speck-like protein containing a caspase-1 recruitment domain, caspase-1, cleaved-caspase-1, gasdermin D [GSDMD], and GSDMD-N) were examined. The expression of maternally expressed gene 3 (MEG3), spleen focus forming virus proviral integration oncogene (SPI1), methyltransferase 3 (METTL3), and TREM-1 was detected and the binding relationships among them were verified. MEG3 increased N6-methyladenosine methylation of TREM-1 by recruiting SPI1 to activate METTL3. Overexpression of TREM-1 or METTL3 negated the alleviative effects of MEG3 inhibition on M1 polarization and pyroptosis. In mice exposed to CS, EXO<sup>-CSE</sup> further aggravated lung injury, M1 polarization, and pyroptosis, which were reversed by MEG3 inhibition. TREM-1 overexpression negated the palliative effects of MEG3 inhibition on COPD mouse lung injury. Collectively, CSE-treated MAECs-derived exosomal long non-coding RNA MEG3 may expedite M1 macrophage polarization and pyroptosis in COPD via the SPI1/METTL3/TREM-1 axis.</p>","PeriodicalId":13307,"journal":{"name":"Immune Network","volume":"24 2","pages":"e3"},"PeriodicalIF":6.0,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11076299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140898300","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}
Pub Date : 2024-01-15eCollection Date: 2024-02-01DOI: 10.4110/in.2024.24.e1
Soohyun Kim, Hyeon Yu, Tania Azam, Charles A Dinarello
IL-18 binding protein (IL-18BP) was originally discovered in 1999 while attempting to identify an IL-18 receptor ligand binding chain (also known as IL-18Rα) by subjecting concentrated human urine to an IL-18 ligand affinity column. The IL-18 ligand chromatography purified molecule was analyzed by protein microsequencing. The result revealed a novel 40 amino acid polypeptide. To isolate the complete open reading frame (ORF), various human and mouse cDNA libraries were screened using cDNA probe derived from the novel IL-18 affinity column bound molecule. The identified entire ORF gene was thought to be an IL-18Rα gene. However, IL-18BP has been proven to be a unique soluble antagonist that shares homology with a variety of viral proteins that are distinct from the IL-18Rα and IL-18Rβ chains. The IL-18BP cDNA was used to generate recombinant IL-18BP (rIL-18BP), which was indispensable for characterizing the role of IL-18BP in vitro and in vivo. Mammalian cell lines were used to produce rIL-18BP due to its glycosylation-dependent activity of IL-18BP (approximately 20 kDa). Various forms of rIL-18BP, intact, C-terminal his-tag, and Fc fusion proteins were produced for in vitro and in vivo experiments. Data showed potent neutralization of IL-18 activity, which seems promising for clinical application in immune diseases involving IL-18. However, it was a long journey from discovery to clinical use although there have been various clinical trials since IL-18BP was discovered in 1999. This review primarily covers the discovery of IL-18BP along with how basic research influences the clinical development of IL-18BP.
{"title":"Interleukin-18 Binding Protein (IL-18BP): A Long Journey From Discovery to Clinical Application.","authors":"Soohyun Kim, Hyeon Yu, Tania Azam, Charles A Dinarello","doi":"10.4110/in.2024.24.e1","DOIUrl":"10.4110/in.2024.24.e1","url":null,"abstract":"<p><p>IL-18 binding protein (IL-18BP) was originally discovered in 1999 while attempting to identify an IL-18 receptor ligand binding chain (also known as IL-18Rα) by subjecting concentrated human urine to an IL-18 ligand affinity column. The IL-18 ligand chromatography purified molecule was analyzed by protein microsequencing. The result revealed a novel 40 amino acid polypeptide. To isolate the complete open reading frame (ORF), various human and mouse cDNA libraries were screened using cDNA probe derived from the novel IL-18 affinity column bound molecule. The identified entire ORF gene was thought to be an IL-18Rα gene. However, IL-18BP has been proven to be a unique soluble antagonist that shares homology with a variety of viral proteins that are distinct from the IL-18Rα and IL-18Rβ chains. The IL-18BP cDNA was used to generate recombinant IL-18BP (rIL-18BP), which was indispensable for characterizing the role of IL-18BP <i>in vitro</i> and <i>in vivo</i>. Mammalian cell lines were used to produce rIL-18BP due to its glycosylation-dependent activity of IL-18BP (approximately 20 kDa). Various forms of rIL-18BP, intact, C-terminal his-tag, and Fc fusion proteins were produced for <i>in vitro</i> and <i>in vivo</i> experiments. Data showed potent neutralization of IL-18 activity, which seems promising for clinical application in immune diseases involving IL-18. However, it was a long journey from discovery to clinical use although there have been various clinical trials since IL-18BP was discovered in 1999. This review primarily covers the discovery of IL-18BP along with how basic research influences the clinical development of IL-18BP.</p>","PeriodicalId":13307,"journal":{"name":"Immune Network","volume":"24 1","pages":"e1"},"PeriodicalIF":6.0,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059236","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}
Pub Date : 2023-12-18eCollection Date: 2023-12-01DOI: 10.4110/in.2023.23.e48
Jooyeon Lee, Jimin Jang, Sang-Ryul Cha, Se Bi Lee, Seok-Ho Hong, Han-Sol Bae, Young Jin Lee, Se-Ran Yang
