Pub Date : 2025-02-06DOI: 10.1016/j.intimp.2024.113912
Ruo-Xi Chen , Zheng Luan , Chong Shen , Meng-Di Dai , Chang-Yu Qiu , Xin-Jie Zhu , Qing-Zhao Zhang , Mei-Ping Lu , Lei Cheng
Background
The etiology of allergic rhinitis (AR), in which genetic and environmental factors are closely intertwined, has not yet been completely clarified. Programmed cell death 1 (PD-1) and its ligands (PD-L1 and PD-L2) regulate the immune and inflammatory responses during the development of immune-related and atopic diseases. To clarify the associations of genetic variants in PD-1, PD-L1 and PD-L2 with susceptibility to AR, gene–gene and gene–environment interactions were investigated.
Methods
A total of 452 AR patients and 495 controls were enrolled in this hospital-based case-control study. Eight single nucleotide polymorphisms (SNPs) in the PDCD1, PDCD1LG1 and PDCD1LG2 genes were genotyped. The correlations between SNPs and AR incidence, as well as gene–gene and gene–environment interactions were explored. Differentially expressed genes were screened by the Limma package in two Gene Expression Omnibus (GEO) datasets of AR patients. Expression qualitative trait locus (eQTL) analysis was performed via the Genotype-Tissue Expression (GTEx) database.
Results
The rs2297136 (A/G) in PDCD1LG1 was associated with a significantly increased risk of AR, whereas the PDCD1LG2 rs16923189 G allele was associated with a reduced risk of AR. In the subgroups according to AR-related phenotypes, the rs2297136 G allele increased, while the rs16923189 G allele reduced AR risk. Gene–gene interactions and gene–environment interactions (e.g., PDCD1LG1 polymorphisms with factors such as smoke, main road and cooking fumes) were verified in AR patients, but they were not significant after Bonferroni correction.
Conclusion
PDCD1LG1 rs2297136 and PDCD1LG2 rs16923189 are associated with susceptibility to AR in this Chinese population. The PD-1/PD-L1 and PD-1/PD-L2 signaling pathways may regulate gene–gene and gene–environment interactions in the pathogenesis of AR.
{"title":"Genetic variants in PD-1 and its ligands, gene–gene and gene–environment interactions in allergic rhinitis","authors":"Ruo-Xi Chen , Zheng Luan , Chong Shen , Meng-Di Dai , Chang-Yu Qiu , Xin-Jie Zhu , Qing-Zhao Zhang , Mei-Ping Lu , Lei Cheng","doi":"10.1016/j.intimp.2024.113912","DOIUrl":"10.1016/j.intimp.2024.113912","url":null,"abstract":"<div><h3>Background</h3><div>The etiology of allergic rhinitis (AR), in which genetic and environmental factors are closely intertwined, has not yet been completely clarified. Programmed cell death 1 (PD-1) and its ligands (PD-L1 and PD-L2) regulate the immune and inflammatory responses during the development of immune-related and atopic diseases. To clarify the associations of genetic variants in PD-1, PD-L1 and PD-L2 with susceptibility to AR, gene–gene and gene–environment interactions were investigated.</div></div><div><h3>Methods</h3><div>A total of 452 AR patients and 495 controls were enrolled in this hospital-based case-control study. Eight single nucleotide polymorphisms (SNPs) in the <em>PDCD1</em>, <em>PDCD1LG1</em> and <em>PDCD1LG2</em> genes were genotyped. The correlations between SNPs and AR incidence, as well as gene–gene and gene–environment interactions were explored. Differentially expressed genes were screened by the Limma package in two Gene Expression Omnibus (GEO) datasets of AR patients. Expression qualitative trait locus (eQTL) analysis was performed via the Genotype-Tissue Expression (GTEx) database.</div></div><div><h3>Results</h3><div>The rs2297136 (A/G) in <em>PDCD1LG1</em> was associated with a significantly increased risk of AR, whereas the <em>PDCD1LG2</em> rs16923189 G allele was associated with a reduced risk of AR. In the subgroups according to AR-related phenotypes, the rs2297136 G allele increased, while the rs16923189 G allele reduced AR risk. Gene–gene interactions and gene–environment interactions (e.g., <em>PDCD1LG1</em> polymorphisms with factors such as smoke, main road and cooking fumes) were verified in AR patients, but they were not significant after Bonferroni correction.</div></div><div><h3>Conclusion</h3><div><em>PDCD1LG1</em> rs2297136 and <em>PDCD1LG2</em> rs16923189 are associated with susceptibility to AR in this Chinese population. The PD-1/PD-L1 and PD-1/PD-L2 signaling pathways may regulate gene–gene and gene–environment interactions in the pathogenesis of AR.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113912"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06Epub Date: 2025-01-07DOI: 10.1016/j.intimp.2025.114036
Shuqin Lai, Huaqing Chen, Xiaojuan Ji, Wenjie Zhu, Zhiwei Wu, Shan Huang, Chunli Lin, Tao Yang, Zhaolin Zeng, Longnian Li
Background: Psoriasis is a chronic inflammatory skin disease regulated by autoimmunity, and pyroptosis plays an important role in this condition. This research sought to examine the function and potential molecular pathway of Gasdermin D (GSDMD) in psoriasis.
