The spike protein of SARS-CoV-2 as well as its receptor binding domain (RBD) has been demonstrated to be capable of activating the release of pro-inflammatory mediators in endothelial cells and immune cells such as monocytes. However, the effects of spike protein or its RBD on airway epithelial cells and mechanisms underlying these effects have not been adequately characterized. Here, we show that the RBD of spike protein alone can induce bronchial epithelial inflammation in a manner of ATP/P2Y2 dependence. Incubation of human bronchial epithelia with RBD induced IL-6 and IL-8 release, which could be inhibited by antibody. The incubation of RBD also up-regulated the expression of inflammatory indicators such as ho-1 and mkp-1. Furthermore, ATP secretion was observed after RBD treatment, P2Y2 receptor knock down by siRNA significantly suppressed the IL-6 and IL-8 release evoked by RBD. Additionally, S-RBD elevated the phosphorylation level of ERK1/2, and the effect that PD98059 can inhibit the pro-inflammatory cytokine release suggested the participation of ERK1/2. These novel findings provide new evidence of SARS-CoV-2 on airway inflammation and introduce purinergic signaling as promising treatment target.
{"title":"SARS-CoV-2 spike protein receptor binding domain promotes IL-6 and IL-8 release via ATP/P2Y2 and ERK1/2 signaling pathways in human bronchial epithelia","authors":"Rui-Gang Zhang , Xing-Jian Liu , Yu-Ling Guo , Chun-Ling Chen","doi":"10.1016/j.molimm.2024.02.005","DOIUrl":"https://doi.org/10.1016/j.molimm.2024.02.005","url":null,"abstract":"<div><p>The spike protein of SARS-CoV-2 as well as its receptor binding domain (RBD) has been demonstrated to be capable of activating the release of pro-inflammatory mediators in endothelial cells and immune cells such as monocytes. However, the effects of spike protein or its RBD on airway epithelial cells and mechanisms underlying these effects have not been adequately characterized. Here, we show that the RBD of spike protein alone can induce bronchial epithelial inflammation in a manner of ATP/P2Y<sub>2</sub> dependence. Incubation of human bronchial epithelia with RBD induced IL-6 and IL-8 release, which could be inhibited by antibody. The incubation of RBD also up-regulated the expression of inflammatory indicators such as ho-1 and mkp-1. Furthermore, ATP secretion was observed after RBD treatment, P2Y<sub>2</sub> receptor knock down by siRNA significantly suppressed the IL-6 and IL-8 release evoked by RBD. Additionally, S-RBD elevated the phosphorylation level of ERK1/2, and the effect that PD98059 can inhibit the pro-inflammatory cytokine release suggested the participation of ERK1/2. These novel findings provide new evidence of SARS-CoV-2 on airway inflammation and introduce purinergic signaling as promising treatment target.</p></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139731901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-10DOI: 10.1016/j.molimm.2024.01.011
Hsiangyu Ku , Jamie Jiin-Yi Chen , Wei Chen , Peng-Tai Tien , Hui-Ju Lin , Lei Wan , Gezhi Xu
Myopia is widely recognized as an epidemic. Studies have found a link between Transforming Growth Factor-beta (TGF-β) and myopia, but the specific molecular mechanisms are not fully understood. In this study, a monocular model in tree shrews (Tupaia belangeri) was established to verify the molecular mechanism of TGF-β in myopia. The results indicated that there were significant changes in TGF-βs during the treatment of myopia, which could enhance the refractive ability and axial length of the eye. Immunohistochemical staining, real-time fluorescent quantitative PCR, and immunoblotting results showed a significant upregulation of MMP2 and NF-κB levels, and a significant downregulation of COL-I expression in the TGF-β treated eyes, suggesting that NF-κB and MMP2 are involved in the signaling pathways of TGF-βs induced myopia and axial elongation. Moreover, the expression levels of IL-6, IL-8, MCP-1, IL-1β, TNF-α, TAK1, and NF-κB in the retina were all significantly elevated. This indicates that TGF-β stimulates the inflammatory response of retinal pigment epithelial cells through the TAK1-NF-κB signaling pathway. In conclusion, this study suggests that TGF-β promotes the progression of myopia by enhancing intraocular inflammation.