Mesenchymal stromal/stem cells (MSCs) possess immunoregulatory properties and their regulatory functions represent a potential therapy for acute lung injury (ALI). However, uncertainties remain with respect to defining MSCs-derived immunomodulatory pathways. Therefore, this study aimed to investigate the mechanism underlying the enhanced effect of human recombinant bone morphogenic protein-2 (rhBMP-2) primed ES-MSCs (MSCBMP2) in promoting Tregs in ALI mice. MSC were preconditioned with 100 ng/ml rhBMP-2 for 24 h, and then administrated to mice by intravenous injection after intratracheal injection of 1 mg/kg LPS. Treating MSCs with rhBMP-2 significantly increased cellular proliferation and migration, and cytokines array reveled that cytokines release by MSCBMP2 were associated with migration and growth. MSCBMP2 ameliorated LPS induced lung injury and reduced myeloperoxidase activity and permeability in mice exposed to LPS. Levels of inducible nitric oxide synthase were decreased while levels of total glutathione and superoxide dismutase activity were further increased via inhibition of phosphorylated STAT1 in ALI mice treated with MSCBMP2. MSCBMP2 treatment increased the protein level of IDO1, indicating an increase in Treg cells, and Foxp3+CD25+ Treg of CD4+ cells were further increased in ALI mice treated with MSCBMP2. In co-culture assays with MSCs and RAW264.7 cells, the protein level of IDO1 was further induced in MSCBMP2. Additionally, cytokine release of IL-10 was enhanced while both IL-6 and TNF-α were further inhibited. In conclusion, these findings suggest that MSCBMP2 has therapeutic potential to reduce massive inflammation of respiratory diseases by promoting Treg cells.
{"title":"Recombinant Human Bone Morphogenetic Protein-2 Priming of Mesenchymal Stem Cells Ameliorate Acute Lung Injury by Inducing Regulatory T Cells.","authors":"Jooyeon Lee, Jimin Jang, Sang-Ryul Cha, Se Bi Lee, Seok-Ho Hong, Han-Sol Bae, Young Jin Lee, Se-Ran Yang","doi":"10.4110/in.2023.23.e48","DOIUrl":"10.4110/in.2023.23.e48","url":null,"abstract":"<p><p>Mesenchymal stromal/stem cells (MSCs) possess immunoregulatory properties and their regulatory functions represent a potential therapy for acute lung injury (ALI). However, uncertainties remain with respect to defining MSCs-derived immunomodulatory pathways. Therefore, this study aimed to investigate the mechanism underlying the enhanced effect of human recombinant bone morphogenic protein-2 (rhBMP-2) primed ES-MSCs (MSC<sup>BMP2</sup>) in promoting Tregs in ALI mice. MSC were preconditioned with 100 ng/ml rhBMP-2 for 24 h, and then administrated to mice by intravenous injection after intratracheal injection of 1 mg/kg LPS. Treating MSCs with rhBMP-2 significantly increased cellular proliferation and migration, and cytokines array reveled that cytokines release by MSC<sup>BMP2</sup> were associated with migration and growth. MSC<sup>BMP2</sup> ameliorated LPS induced lung injury and reduced myeloperoxidase activity and permeability in mice exposed to LPS. Levels of inducible nitric oxide synthase were decreased while levels of total glutathione and superoxide dismutase activity were further increased via inhibition of phosphorylated STAT1 in ALI mice treated with MSC<sup>BMP2</sup>. MSC<sup>BMP2</sup> treatment increased the protein level of IDO1, indicating an increase in Treg cells, and Foxp3<sup>+</sup>CD25<sup>+</sup> Treg of CD4<sup>+</sup> cells were further increased in ALI mice treated with MSC<sup>BMP2</sup>. In co-culture assays with MSCs and RAW264.7 cells, the protein level of IDO1 was further induced in MSC<sup>BMP2</sup>. Additionally, cytokine release of IL-10 was enhanced while both IL-6 and TNF-α were further inhibited. In conclusion, these findings suggest that MSC<sup>BMP2</sup> has therapeutic potential to reduce massive inflammation of respiratory diseases by promoting Treg cells.</p>","PeriodicalId":13307,"journal":{"name":"Immune Network","volume":"23 6","pages":"e48"},"PeriodicalIF":6.0,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10767548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139377500","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}
Pub Date : 2023-12-15eCollection Date: 2023-12-01DOI: 10.4110/in.2023.23.e47
Cheol Gyun Kim, Won Kyong Kim, Narae Kim, Young Jin Pyung, Da-Jeong Park, Jeong-Cheol Lee, Chong-Su Cho, Hyuk Chu, Cheol-Heui Yun
Scrub typhus, a mite-borne infectious disease, is caused by Orientia tsutsugamushi. Despite many attempts to develop a protective strategy, an effective preventive vaccine has not been developed. The identification of appropriate Ags that cover diverse antigenic strains and provide long-lasting immunity is a fundamental challenge in the development of a scrub typhus vaccine. We investigated whether this limitation could be overcome by harnessing the nanoparticle-forming polysorbitol transporter (PST) for an O. tsutsugamushi vaccine strategy. Two target proteins, 56-kDa type-specific Ag (TSA56) and surface cell Ag A (ScaA) were used as vaccine candidates. PST formed stable nano-size complexes with TSA56 (TSA56-PST) and ScaA (ScaA-PST); neither exhibited cytotoxicity. The formation of Ag-specific IgG2a, IgG2b, and IgA in mice was enhanced by intranasal vaccination with TSA56-PST or ScaA-PST. The vaccines containing PST induced Ag-specific proliferation of CD8+ and CD4+ T cells. Furthermore, the vaccines containing PST improved the mouse survival against O. tsutsugamushi infection. Collectively, the present study indicated that PST could enhance both Ag-specific humoral immunity and T cell response, which are essential to effectively confer protective immunity against O. tsutsugamushi infection. These findings suggest that PST has potential for use in an intranasal vaccination strategy.