Methods: GSDMD expression was examined by immunohistochemistry in biopsied skin tissues from patients with psoriasis. Pyroptosis-related genes and inflammatory factors were quantified using qRT-PCR and ELISA, respectively. HaCaT cells were treated with M5 cytokines to develop an in vitro psoriasis model, while imiquimod (IMQ) was administered to construct an in vivo psoriasis model. To counteract the inhibition of the NOD-like receptor (NLR) pathway caused by GSDMD knockdown, the pathway activator M-TriDAP was employed.
Results: In the lesional skin tissues of patients with psoriasis, GSDMD expression was highly expressed. The levels of pro-pyroptosis mediators were increased, whereas the level of anti-inflammatory factor was lowered. GSDMD knockdown and disulfiram treatment inhibited pyroptosis and promoted apoptosis in M5-induced HaCaT cells. In the IMQ-induced psoriasis-like mouse model, GSDMD knockdown suppressed pyroptosis and improved skin lesion severity, alleviating erythema, epidermal thickness, and inflammatory cell infiltration. Mechanistically, GSDMD knockdown inhibited the NLR pathway, accompanied by reduced protein levels of NLRP3, NOD1, NOD2, and PYCARD. NLR pathway activator, M-TriDAP treatment significantly reversed the effects of GSDMD knockdown on psoriasis progression.
Conclusions: Knockdown of GSDMD inhibits pyroptosis in psoriasis by blocking the NLR signaling pathway, presenting a novel potential strategy for psoriasis treatment.
{"title":"Knockdown of GSDMD inhibits pyroptosis in psoriasis by blocking the NOD-like receptor signaling pathway.","authors":"Shuqin Lai, Huaqing Chen, Xiaojuan Ji, Wenjie Zhu, Zhiwei Wu, Shan Huang, Chunli Lin, Tao Yang, Zhaolin Zeng, Longnian Li","doi":"10.1016/j.intimp.2025.114036","DOIUrl":"10.1016/j.intimp.2025.114036","url":null,"abstract":"<p><strong>Background: </strong>Psoriasis is a chronic inflammatory skin disease regulated by autoimmunity, and pyroptosis plays an important role in this condition. This research sought to examine the function and potential molecular pathway of Gasdermin D (GSDMD) in psoriasis.</p><p><strong>Methods: </strong>GSDMD expression was examined by immunohistochemistry in biopsied skin tissues from patients with psoriasis. Pyroptosis-related genes and inflammatory factors were quantified using qRT-PCR and ELISA, respectively. HaCaT cells were treated with M5 cytokines to develop an in vitro psoriasis model, while imiquimod (IMQ) was administered to construct an in vivo psoriasis model. To counteract the inhibition of the NOD-like receptor (NLR) pathway caused by GSDMD knockdown, the pathway activator M-TriDAP was employed.</p><p><strong>Results: </strong>In the lesional skin tissues of patients with psoriasis, GSDMD expression was highly expressed. The levels of pro-pyroptosis mediators were increased, whereas the level of anti-inflammatory factor was lowered. GSDMD knockdown and disulfiram treatment inhibited pyroptosis and promoted apoptosis in M5-induced HaCaT cells. In the IMQ-induced psoriasis-like mouse model, GSDMD knockdown suppressed pyroptosis and improved skin lesion severity, alleviating erythema, epidermal thickness, and inflammatory cell infiltration. Mechanistically, GSDMD knockdown inhibited the NLR pathway, accompanied by reduced protein levels of NLRP3, NOD1, NOD2, and PYCARD. NLR pathway activator, M-TriDAP treatment significantly reversed the effects of GSDMD knockdown on psoriasis progression.</p><p><strong>Conclusions: </strong>Knockdown of GSDMD inhibits pyroptosis in psoriasis by blocking the NLR signaling pathway, presenting a novel potential strategy for psoriasis treatment.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"114036"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.intimp.2024.113949
Ruohan Li , Chuchu Zhang , Jiajia Ren , Guorong Deng , Ya Gao , Xiaoming Gao , Jiamei Li , Jingjing Zhang , Xi Xu , Xuting Jin , Xiaochuang Wang , Gang Wang
Background
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are significant burdens on global health. Remimazolam (REM), a novel sedative, has shown potential in its anti-inflammatory effects. However, a lack of evidence currently hinders our ability to determine if REM can improve ALI/ARDS.
Methods
We initially evaluated REM’s impact on lung injury in a lipopolysaccharide (LPS)–induced ALI mouse model. Subsequently, a network pharmacology (NP) strategy and ribonucleic acid–sequencing (RNA-seq) technique were used to investigate the potential molecular mechanisms underlying REM’s action against ALI. Finally, we carried out in vivo and in vitro experiments to validate our findings on these mechanisms.