{"title":"The role of transforming growth factor beta in myopia development","authors":"Hsiangyu Ku , Jamie Jiin-Yi Chen , Wei Chen , Peng-Tai Tien , Hui-Ju Lin , Lei Wan , Gezhi Xu","doi":"10.1016/j.molimm.2024.01.011","DOIUrl":"10.1016/j.molimm.2024.01.011","url":null,"abstract":"<div><p>Myopia is widely recognized as an epidemic. Studies have found a link between Transforming Growth Factor-beta (TGF-β) and myopia, but the specific molecular mechanisms are not fully understood. In this study, a monocular model in tree shrews (<em>Tupaia belangeri</em>) was established to verify the molecular mechanism of TGF-β in myopia. The results indicated that there were significant changes in TGF-βs during the treatment of myopia, which could enhance the refractive ability and axial length of the eye. Immunohistochemical staining, real-time fluorescent quantitative PCR, and immunoblotting results showed a significant upregulation of MMP2 and NF-κB levels, and a significant downregulation of COL-I expression in the TGF-β treated eyes, suggesting that NF-κB and MMP2 are involved in the signaling pathways of TGF-βs induced myopia and axial elongation. Moreover, the expression levels of IL-6, IL-8, MCP-1, IL-1β, TNF-α, TAK1, and NF-κB in the retina were all significantly elevated. This indicates that TGF-β stimulates the inflammatory response of retinal pigment epithelial cells through the TAK1-NF-κB signaling pathway. In conclusion, this study suggests that TGF-β promotes the progression of myopia by enhancing intraocular inflammation.</p></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139716226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute lung injury (ALI) is a prevailing and deadly complication of sepsis coupled with increasing incidence and fatality rate. Annexin A3 (ANXA3) has been unraveled to be upregulated during sepsis. This study purposed to assess the role and the mechanism of ANXA3 in sepsis-induced ALI. After the construction of mouse model of sepsis, the pathological changes of mice lung tissues were estimated by H&E staining. ANXA3 expression in mice lung tissues and serum was examined. The degree of pulmonary edema and the levels of inflammatory factors in bronchoalveolar lavage fluid (BALF) were analyzed. In lipopolysaccharide (LPS)-induced mouse ALI model in vitro, CCK-8 assay measured cell viability and flow cytometry analysis detected cell apoptosis. Besides, ELISA assay detected the release of inflammatory cytokines. Western blot analyzed the expression of proteins associated with inflammation, apoptosis and extracellular-signal-regulated kinase (ERK)/ETS-like gene 1 (ELK1) signaling. Results revealed that ANXA3 was overexpressed in the lung tissues and serum of septic mice. Following the knockdown of ANXA3, sepsis-induced lung injury was alleviated, manifested as reduced lung edema, decreased inflammatory cell infiltration and inhibited cell apoptosis. Additionally, ANXA3 silence blocked ERK/ELK1 signaling both in sepsis mouse models and in vitro model of ALI induced by lipopolysaccharide (LPS). Moreover, the inhibitory effects of ANXA3 silencing on ERK/ELK1 signaling activation, the viability damage, inflammation and apoptosis in LPS-induced mouse ALI model in vitro were partially reversed by ERK activator. Collectively, depletion of ANXA3 exerted suppressive effects on the inflammation and apoptosis in sepsis-induced ALI through blocking ERK/ELK1 signaling.
急性肺损伤(ALI)是败血症的一种常见且致命的并发症,其发病率和死亡率不断上升。研究发现,Annexin A3(ANXA3)在败血症期间会上调。本研究旨在评估 ANXA3 在脓毒症诱导的 ALI 中的作用和机制。建立脓毒症小鼠模型后,通过H&E染色评估小鼠肺组织的病理变化。检测小鼠肺组织和血清中ANXA3的表达。分析了肺水肿的程度和支气管肺泡灌洗液(BALF)中炎症因子的水平。在脂多糖(LPS)诱导的小鼠 ALI 体外模型中,CCK-8 检测法测定细胞存活率,流式细胞术分析法检测细胞凋亡。此外,酶联免疫吸附试验检测了炎症细胞因子的释放。Western 印迹分析了与炎症、细胞凋亡和细胞外信号调节激酶(ERK)/ETS 样基因 1(ELK1)信号转导相关的蛋白质的表达。结果显示,ANXA3在败血症小鼠的肺组织和血清中过表达。敲除ANXA3后,脓毒症诱导的肺损伤得到缓解,表现为肺水肿减轻、炎症细胞浸润减少和细胞凋亡受到抑制。此外,在脓毒症小鼠模型和脂多糖(LPS)诱导的 ALI 体外模型中,ANXA3 沉默都能阻断 ERK/ELK1 信号传导。此外,在 LPS 诱导的小鼠 ALI 体外模型中,ERK 激活剂可部分逆转 ANXA3 沉默对 ERK/ELK1 信号激活、活力损伤、炎症和细胞凋亡的抑制作用。总之,通过阻断ERK/ELK1信号转导,抑制ANXA3可抑制败血症诱导的ALI模型中的炎症和细胞凋亡。