恙虫病是一种螨媒传染病,由恙虫病原虫(Orientia tsutsugamushi)引起。尽管人们多次尝试开发保护性策略,但仍未研制出有效的预防性疫苗。在开发恙虫病疫苗的过程中,一个基本的挑战是如何确定适当的抗原,以覆盖不同的抗原菌株并提供持久的免疫力。我们研究了利用纳米颗粒形成的多聚山梨醇转运体(PST)来开发恙虫疫苗是否能克服这一限制。两种目标蛋白,56-kDa 型特异性 Ag(TSA56)和表面细胞 Ag A(ScaA)被用作候选疫苗。PST 与 TSA56(TSA56-PST)和 ScaA(ScaA-PST)形成稳定的纳米级复合物;两者均不表现细胞毒性。通过鼻内接种 TSA56-PST 或 ScaA-PST 可增强小鼠体内 Ag 特异性 IgG2a、IgG2b 和 IgA 的形成。含有 PST 的疫苗可诱导 Ag 特异性 CD8+ 和 CD4+ T 细胞增殖。此外,含有 PST 的疫苗提高了小鼠在恙虫感染中的存活率。总之,本研究表明,PST 可增强恙虫特异性体液免疫和 T 细胞应答,而这两种免疫对于有效抵抗恙虫感染至关重要。这些研究结果表明,PST 有潜力用于鼻内疫苗接种策略。
{"title":"Intranasal Immunization With Nanoparticles Containing an <i>Orientia tsutsugamushi</i> Protein Vaccine Candidate and a Polysorbitol Transporter Adjuvant Enhances Both Humoral and Cellular Immune Responses.","authors":"Cheol Gyun Kim, Won Kyong Kim, Narae Kim, Young Jin Pyung, Da-Jeong Park, Jeong-Cheol Lee, Chong-Su Cho, Hyuk Chu, Cheol-Heui Yun","doi":"10.4110/in.2023.23.e47","DOIUrl":"10.4110/in.2023.23.e47","url":null,"abstract":"<p><p>Scrub typhus, a mite-borne infectious disease, is caused by <i>Orientia tsutsugamushi</i>. Despite many attempts to develop a protective strategy, an effective preventive vaccine has not been developed. The identification of appropriate Ags that cover diverse antigenic strains and provide long-lasting immunity is a fundamental challenge in the development of a scrub typhus vaccine. We investigated whether this limitation could be overcome by harnessing the nanoparticle-forming polysorbitol transporter (PST) for an <i>O. tsutsugamushi</i> vaccine strategy. Two target proteins, 56-kDa type-specific Ag (TSA56) and surface cell Ag A (ScaA) were used as vaccine candidates. PST formed stable nano-size complexes with TSA56 (TSA56-PST) and ScaA (ScaA-PST); neither exhibited cytotoxicity. The formation of Ag-specific IgG2a, IgG2b, and IgA in mice was enhanced by intranasal vaccination with TSA56-PST or ScaA-PST. The vaccines containing PST induced Ag-specific proliferation of CD8<sup>+</sup> and CD4<sup>+</sup> T cells. Furthermore, the vaccines containing PST improved the mouse survival against <i>O. tsutsugamushi</i> infection. Collectively, the present study indicated that PST could enhance both Ag-specific humoral immunity and T cell response, which are essential to effectively confer protective immunity against <i>O. tsutsugamushi</i> infection. These findings suggest that PST has potential for use in an intranasal vaccination strategy.</p>","PeriodicalId":13307,"journal":{"name":"Immune Network","volume":"23 6","pages":"e47"},"PeriodicalIF":6.0,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10767547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139377497","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}