Results
REM effectively mitigated lung injury in the mouse model. NP and RNA-seq analyses revealed significant enrichment of apoptosis-related pathways. Both in vivo and in vitro experiments revealed that REM significantly reduced levels of cleaved cysteine–aspartic acid–specific protease/proteinases 7 and 3 (cleaved Caspases-7 and −3) and cytochrome c (Cyt c) while enhancing the B-cell lymphoma 2 (Bcl-2)/Bcl-2–like protein 4 (Bax) ratio and phosphorylated protein kinase B (P-AKT) levels in lung tissue, endothelial cells, and epithelial cells. Furthermore, in vitro experiments confirmed that inhibiting the phosphoinositide 3-kinase (PI3K)/AKT pathway with LY294002 weakened REM’s antiapoptotic effects. In addition, pretreatment with PK11195 (the ligand of 18-kDa translocator protein [TSPO]) attenuated REM’s upregulation of the PI3K/AKT pathway and antiapoptotic effect in LPS-induced endothelial cells.
Conclusions
This study presents novel findings elucidating the beneficial effect of REM in ALI. This effect can be attributed to REM’s ability to inhibit apoptosis by activating of the PI3K/AKT pathway in endothelial and epithelial cells. Additionally, REM targeted TSPO to regulate this pathway in endothelial cells. These results suggested a potential protective role for REM in ALI/ARDS management.
{"title":"Remimazolam inhibits apoptosis of endothelial and epithelial cells by activating the PI3K/AKT pathway in acute lung injury","authors":"Ruohan Li , Chuchu Zhang , Jiajia Ren , Guorong Deng , Ya Gao , Xiaoming Gao , Jiamei Li , Jingjing Zhang , Xi Xu , Xuting Jin , Xiaochuang Wang , Gang Wang","doi":"10.1016/j.intimp.2024.113949","DOIUrl":"10.1016/j.intimp.2024.113949","url":null,"abstract":"<div><h3>Background</h3><div>Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are significant burdens on global health. Remimazolam (REM), a novel sedative, has shown potential in its anti-inflammatory effects. However, a lack of evidence currently hinders our ability to determine if REM can improve ALI/ARDS.</div></div><div><h3>Methods</h3><div>We initially evaluated REM’s impact on lung injury in a lipopolysaccharide (LPS)–induced ALI mouse model. Subsequently, a network pharmacology (NP) strategy and ribonucleic acid–sequencing (RNA-seq) technique were used to investigate the potential molecular mechanisms underlying REM’s action against ALI. Finally, we carried out <em>in vivo</em> and <em>in vitro</em> experiments to validate our findings on these mechanisms.</div></div><div><h3>Results</h3><div>REM effectively mitigated lung injury in the mouse model. NP and RNA-seq analyses revealed significant enrichment of apoptosis-related pathways. Both <em>in vivo</em> and <em>in vitro</em> experiments revealed that REM significantly reduced levels of cleaved cysteine–aspartic acid–specific protease/proteinases 7 and 3 (cleaved Caspases-7 and −3) and cytochrome <em>c</em> (Cyt c) while enhancing the B-cell lymphoma 2 (Bcl-2)/Bcl-2–like protein 4 (Bax) ratio and phosphorylated protein kinase B (P-AKT) levels in lung tissue, endothelial cells, and epithelial cells. Furthermore, <em>in vitro</em> experiments confirmed that inhibiting the phosphoinositide 3-kinase (PI3K)/AKT pathway with LY294002 weakened REM’s antiapoptotic effects. In addition, pretreatment with PK11195 (the ligand of 18-kDa translocator protein [TSPO]) attenuated REM’s upregulation of the PI3K/AKT pathway and antiapoptotic effect in LPS-induced endothelial cells.</div></div><div><h3>Conclusions</h3><div>This study presents novel findings elucidating the beneficial effect of REM in ALI. This effect can be attributed to REM’s ability to inhibit apoptosis by activating of the PI3K/AKT pathway in endothelial and epithelial cells. Additionally, REM targeted TSPO to regulate this pathway in endothelial cells. These results suggested a potential protective role for REM in ALI/ARDS management.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113949"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.intimp.2024.113960
Chih-Chen Tzang , Liang-Yun Chi , Chen-Yu Lee , Zi-Yi Chang , Chiao-An Luo , Yan-Hua Chen , Tzu-An Lin , Liang-Chien Yu , Yo-Rong Chen , Bor-Show Tzang , Tsai-Ching Hsu
Parvovirus B19 (B19V) is a human pathogen from the Parvoviridae family that primarily targets and replicates in erythroid progenitor cells (EPCs). While its symptoms are typically self-limiting in healthy individuals, B19V can cause or exacerbate autoimmune diseases in vulnerable patients. This review integrates the involvement of B19V in the development and worsening of several autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), hematological disorders (thalassemia, anemia, and thrombocytopenia), vasculitis, antiphospholipid syndrome (APS), dermatological disease (systemic sclerosis, psoriasis), autoimmune thyroid disease, myocarditis, and myasthenia gravis, and autoinflammatory disease of adult-onset Still’s disease (AOSD). B19V contributes to autoimmunity and autoimmune disease onset and progression through mechanisms such as molecular mimicry, immune system disruption, and chronic infection. By summarizing findings from in vitro experiments, clinical case studies, seroprevalence data, and biopsy results, this review highlights the critical connection between B19V and autoimmune disease development. Recognizing the role of B19V in the early diagnosis and management of these conditions is essential, as its presence may influence the disease course and severity. Greater awareness among healthcare professionals and the public is necessary to address the impact of B19V, leading to more accurate diagnoses and better-informed treatment approaches for autoimmune diseases linked to the virus.