{"title":"ANXA3 interference inactivates ERK/ELK1 pathway to mitigate inflammation and apoptosis in sepsis-associated acute lung injury","authors":"Jifang Liang , Junkun Zhang , Jixiu Fan , Shuxian Chen , Weidong Wu","doi":"10.1016/j.molimm.2024.01.006","DOIUrl":"https://doi.org/10.1016/j.molimm.2024.01.006","url":null,"abstract":"<div><p><span><span><span>Acute lung injury (ALI) is a prevailing and deadly complication of sepsis coupled with increasing incidence and fatality rate. </span>Annexin A3<span> (ANXA3) has been unraveled to be upregulated during sepsis. This study purposed to assess the role and the mechanism of ANXA3 in sepsis-induced ALI. After the construction of mouse model of sepsis, the pathological changes of mice lung tissues were estimated by H&E staining. ANXA3 expression in mice lung tissues and serum was examined. The degree of pulmonary edema and the levels of inflammatory factors in bronchoalveolar lavage fluid (BALF) were analyzed. In </span></span>lipopolysaccharide<span><span> (LPS)-induced mouse ALI model in vitro, CCK-8 assay measured cell viability and flow cytometry analysis detected cell </span>apoptosis<span><span>. Besides, ELISA assay detected the release of </span>inflammatory cytokines<span>. Western blot analyzed the expression of proteins associated with inflammation, apoptosis and extracellular-signal-regulated kinase (ERK)/ETS-like gene 1 (ELK1) signaling. Results revealed that ANXA3 was overexpressed in the lung tissues and serum of septic mice. Following the knockdown of ANXA3, sepsis-induced lung injury was alleviated, manifested as reduced lung edema, decreased </span></span></span></span>inflammatory cell infiltration and inhibited cell apoptosis. Additionally, ANXA3 silence blocked ERK/ELK1 signaling both in sepsis mouse models and in vitro model of ALI induced by lipopolysaccharide (LPS). Moreover, the inhibitory effects of ANXA3 silencing on ERK/ELK1 signaling activation, the viability damage, inflammation and apoptosis in LPS-induced mouse ALI model in vitro were partially reversed by ERK activator. Collectively, depletion of ANXA3 exerted suppressive effects on the inflammation and apoptosis in sepsis-induced ALI through blocking ERK/ELK1 signaling.</p></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139675487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-03DOI: 10.1016/j.molimm.2024.01.010
Guihua Song , Mengmeng Sun , Yan Zhang , Bingxue Zhang , Minghao Peng , Beibei Bao
Asthma is a common chronic respiratory disease characterized by Th2-type inflammation in the airways. Leucine zip transcription factor-like 1 (LZTFL1) has been implicated in the regulation of Th2-related factors. The knockdown of LZTFL1 resulted in decreased levels of IL-4, IL-5, and IL-13. We hypothesize that LZTFL1 may have an effect on asthma. We established an acute asthmatic mouse model using the Ovalbumin (OVA) sensitization, and we found that LZTFL1 expression was upregulated in OVA-induced CD4 + T cells. Mice challenged with OVA were administered 5 × 107 TU of lentivirus via tail vein injection. LZTFL1 knockdown reversed the frequency of sneezing and nose rubbing in OVA mice. LZTFL1 knockdown reduced inflammatory cell infiltration, reduced goblet cell numbers, and mitigated collagen deposition in lung tissue. LZTFL1 knockdown decreased the levels of OVA-specific IgE, IL-4, IL-5, and IL-13 in alveolar lavage fluid of asthmatic mice. Furthermore, LZTFL1 knockdown inhibited the aberrant activation of MEK/ERK signaling pathway in asthmatic mice. GATA binding protein 3 (GATA3) is an essential transcription factor in Th2 differentiation. Flow cytometry results revealed that LZTFL1 knockdown reduced the number of GATA3 + CD4 + Th2 cells, while it did not affect the stability of GATA3 mRNA. This may be attributed to ERK signaling which stabilized GATA3 by preventing its ubiquitination and subsequent degradation. In conclusion, LZTFL1 knockdown attenuates inflammation and pathological changes in OVA-induced asthmatic mice through ERK/GATA3 signaling pathway.
哮喘是一种常见的慢性呼吸道疾病,其特征是气道中的 Th2 型炎症。亮氨酸拉链转录因子样 1(LZTFL1)与 Th2 相关因子的调控有关。敲除 LZTFL1 会导致 IL-4、IL-5 和 IL-13 水平下降。我们假设 LZTFL1 可能对哮喘有影响。我们利用卵清蛋白(OVA)致敏法建立了急性哮喘小鼠模型,并发现 LZTFL1 在 OVA 诱导的 CD4 + T 细胞中表达上调。我们发现 LZTFL1 在 OVA 诱导的 CD4 + T 细胞中表达上调。LZTFL1 基因敲除可逆转 OVA 小鼠打喷嚏和揉鼻子的频率。LZTFL1 基因敲除可减少炎症细胞浸润、减少鹅口疮细胞数量并减轻肺组织中的胶原沉积。LZTFL1 基因敲除降低了哮喘小鼠肺泡灌洗液中 OVA 特异性 IgE、IL-4、IL-5 和 IL-13 的水平。此外,LZTFL1敲除抑制了哮喘小鼠体内MEK/ERK信号通路的异常激活。GATA结合蛋白3(GATA3)是Th2分化过程中必不可少的转录因子。流式细胞术结果显示,LZTFL1敲除减少了GATA3 + CD4 + Th2细胞的数量,但并不影响GATA3 mRNA的稳定性。这可能是由于ERK信号通过阻止GATA3的泛素化和随后的降解而稳定了GATA3。总之,LZTFL1敲除可通过ERK/GATA3信号通路减轻OVA诱导的哮喘小鼠的炎症和病理变化。
{"title":"Anti-inflammation of LZTFL1 knockdown in OVA-induced asthmatic mice: Through ERK/GATA3 signaling pathway","authors":"Guihua Song , Mengmeng Sun , Yan Zhang , Bingxue Zhang , Minghao Peng , Beibei Bao","doi":"10.1016/j.molimm.2024.01.010","DOIUrl":"https://doi.org/10.1016/j.molimm.2024.01.010","url":null,"abstract":"<div><p><span><span><span>Asthma is a common chronic respiratory disease characterized by Th2-type inflammation in the airways. </span>Leucine zip transcription factor-like 1 (LZTFL1) has been implicated in the regulation of Th2-related factors. The knockdown of LZTFL1 resulted in decreased levels of IL-4, IL-5, and IL-13. We hypothesize that LZTFL1 may have an effect on asthma. We established an acute asthmatic mouse model using the </span>Ovalbumin (OVA) sensitization, and we found that LZTFL1 expression was upregulated in OVA-induced CD4 + T cells. Mice challenged with OVA were administered 5 × 10</span><sup>7</sup><span><span><span> TU of lentivirus<span> via tail vein injection. LZTFL1 knockdown reversed the frequency of sneezing and nose rubbing in OVA mice. LZTFL1 knockdown reduced </span></span>inflammatory cell<span><span> infiltration, reduced goblet cell<span> numbers, and mitigated collagen deposition in lung tissue. LZTFL1 knockdown decreased the levels of OVA-specific IgE, IL-4, IL-5, and IL-13 in alveolar lavage fluid<span> of asthmatic mice. Furthermore, LZTFL1 knockdown inhibited the aberrant activation of MEK/ERK signaling pathway in asthmatic mice. GATA binding </span></span></span>protein 3<span> (GATA3) is an essential transcription factor in Th2 differentiation. Flow cytometry results revealed that LZTFL1 knockdown reduced the number of GATA3 + CD4 + Th2 cells, while it did not affect the stability of GATA3 mRNA. This may be attributed to ERK signaling which stabilized GATA3 by preventing its </span></span></span>ubiquitination and subsequent degradation. In conclusion, LZTFL1 knockdown attenuates inflammation and pathological changes in OVA-induced asthmatic mice through ERK/GATA3 signaling pathway.</span></p></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139675486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01DOI: 10.1016/j.molimm.2024.01.012
Chunming Xiong , Bohan Li , Renxing Song , Zizhe Ma , Sally A. Huber , Wei Liu
Myocarditis is an inflammation of the heart muscle often associated with viral infections and can lead to dilated cardiomyopathy. Interferon-induced transmembrane protein 3 (IFITM3) is a small endosomal membrane protein with anti-viral activity against multiple viruses and is also implicated in non-infectious diseases such as cancer and Alzheimer’s Disease. Since the IFITM3 proteins are expressed both in T cells and in cardiomyocytes, it is reasonable to hypothesize that these molecules could affect myocarditis either through their effect on the autoimmune response or through direct modulation of cardiomyocyte damage. The aim of this study was to investigate the role of IFITM3 in experimental autoimmune myocarditis (EAM)-mediated myocardial injury. Immunization of rats with cardiac myosin results in substantial cardiac inflammation and is associated with increased expression of IFITM3 after 21 days. In vivo IFITM3 shRNA knockdown using the lentivirus transfection method reduced cardiac injury while restoring IFITM3 expression reversed the protective effect of IFITM3 RNA interference. To determine the direct impact of IFITM3, the rat ventricular cell line, H9c2, was treated with palmitic acid which causes apoptosis in these cells. Suppressing IFITM3 expression protects H9c2 cells while overexpressing IFITM3 enhances cell injury. JAK inhibitors reduced IFITM3-mediated myocardial cell injury. In conclusion, IFITM3 may mediate myocardial injury in EAM rats and palmitic acid-induced damage to H9c2 cells through the JAK2/STAT3 pathway.