{"title":"Clinical implications of human Parvovirus B19 infection on autoimmunity and autoimmune diseases","authors":"Chih-Chen Tzang , Liang-Yun Chi , Chen-Yu Lee , Zi-Yi Chang , Chiao-An Luo , Yan-Hua Chen , Tzu-An Lin , Liang-Chien Yu , Yo-Rong Chen , Bor-Show Tzang , Tsai-Ching Hsu","doi":"10.1016/j.intimp.2024.113960","DOIUrl":"10.1016/j.intimp.2024.113960","url":null,"abstract":"<div><div>Parvovirus B19 (B19V) is a human pathogen from the Parvoviridae family that primarily targets and replicates in erythroid progenitor cells (EPCs). While its symptoms are typically self-limiting in healthy individuals, B19V can cause or exacerbate autoimmune diseases in vulnerable patients. This review integrates the involvement of B19V in the development and worsening of several autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), hematological disorders (thalassemia, anemia, and thrombocytopenia), vasculitis, antiphospholipid syndrome (APS), dermatological disease (systemic sclerosis, psoriasis), autoimmune thyroid disease, myocarditis, and myasthenia gravis, and autoinflammatory disease of adult-onset Still’s disease (AOSD). B19V contributes to autoimmunity and autoimmune disease onset and progression through mechanisms such as molecular mimicry, immune system disruption, and chronic infection. By summarizing findings from in vitro experiments, clinical case studies, seroprevalence data, and biopsy results, this review highlights the critical connection between B19V and autoimmune disease development. Recognizing the role of B19V in the early diagnosis and management of these conditions is essential, as its presence may influence the disease course and severity. Greater awareness among healthcare professionals and the public is necessary to address the impact of B19V, leading to more accurate diagnoses and better-informed treatment approaches for autoimmune diseases linked to the virus.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113960"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.intimp.2024.113948
Huan Qin , Jiangang Wang , Luyuan Bai , Huiqin Ding , Hailing Ding , Fengyi Zhang , Yantao Han
This study investigates the therapeutic effects of recombinant human IL-10 (rhIL-10) administered via aerosol inhalation in acute lung injury (ALI), with a particular focus on neutrophils. It explores how rhIL-10, in the presence of platelets, modulates neutrophil polarization to ameliorate acute lung injury. Initially, the ALI model established in mice demonstrated that aerosol inhalation of rhIL-10 significantly mitigated the cytokine storm in the lungs, reduced pulmonary edema, and alleviated histopathological damage to lung tissue. Additionally, rhIL-10 administration was found to decrease neutrophil infiltration and platelet activation in the lungs of mice, inhibiting the formation of platelet-neutrophil aggregates (PNAs) and promoting the differentiation of neutrophils toward an anti-inflammatory phenotype in the presence of platelets. Subsequently, primary neutrophils and platelets were isolated from mouse bone marrow and blood to explore the underlying mechanisms. The results indicated that rhIL-10 promotes the expression of the signal transducer and activator of transcription 3 (STAT3) and the suppressor of cytokine signaling 3 (SOCS3) in neutrophils while inhibiting the activation of the nuclear factor kappa B (NF-κB) and the NF-κB inhibitor (IκB), which in turn enhances CD40 expression. This interaction facilitates the formation of PNAs and influences neutrophil phenotype differentiation. Furthermore, the application of the STAT3 phosphorylation inhibitor Stattic and CD40 antibody in vivo provided further validation of this potential mechanism. In conclusion, these results indicate that aerosol inhalation of rhIL-10 effectively ameliorates ALI. The underlying mechanism may involve the modulation of the neutrophil STAT/SOCS-IκB/NF-κB-CD40 signaling pathway, promoting interactions between neutrophils and platelets that facilitate the differentiation of neutrophils toward an anti-inflammatory phenotype.