{"title":"IFITM3 mediates inflammation induced myocardial injury through JAK2/STAT3 signaling pathway","authors":"Chunming Xiong , Bohan Li , Renxing Song , Zizhe Ma , Sally A. Huber , Wei Liu","doi":"10.1016/j.molimm.2024.01.012","DOIUrl":"10.1016/j.molimm.2024.01.012","url":null,"abstract":"<div><p><span><span>Myocarditis is an inflammation of the heart muscle often associated with </span>viral infections<span><span><span> and can lead to dilated cardiomyopathy. Interferon-induced transmembrane protein<span> 3 (IFITM3) is a small endosomal membrane protein with anti-viral activity against multiple viruses<span> and is also implicated in non-infectious diseases such as cancer and Alzheimer’s Disease. Since the IFITM3 proteins are expressed both in T cells<span> and in cardiomyocytes, it is reasonable to hypothesize that these molecules could affect myocarditis either through their effect on the autoimmune response or through direct modulation of cardiomyocyte damage. The aim of this study was to investigate the role of IFITM3 in </span></span></span></span>experimental autoimmune myocarditis (EAM)-mediated </span>myocardial injury<span><span>. Immunization of rats with cardiac myosin results in substantial </span>cardiac inflammation<span> and is associated with increased expression of IFITM3 after 21 days. In vivo IFITM3 shRNA<span> knockdown using the lentivirus transfection method reduced cardiac injury while restoring IFITM3 expression reversed the protective effect of IFITM3 RNA interference. To determine the direct impact of IFITM3, the rat ventricular cell line, H9c2, was treated with </span></span></span></span></span>palmitic acid<span><span> which causes apoptosis in these cells. Suppressing IFITM3 expression protects H9c2 cells while overexpressing IFITM3 enhances cell injury. </span>JAK inhibitors reduced IFITM3-mediated myocardial cell injury. In conclusion, IFITM3 may mediate myocardial injury in EAM rats and palmitic acid-induced damage to H9c2 cells through the JAK2/STAT3 pathway.</span></p></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139668636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01DOI: 10.1016/j.molimm.2023.11.013
Yuying Yang , Yuqing Deng , Guoqiang Zhang , Xiaoting Xu , Xiaoxiao Xiong , Si Yu , Fanrong Peng , Xuyan Tian , Weiying Ye , Huanpeng Chen , Bolan Yu , Zhonghua Liu , Xixin He , Zhaofeng Huang
Th17 cell, an important subpopulation of helper T cell, plays an important role in the development of inflammatory bowel disease (IBD) and is thought to be a potential target for the treatment of IBD. In our previous study, we demonstrated that α-mangostin could relieve lupus nephritis via inhibiting Th17 cell function. In our preliminary study, we obtained four derivatives by adding chemical modification of α-mangostin which could also inhibit Th17 cell differentiation in vitro. In this study, we constructed a chronic IBD mouse model and demonstrated the therapeutic effects of α-mangostin and its derivatives as therapeutic agents for IBD. In compounds treating groups, intestinal inflammation showed significant improvement in symptoms which included weight loss, high disease activity index, colon length shorten and the change of intestinal flora. We also found that compounds could effectively either suppress the number of Th17 cell or increase the number of Treg cell detected by flow cytometry, thus reducing the Th17/Treg ratio and suppressing the level of intestinal inflammation. Notably, IL17-F levels, rather than IL17-A, were reduced in the colon of mice of compounds treating groups. Thus, α-mangostin and its derivatives ameliorate DSS-induced chronic colitis in mice by regulating Th17/Treg balance to alleviate intestinal inflammation and can modulate the intestinal microbial community. These results suggest that α-mangostin and its derivatives may be the new therapeutic option for chronic colitis.
{"title":"α-mangostin derivatives ameliorated mouse DSS-induced chronic colitis via regulating Th17/Treg balance","authors":"Yuying Yang , Yuqing Deng , Guoqiang Zhang , Xiaoting Xu , Xiaoxiao Xiong , Si Yu , Fanrong Peng , Xuyan Tian , Weiying Ye , Huanpeng Chen , Bolan Yu , Zhonghua Liu , Xixin He , Zhaofeng Huang","doi":"10.1016/j.molimm.2023.11.013","DOIUrl":"10.1016/j.molimm.2023.11.013","url":null,"abstract":"<div><p>Th17 cell, an important subpopulation of helper T cell, plays an important role in the development of inflammatory bowel disease (IBD) and is thought to be a potential target for the treatment of IBD. In our previous study, we demonstrated that α-mangostin could relieve lupus nephritis via inhibiting Th17 cell function. In our preliminary study, we obtained four derivatives by adding chemical modification of α-mangostin which could also inhibit Th17 cell differentiation in vitro<em>.</em> In this study, we constructed a chronic IBD mouse model and demonstrated the therapeutic effects of α-mangostin and its derivatives as therapeutic agents for IBD. In compounds treating groups, intestinal inflammation showed significant improvement in symptoms which included weight loss, high disease activity index, colon length shorten and the change of intestinal flora. We also found that compounds could effectively either suppress the number of Th17 cell or increase the number of Treg cell detected by flow cytometry, thus reducing the Th17/Treg ratio and suppressing the level of intestinal inflammation. Notably, IL17-F levels, rather than IL17-A, were reduced in the colon of mice of compounds treating groups. Thus, α-mangostin and its derivatives ameliorate DSS-induced chronic colitis in mice by regulating Th17/Treg balance to alleviate intestinal inflammation and can modulate the intestinal microbial community. These results suggest that α-mangostin and its derivatives may be the new therapeutic option for chronic colitis.</p></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139571164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01DOI: 10.1016/j.molimm.2024.01.008
Tetiana Hourani , Mahtab Eivazitork , Thivya Balendran , Kevin MC. Lee , John A. Hamilton , Hong-Jian Zhu , Josephine Iaria , Andrew P. Morokoff , Rodney B. Luwor , Adrian A. Achuthan
Transforming growth factor-β (TGF-β) is a pleiotropic cytokine essential for multiple biological processes, including the regulation of inflammatory and immune responses. One of the important functions of TGF-β is the suppression of the proinflammatory cytokine interleukin-12 (IL-12), which is crucial for mounting an anti-tumorigenic response. Although the regulation of the IL-12p40 subunit (encoded by the IL-12B gene) of IL-12 has been extensively investigated, the knowledge of IL-12p35 (encoded by IL-12A gene) subunit regulation is relatively limited. This study investigates the molecular regulation of IL-12A by TGF-β-activated signaling pathways in THP-1 monocytes. Our study identifies a complex regulation of IL-12A gene expression by TGF-β, which involves multiple cellular signaling pathways, such as Smad2/3, NF-κB, p38 and JNK1/2. Pharmacological inhibition of NF-κB signaling decreased IL-12A expression, while blocking the Smad2/3 signaling pathway by overexpression of Smad7 and inhibiting JNK1/2 signaling with a pharmacological inhibitor, SP600125, increased its expression. The elucidated signaling pathways that regulate IL-12A gene expression potentially provide new therapeutic targets to increase IL-12 levels in the tumor microenvironment.
{"title":"Signaling pathways underlying TGF-β mediated suppression of IL-12A gene expression in monocytes","authors":"Tetiana Hourani , Mahtab Eivazitork , Thivya Balendran , Kevin MC. Lee , John A. Hamilton , Hong-Jian Zhu , Josephine Iaria , Andrew P. Morokoff , Rodney B. Luwor , Adrian A. Achuthan","doi":"10.1016/j.molimm.2024.01.008","DOIUrl":"10.1016/j.molimm.2024.01.008","url":null,"abstract":"<div><p>Transforming growth factor-β (TGF-β) is a pleiotropic cytokine essential for multiple biological processes, including the regulation of inflammatory and immune responses. One of the important functions of TGF-β is the suppression of the proinflammatory cytokine interleukin-12 (IL-12), which is crucial for mounting an anti-tumorigenic response. Although the regulation of the IL-12p40 subunit (encoded by the <em>IL-12B</em> gene) of IL-12 has been extensively investigated, the knowledge of IL-12p35 (encoded by <em>IL-12A</em> gene) subunit regulation is relatively limited. This study investigates the molecular regulation of <em>IL-12A</em> by TGF-β-activated signaling pathways in THP-1 monocytes. Our study identifies a complex regulation of <em>IL-12A</em> gene expression by TGF-β, which involves multiple cellular signaling pathways, such as Smad2/3, NF-κB, p38 and JNK1/2. Pharmacological inhibition of NF-κB signaling decreased <em>IL-12A</em> expression, while blocking the Smad2/3 signaling pathway by overexpression of Smad7 and inhibiting JNK1/2 signaling with a pharmacological inhibitor, SP600125, increased its expression. The elucidated signaling pathways that regulate <em>IL-12A</em> gene expression potentially provide new therapeutic targets to increase IL-12 levels in the tumor microenvironment.</p></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0161589024000166/pdfft?md5=f843cd07e9ac7fd8c064d36102fc02f8&pid=1-s2.0-S0161589024000166-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139555288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-24DOI: 10.1016/j.molimm.2024.01.001
Takeyuki Shimizu , Lin Sun , Kazuo Ohnishi
During B cell development, pre-B cell receptor (pre-BCR), comprising the immunoglobulin heavy chain (HC) and surrogate light chain (SLC), plays a crucial role. The expression of pre-BCR serves as a certification of HC quality, confirming its ability to associate with the SLC and light chain (LC). In mice lacking SLC, the absence of this quality control mechanism leads to a distorted repertoire of HCs in the spleen and bone marrow. In this study, we conducted a comparative analysis of the immunoglobulin gene repertoire in peripheral blood cells of both wild-type mice and pre-BCR–deficient mice. Our findings reveal differences not only in the μ HC repertoire but also in the α HC and κ LC repertoires of the pre-BCR–deficient mice. These results suggest that the pre-BCR–mediated quality check of HC influences the selection of class-switched HC and LC repertoires. To further explore the impact of pre-BCR deficiency, we immunized these mice with thymus-dependent antigens and compared the antigen-responding repertoires. Our observations indicate that the affinity maturation pathways remain consistent between wild-type mice and pre-BCR–deficient mice, albeit with variations in the degree of maturation.