{"title":"Aerosol inhalation of rhIL-10 improves acute lung injury in mice by affecting pulmonary neutrophil phenotypes through neutrophil-platelet aggregates","authors":"Huan Qin , Jiangang Wang , Luyuan Bai , Huiqin Ding , Hailing Ding , Fengyi Zhang , Yantao Han","doi":"10.1016/j.intimp.2024.113948","DOIUrl":"10.1016/j.intimp.2024.113948","url":null,"abstract":"<div><div>This study investigates the therapeutic effects of recombinant human IL-10 (rhIL-10) administered via aerosol inhalation in acute lung injury (ALI), with a particular focus on neutrophils. It explores how rhIL-10, in the presence of platelets, modulates neutrophil polarization to ameliorate acute lung injury. Initially, the ALI model established in mice demonstrated that aerosol inhalation of rhIL-10 significantly mitigated the cytokine storm in the lungs, reduced pulmonary edema, and alleviated histopathological damage to lung tissue. Additionally, rhIL-10 administration was found to decrease neutrophil infiltration and platelet activation in the lungs of mice, inhibiting the formation of platelet-neutrophil aggregates (PNAs) and promoting the differentiation of neutrophils toward an anti-inflammatory phenotype in the presence of platelets. Subsequently, primary neutrophils and platelets were isolated from mouse bone marrow and blood to explore the underlying mechanisms. The results indicated that rhIL-10 promotes the expression of the signal transducer and activator of transcription 3 (STAT3) and the suppressor of cytokine signaling 3 (SOCS3) in neutrophils while inhibiting the activation of the nuclear factor kappa B (NF-κB) and the NF-κB inhibitor (IκB), which in turn enhances CD40 expression. This interaction facilitates the formation of PNAs and influences neutrophil phenotype differentiation. Furthermore, the application of the STAT3 phosphorylation inhibitor Stattic and CD40 antibody in vivo provided further validation of this potential mechanism. In conclusion, these results indicate that aerosol inhalation of rhIL-10 effectively ameliorates ALI. The underlying mechanism may involve the modulation of the neutrophil STAT/SOCS-IκB/NF-κB-CD40 signaling pathway, promoting interactions between neutrophils and platelets that facilitate the differentiation of neutrophils toward an anti-inflammatory phenotype.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113948"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.intimp.2024.113977
Chengjuan Zhang , Bo Wang , Tingjie Wang , Chi Yan , Jing Yuan , Peng Li , Bin Ma , Tao Wang , Benling Xu , Ruihua Bai , Xiance Tang , Youwei Shi , Minqing Wu , Tianqi Lei , Wenhao Xu , Ning Li , Yongjun Guo
Background
Lung squamous cell carcinoma (LUSC) is a significant health concern, characterized by a lack of specific therapies and limited treatment options for patients in advanced stages. This study aims to identify key molecules of prognostic importance in LUSC and provide an experimental foundation for their potential therapeutic applications.
Methods
Immune-related transcriptome expression analysis was performed on LUSC samples using the NanoString digital gene analysis system to develop a prognostic transcriptomic signature. This was followed by validation within the LUSC cohort database, and the immune properties and cellular functions of the critical molecule were examined through molecular biology experiments.
Results
Advanced nCounter analysis revealed significant differences in the numbers of T cells, cytotoxic cells, B cells, and CD45+ and CD8+ T cells between the OS1 (short-term survival) group and the OS2 (long-term survival) group. A comparison of the differences in tumor immune-related pathways between the two groups revealed that signaling pathways such as the PI3K-AKT, NF-kappaB signaling, Notch signaling, angiogenesis, matrix remodeling, and metastasis pathways were activated in the OS1 subgroup, and DNA damage repair and lymphatic chamber signaling pathways were activated in the OS2 subgroup. We analyzed and compared differentially expressed mRNAs with high expression levels in the OS1 and stage IV groups. Collagen type V alpha 1 (COL5A1) was found to be associated with the prognosis of LUSC. Phenotypic analysis revealed that COL5A1 knockdown inhibited the proliferation, migration, and invasion of SKMES1 cells. Locating COL5A1 was shown to be expressed in CAFs, T cells, and EPI cells through single-cell omics analysis.
Conclusion
COL5A1 plays a crucial role in tumor progression, indicating that COL5A1 inhibitors may represent a promising therapeutic strategy for the treatment of LUSC.
{"title":"Role of COL5A1 in lung squamous cell Carcinoma: Prognostic Implications and therapeutic potential","authors":"Chengjuan Zhang , Bo Wang , Tingjie Wang , Chi Yan , Jing Yuan , Peng Li , Bin Ma , Tao Wang , Benling Xu , Ruihua Bai , Xiance Tang , Youwei Shi , Minqing Wu , Tianqi Lei , Wenhao Xu , Ning Li , Yongjun Guo","doi":"10.1016/j.intimp.2024.113977","DOIUrl":"10.1016/j.intimp.2024.113977","url":null,"abstract":"<div><h3>Background</h3><div>Lung squamous cell carcinoma (LUSC) is a significant health concern, characterized by a lack of specific therapies and limited treatment options for patients in advanced stages. This study aims to identify key molecules of prognostic importance in LUSC and provide an experimental foundation for their potential therapeutic applications.</div></div><div><h3>Methods</h3><div>Immune-related transcriptome expression analysis was performed on LUSC samples using the NanoString digital gene analysis system to develop a prognostic transcriptomic signature. This was followed by validation within the LUSC cohort database, and the immune properties and cellular functions of the critical molecule were examined through molecular biology experiments.</div></div><div><h3>Results</h3><div>Advanced nCounter analysis revealed significant differences in the numbers of T cells, cytotoxic cells, B cells, and CD45<sup>+</sup> and CD8<sup>+</sup> T cells between the OS1 (short-term survival) group and the OS2 (long-term survival) group. A comparison of the differences in tumor immune-related pathways between the two groups revealed that signaling pathways such as the PI3K-AKT, NF-kappaB signaling, Notch signaling, angiogenesis, matrix remodeling, and metastasis pathways were activated in the OS1 subgroup, and DNA damage repair and lymphatic chamber signaling pathways were activated in the OS2 subgroup. We analyzed and compared differentially expressed mRNAs with high expression levels in the OS1 and stage IV groups. Collagen type V alpha 1 (COL5A1) was found to be associated with the prognosis of LUSC. Phenotypic analysis revealed that COL5A1 knockdown inhibited the proliferation, migration, and invasion of SKMES1 cells. Locating COL5A1 was shown to be expressed in CAFs, T cells, and EPI cells through single-cell omics analysis.</div></div><div><h3>Conclusion</h3><div>COL5A1 plays a crucial role in tumor progression, indicating that COL5A1 inhibitors may represent a promising therapeutic strategy for the treatment of LUSC.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113977"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.intimp.2024.113993
Zhu Xiaoli , Qi Xi , Gao Hongjun , Zhu Ziqing , Sha Yuxuan , Qin Yi , Li Anming , Zhu Jianfeng , Sha Yayun , Han Junling , Gao Lingbao
Objective
The objective of this study was to rigorously investigate and elucidate the genetic mechanisms underlying the formation of the RHnull blood group in a specific case and to systematically analyse the RH blood group genes among the family members of the proband.