在 B 细胞发育过程中,由免疫球蛋白重链(HC)和替代轻链(SLC)组成的前 B 细胞受体(pre-BCR)起着至关重要的作用。前 BCR 的表达可作为 HC 质量的证明,确认其与 SLC 和轻链(LC)结合的能力。在缺乏 SLC 的小鼠中,这种质量控制机制的缺失会导致脾脏和骨髓中的 HC 出现扭曲。在这项研究中,我们对野生型小鼠和前 BCR 缺陷小鼠外周血细胞中的免疫球蛋白基因库进行了比较分析。我们的研究结果表明,前 BCR 基因缺陷小鼠不仅在 μ HC 基因库中存在差异,而且在 α HC 和 κ LC 基因库中也存在差异。这些结果表明,前 BCR 介导的 HC 质量检查影响了类开关 HC 和 LC 重奏的选择。为了进一步探讨前BCR缺陷的影响,我们用胸腺依赖性抗原对这些小鼠进行了免疫,并比较了抗原反应序列。我们的观察结果表明,野生型小鼠和前BCR缺陷小鼠的亲和力成熟途径保持一致,只是成熟程度有所不同。
{"title":"Influence of pre-B cell receptor deficiency on the immunoglobulin repertoires in peripheral blood B cells before and after immunization","authors":"Takeyuki Shimizu , Lin Sun , Kazuo Ohnishi","doi":"10.1016/j.molimm.2024.01.001","DOIUrl":"https://doi.org/10.1016/j.molimm.2024.01.001","url":null,"abstract":"<div><p><span><span><span>During B cell development, pre-B cell receptor (pre-BCR), comprising the </span>immunoglobulin heavy chain (HC) and </span>surrogate light chain<span> (SLC), plays a crucial role. The expression of pre-BCR serves as a certification of HC quality, confirming its ability to associate with the SLC and light chain (LC). In mice lacking SLC, the absence of this quality control mechanism leads to a distorted repertoire of HCs in the spleen and bone marrow. In this study, we conducted a comparative analysis of the immunoglobulin gene repertoire in peripheral </span></span>blood cells<span><span> of both wild-type mice and pre-BCR–deficient mice. Our findings reveal differences not only in the μ HC repertoire but also in the α HC and κ LC repertoires of the pre-BCR–deficient mice. These results suggest that the pre-BCR–mediated quality check of HC influences the selection of class-switched HC and LC repertoires. To further explore the impact of pre-BCR deficiency, we immunized these mice with thymus-dependent antigens and compared the antigen-responding repertoires. Our observations indicate that the </span>affinity maturation pathways remain consistent between wild-type mice and pre-BCR–deficient mice, albeit with variations in the degree of maturation.</span></p></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139548534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-24DOI: 10.1016/j.molimm.2024.01.009
Dongming Wu , Yong Wang , Jian Xu , Dong Wang , Jiawei Zhang , Lijuan Meng , Yuanchang Hu , Ping Wang , Jinde Lin , Shun Zhou
Background
Liver ischemia reperfusion (IR) injury is a common cause of liver dysfunction in patients post liver partial resection and liver transplantation. However, the cellular defense mechanisms underlying IR are not well understood. Macrophage mediated sterile inflammation plays critical roles in liver IR injury. Sorting nexin (SNX) 10, a member of the SNX family which functions in regulation of endosomal sorting. This study aimed to explore the role of sorting nexin 10 (SNX10) during liver IR injury with a focus on regulating macrophage function.
Methods
Both the gene and protein expression levels of SNX10 were analyzed in human specimens from 10 patients undergoing liver partial resection with ischemic insult and in a mouse model of liver IR. The in vivo effects of SNX10 in liver IR injury and sterile inflammation in mice were investigated. Bone marrow derived macrophages (BMDMs) were used to determine the role of SNX10 in modulating macrophage function in vitro.
Results
Increased expression of SNX10 was observed both in human specimens and mice livers post IR. SNX10 knockdown alleviated IR induced sterile inflammation and liver damage in mice. SNX10 promoted M1 polarization of macrophage treated with LPS and facilitated inflammatory response by activating NLRP3 inflammasome.
Conclusions
We report for the first time that SNX10 is upregulated in IR-stressed livers. SNX10 activation aggravates liver IR injury and sterile inflammation by facilitating macrophage M1 polarization and inflammatory response suggesting SNX10 as a potential therapeutic target for liver IR injury.