Methods
Serological methods were used to determine the RH blood group phenotype of the proband. To elucidate the underlying genetic mechanism responsible for the RHnull phenotype, a comprehensive approach was undertaken, including RHCE genotyping, sequencing of RHD and RHCE genes, and exon sequencing of RHAG. For a comparative analysis, the same methodologies were applied to two family members of the proband.
Results
The genotype of the proband was determined as CcDEe. Subsequent RHAG exon sequencing analysis revealed a homozygous frameshift mutation in exon 5. Specifically, a nucleotide deletion at position c.732 in RHAG resulted in an amino acid substitution from phenylalanine to serine, followed by a frameshift and premature termination at codon 245 (p.Phe245Serfs*16). This mutation was confirmed as a novel genetic variant in the NCBI database.
Furthermore, serological findings, genotyping results, and RHAG exon sequencing data obtained from the proband’s sister were identical to those of the proband. In contrast, the proband’s son exhibited a serological phenotype of CCDee with a corresponding genotyping result for CCDee. RHAG exon sequencing of the son revealed a heterozygous frameshift mutation, which was consistent with the findings observed in the proband.
Conclusion
A novel mutation, specifically c.732delC, was identified in RHAG. The RHnull phenotype observed in this subject was attributed to a homozygous frameshift mutation in this gene. This mutation results in a truncated and nonfunctional RHAG protein, which subsequently disrupts the expression of other RH antigens on the cell membrane. Therefore, the serological phenotype associated with this genetic anomaly was classified as RHnull.
{"title":"Rhnull blood group caused by novel base deletion and comprehensive pedigree analysis","authors":"Zhu Xiaoli , Qi Xi , Gao Hongjun , Zhu Ziqing , Sha Yuxuan , Qin Yi , Li Anming , Zhu Jianfeng , Sha Yayun , Han Junling , Gao Lingbao","doi":"10.1016/j.intimp.2024.113993","DOIUrl":"10.1016/j.intimp.2024.113993","url":null,"abstract":"<div><h3>Objective</h3><div>The objective of this study was to rigorously investigate and elucidate the genetic mechanisms underlying the formation of the RH<sub>null</sub> blood group in a specific case and to systematically analyse the RH blood group genes among the family members of the proband.</div></div><div><h3>Methods</h3><div>Serological methods were used to determine the RH blood group phenotype of the proband. To elucidate the underlying genetic mechanism responsible for the RH<sub>null</sub> phenotype, a comprehensive approach was undertaken, including RHCE genotyping, sequencing of RHD and RHCE genes, and exon sequencing of RHAG. For a comparative analysis, the same methodologies were applied to two family members of the proband.</div></div><div><h3>Results</h3><div>The genotype of the proband was determined as <em>CcDEe</em>. Subsequent RHAG exon sequencing analysis revealed a homozygous frameshift mutation in exon 5. Specifically, a nucleotide deletion at position c.732 in RHAG resulted in an amino acid substitution from phenylalanine to serine, followed by a frameshift and premature termination at codon 245 (p.Phe245Serfs*16). This mutation was confirmed as a novel genetic variant in the NCBI database.</div><div>Furthermore, serological findings, genotyping results, and RHAG exon sequencing data obtained from the proband’s sister were identical to those of the proband. In contrast, the proband’s son exhibited a serological phenotype of CCDee with a corresponding genotyping result for <em>CCDee.</em> RHAG exon sequencing of the son revealed a heterozygous frameshift mutation, which was consistent with the findings observed in the proband.</div></div><div><h3>Conclusion</h3><div>A novel mutation, specifically c.732delC, was identified in RHAG. The RH<sub>null</sub> phenotype observed in this subject was attributed to a homozygous frameshift mutation in this gene. This mutation results in a truncated and nonfunctional RHAG protein, which subsequently disrupts the expression of other RH antigens on the cell membrane. Therefore, the serological phenotype associated with this genetic anomaly was classified as RH<sub>null</sub>.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113993"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.intimp.2024.113943
Ruoyuan Sun , Jinxi Yu , Zeyang Zou , Shuaini Yang , Yuqing Tuo , Lu Tan , Hong Zhang , Longhao Sun , Hong Bai
Background
FcγRI, a pivotal cell surface receptor, is implicated in diverse immune responses and is ubiquitously expressed on numerous immune cells. However, its role in intracellular bacterial infections remains understudied.
Methods
Wild-type (WT) and FcγRI knockout (FcγRI-KO) mice were inoculated intranasally with a specific dose of C. muridarum. Lung tissues were harvested for transcriptome sequencing, and flow cytometry was employed to validate bioinformatics immune infiltration analysis. Differentially expressed DC-associated genes were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses to elucidate their functions during infection. A PPI network was constructed to pinpoint crucial genes, and qPCR was utilized to confirm their expression changes. Additionally, we compared body weight, lung Chlamydia load, and pathological alterations between WT and FcγRI-KO mice post-infection to assess the effect of FcγRI on inflammation via gene regulation. Lastly, an mRNA-miRNA-lncRNA network was formulated to further probe the molecular mechanisms of FcγRI in C. muridarum infection.
Results
Post-C. muridarum infection, FcγRI-KO mice exhibited a notable decrease in DC infiltration and maturation, along with downregulated co-stimulatory molecules (CD40, CD80, CD86) in lung tissues. Differential gene analysis identified 26 differentially expressed DC-related genes implicated in DC proliferation, migration, and inflammatory responses. KEGG analysis revealed their close association with key immune pathways. The PPI network delineated two modules, with the top six genes in the pivotal cluster 1 (Ccl4, Il6, Ccl3, Ptgs2, Il 1α, Il7) being significantly downregulated in FcγRI-KO mice. A ceRNA network encompassing 12 miRNAs and 37 lncRNAs regulating four key genes (Ptgs2, Il1α, Il6, Il7) was also constructed.
Conclusions
In C. muridarum respiratory infections, FcγRI facilitates DC infiltration and maturation, upregulates six pro-inflammatory genes (Ccl4, Il6, Ccl3, Ptgs2, Il1α, Il7), and exhibits a pro-inflammatory role. A key ceRNA network was formulated to unravel the underlying molecular mechanisms.
{"title":"FcγRI plays a pro-inflammatory role in the immune response to Chlamydia respiratory infection by upregulating dendritic cell-related genes","authors":"Ruoyuan Sun , Jinxi Yu , Zeyang Zou , Shuaini Yang , Yuqing Tuo , Lu Tan , Hong Zhang , Longhao Sun , Hong Bai","doi":"10.1016/j.intimp.2024.113943","DOIUrl":"10.1016/j.intimp.2024.113943","url":null,"abstract":"<div><h3>Background</h3><div>FcγRI, a pivotal cell surface receptor, is implicated in diverse immune responses and is ubiquitously expressed on numerous immune cells. However, its role in intracellular bacterial infections remains understudied.</div></div><div><h3>Methods</h3><div>Wild-type (WT) and FcγRI knockout (<em>FcγRI</em>-KO) mice were inoculated intranasally with a specific dose of <em>C. muridarum</em>. Lung tissues were harvested for transcriptome sequencing, and flow cytometry was employed to validate bioinformatics immune infiltration analysis. Differentially expressed DC-associated genes were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses to elucidate their functions during infection. A PPI network was constructed to pinpoint crucial genes, and qPCR was utilized to confirm their expression changes. Additionally, we compared body weight, lung Chlamydia load, and pathological alterations between WT and <em>FcγRI</em>-KO mice post-infection to assess the effect of <em>FcγRI</em> on inflammation via gene regulation. Lastly, an mRNA-miRNA-lncRNA network was formulated to further probe the molecular mechanisms of FcγRI in <em>C. muridarum</em> infection.</div></div><div><h3>Results</h3><div>Post-<em>C. muridarum</em> infection, <em>FcγRI</em>-KO mice exhibited a notable decrease in DC infiltration and maturation, along with downregulated co-stimulatory molecules (CD40, CD80, CD86) in lung tissues. Differential gene analysis identified 26 differentially expressed DC-related genes implicated in DC proliferation, migration, and inflammatory responses. KEGG analysis revealed their close association with key immune pathways. The PPI network delineated two modules, with the top six genes in the pivotal cluster 1 (<em>Ccl4, Il6, Ccl3, Ptgs2, Il 1α, Il7</em>) being significantly downregulated in <em>FcγRI</em>-KO mice. A ceRNA network encompassing 12 miRNAs and 37 lncRNAs regulating four key genes (<em>Ptgs2, Il1α, Il6, Il7</em>) was also constructed.</div></div><div><h3>Conclusions</h3><div>In <em>C. muridarum</em> respiratory infections, FcγRI facilitates DC infiltration and maturation, upregulates six pro-inflammatory genes (<em>Ccl4, Il6, Ccl3, Ptgs2, Il1α, Il7</em>), and exhibits a pro-inflammatory role. A key ceRNA network was formulated to unravel the underlying molecular mechanisms.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113943"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.intimp.2024.113992
Arthur Gomes de Andrade , Shayenne Eduarda Ramos Vanderley , Lorrane de Farias Marques , Fernanda Silva Almeida , Luiz Henrique Agra Cavalcante-Silva , Tatjana Souza Lima Keesen
Obesity is a chronic inflammatory disease that affects more than 1 billion people worldwide and is associated with various metabolic and physiological dysfunctions, directly impacting the dynamics of the immune response, partly due to elevated leptin levels. Leptin is an important peptide hormone that regulates neuroendocrine function and energy homeostasis, with its blood levels reflecting energy reserves, fat mass, or energy deprivation. This hormone also plays a fundamental role in regulating immune function, including the activity of NK cells, which are essential components in antiviral and antitumor activity. In obese individuals, leptin resistance is commonly established, however, NK cells and other immune components remain responsive to this hormone. So far, leptin has demonstrated paradoxical activities of these cells, often associated with a dysfunctional profile when associated with obesity. The excessive fat is usually related to metabolic remodeling in NK cells, resulting in compromised antitumor responses due to reduced cytotoxic capacity and decreased expression of cytokines important for these defense mechanisms, such as IFN-γ. Therefore, this review approaches a better understanding of the immunoendocrine interactions between leptin and NK cells in the context of obesity.