{"title":"SNX10 promoted liver IR injury by facilitating macrophage M1 polarization via NLRP3 inflammasome activation","authors":"Dongming Wu , Yong Wang , Jian Xu , Dong Wang , Jiawei Zhang , Lijuan Meng , Yuanchang Hu , Ping Wang , Jinde Lin , Shun Zhou","doi":"10.1016/j.molimm.2024.01.009","DOIUrl":"https://doi.org/10.1016/j.molimm.2024.01.009","url":null,"abstract":"<div><h3>Background</h3><p><span><span>Liver ischemia reperfusion (IR) injury is a common cause of </span>liver dysfunction </span>in patients<span><span> post liver partial resection and </span>liver transplantation<span>. However, the cellular defense<span> mechanisms underlying IR are not well understood. Macrophage mediated sterile inflammation plays critical roles in liver IR injury. Sorting nexin<span> (SNX) 10, a member of the SNX family which functions in regulation of endosomal sorting. This study aimed to explore the role of sorting nexin 10 (SNX10) during liver IR injury with a focus on regulating macrophage function.</span></span></span></span></p></div><div><h3>Methods</h3><p><span>Both the gene and protein expression levels of SNX10 were analyzed in </span>human specimens<span> from 10 patients undergoing liver partial resection with ischemic insult and in a mouse model of liver IR. The in vivo effects of SNX10 in liver IR injury and sterile inflammation in mice were investigated. Bone marrow derived macrophages (BMDMs) were used to determine the role of SNX10 in modulating macrophage function in vitro.</span></p></div><div><h3>Results</h3><p>Increased expression of SNX10 was observed both in human specimens and mice livers post IR. SNX10 knockdown alleviated IR induced sterile inflammation and liver damage in mice. SNX10 promoted M1 polarization of macrophage treated with LPS and facilitated inflammatory response by activating NLRP3<span> inflammasome.</span></p></div><div><h3>Conclusions</h3><p>We report for the first time that SNX10 is upregulated in IR-stressed livers. SNX10 activation aggravates liver IR injury and sterile inflammation by facilitating macrophage M1 polarization and inflammatory response suggesting SNX10 as a potential therapeutic target for liver IR injury.</p></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139548533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-19DOI: 10.1016/j.molimm.2024.01.005
Shu Dong , Hongyuan Pang , Fan Li , Mengqing Hua , Meng Liang , Chuanwang Song
Surfactant protein A (SP-A), a natural immune molecule, plays an important role in lung health. SP-A recognizes and binds microbial surface glycogroups through the C-type carbohydrate recognition domain, and then binds corresponding cell surface receptors (such as C1qRp, CRT-CD91 complex, CD14, SP-R210, Toll-like receptor, SIRP-α, CR3, etc.) through collagen-like region, and subsequently mediates biological effects. SP-A regulates lung innate immunity by promoting surfactant absorption by alveolar type II epithelial cells and phagocytosis of pathogenic microorganisms by alveolar macrophages. SP-A also regulates lung adaptive immunity by inhibiting DC maturation, and T cell proliferation and differentiation. This article reviews latest relationships between SP-A and adaptive and intrinsic immunity.
表面活性蛋白 A(SP-A)是一种天然免疫分子,在肺部健康中发挥着重要作用。SP-A 通过 C 型碳水化合物识别域识别并结合微生物表面糖基,然后通过胶原样区域结合相应的细胞表面受体(如 C1qRp、CRT-CD91 复合物、CD14、SP-R210、Toll 样受体、SIRP-α、CR3 等),继而介导生物效应。SP-A 通过促进肺泡 II 型上皮细胞吸收表面活性物质和肺泡巨噬细胞吞噬病原微生物来调节肺部先天性免疫。SP-A 还通过抑制 DC 成熟、T 细胞增殖和分化来调节肺适应性免疫。本文回顾了 SP-A 与适应性免疫和内在免疫之间的最新关系。
{"title":"Immunoregulatory function of SP-A","authors":"Shu Dong , Hongyuan Pang , Fan Li , Mengqing Hua , Meng Liang , Chuanwang Song","doi":"10.1016/j.molimm.2024.01.005","DOIUrl":"https://doi.org/10.1016/j.molimm.2024.01.005","url":null,"abstract":"<div><p>Surfactant protein A<span><span> (SP-A), a natural immune molecule, plays an important role in lung health. SP-A recognizes and binds microbial surface glycogroups through the C-type carbohydrate recognition domain, and then binds corresponding cell surface receptors<span> (such as C1qRp, CRT-CD91 complex, CD14, SP-R210, Toll-like receptor, SIRP-α, </span></span>CR3<span><span>, etc.) through collagen-like region, and subsequently mediates biological effects. SP-A regulates lung innate immunity by promoting surfactant absorption by alveolar </span>type II epithelial cells<span> and phagocytosis<span><span> of pathogenic microorganisms by alveolar macrophages. SP-A also regulates lung </span>adaptive immunity<span> by inhibiting DC maturation, and T cell proliferation and differentiation. This article reviews latest relationships between SP-A and adaptive and intrinsic immunity.</span></span></span></span></span></p></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139504108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}