{"title":"Leptin, NK cells, and the weight of immunity: Insights into obesity","authors":"Arthur Gomes de Andrade , Shayenne Eduarda Ramos Vanderley , Lorrane de Farias Marques , Fernanda Silva Almeida , Luiz Henrique Agra Cavalcante-Silva , Tatjana Souza Lima Keesen","doi":"10.1016/j.intimp.2024.113992","DOIUrl":"10.1016/j.intimp.2024.113992","url":null,"abstract":"<div><div>Obesity is a chronic inflammatory disease that affects more than 1 billion people worldwide and is associated with various metabolic and physiological dysfunctions, directly impacting the dynamics of the immune response, partly due to elevated leptin levels. Leptin is an important peptide hormone that regulates neuroendocrine function and energy homeostasis, with its blood levels reflecting energy reserves, fat mass, or energy deprivation. This hormone also plays a fundamental role in regulating immune function, including the activity of NK cells, which are essential components in antiviral and antitumor activity. In obese individuals, leptin resistance is commonly established, however, NK cells and other immune components remain responsive to this hormone. So far, leptin has demonstrated paradoxical activities of these cells, often associated with a dysfunctional profile when associated with obesity. The excessive fat is usually related to metabolic remodeling in NK cells, resulting in compromised antitumor responses due to reduced cytotoxic capacity and decreased expression of cytokines important for these defense mechanisms, such as IFN-γ. Therefore, this review approaches a better understanding of the immunoendocrine interactions between leptin and NK cells in the context of obesity.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113992"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sepsis is the leading cause of death among critically ill patients in clinical practice, making it urgent to reduce its incidence and mortality rates. In sepsis, macrophage dysfunction often worsens and complicates the condition. M1 and M2 macrophages, two distinct types, contribute to pro-inflammatory and anti-inflammatory effects, respectively. An imbalance between them is a major cause of sepsis. The aim of this study was to explore the potential of a differential metabolite between M1 and M2 macrophages in mitigating septic colonic injury via multiomics in combination with clinical data and animal experiments. Using nontargeted metabolomics analysis, we found that Kynurenic acid (KYNA), a metabolite of tryptophan metabolism, was significantly upregulated in the supernatant of M2 macrophages. Furthermore, we discovered that the level of KYNA was significantly decreased in sepsis in both human and mouse serum and was negatively correlated with inflammatory factor levels. In vivo experiments demonstrated that KYNA can effectively alleviate septic colon injury and reduce inflammatory factor levels in mice, indicating that KYNA plays a very important protective role in sepsis. Mechanistically, KYNA promotes the transition of M1 macrophages to M2 macrophages by inhibiting the NF-κB signaling pathway and alleviates septic colonic injury through the PPARγ/NF-κB axis. This article reveals that KYNA, a differentially abundant metabolite between M1 and M2 macrophages, can become a new strategy for alleviating septic colon injury.
{"title":"The tryptophan metabolite kynurenic acid ameliorates septic colonic injury through activation of the PPARγ signaling pathway.","authors":"Fei Wang, Meng Zhang, Liping Yin, Ziyang Zhou, Ziyao Peng, Wenweiran Li, Hui Chen, Guohong Yu, Jianguo Tang","doi":"10.1016/j.intimp.2024.113651","DOIUrl":"10.1016/j.intimp.2024.113651","url":null,"abstract":"<p><p>Sepsis is the leading cause of death among critically ill patients in clinical practice, making it urgent to reduce its incidence and mortality rates. In sepsis, macrophage dysfunction often worsens and complicates the condition. M1 and M2 macrophages, two distinct types, contribute to pro-inflammatory and anti-inflammatory effects, respectively. An imbalance between them is a major cause of sepsis. The aim of this study was to explore the potential of a differential metabolite between M1 and M2 macrophages in mitigating septic colonic injury via multiomics in combination with clinical data and animal experiments. Using nontargeted metabolomics analysis, we found that Kynurenic acid (KYNA), a metabolite of tryptophan metabolism, was significantly upregulated in the supernatant of M2 macrophages. Furthermore, we discovered that the level of KYNA was significantly decreased in sepsis in both human and mouse serum and was negatively correlated with inflammatory factor levels. In vivo experiments demonstrated that KYNA can effectively alleviate septic colon injury and reduce inflammatory factor levels in mice, indicating that KYNA plays a very important protective role in sepsis. Mechanistically, KYNA promotes the transition of M1 macrophages to M2 macrophages by inhibiting the NF-κB signaling pathway and alleviates septic colonic injury through the PPARγ/NF-κB axis. This article reveals that KYNA, a differentially abundant metabolite between M1 and M2 macrophages, can become a new strategy for alleviating septic colon injury.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"113651"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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