Journal of Innate Immunity最新文献

{"title":"Pore-Forming Toxin-Like Proteins in the Anti-Parasitoid Immune Response of Drosophila.","authors":"Lilla B Magyar, Edit Ábrahám, Zoltán Lipinszki, Rebecca L Tarnopol, Noah K Whiteman, Viktória Varga, Dan Hultmark, István Andó, Gyöngyi Cinege","doi":"10.1159/000542583","DOIUrl":"10.1159/000542583","url":null,"abstract":"<p><strong>Introduction: </strong>Species of the ananassae subgroup of Drosophilidae are highly resistant to parasitoid wasp infections. We have previously shown that the genes encoding cytolethal distending toxin B (CdtB) and the apoptosis inducing protein of 56 kDa (AIP56) were horizontally transferred to these fly species from prokaryotes and are now instrumental in the anti-parasitoid immune defense of Drosophila ananassae. Here we describe a new family of genes, which encode proteins with hemolysin E domains, heretofore only identified in prokaryotes. Hemolysin E proteins are pore-forming toxins, important virulence factors of bacteria.</p><p><strong>Methods: </strong>Bioinformatical, transcriptional, and protein expressional studies were used.</p><p><strong>Results: </strong>The hemolysin E-like genes have a scattered distribution among the genomes of species belonging to several different monophyletic lineages in the family Drosophilidae. We detected structural homology with the bacterial Hemolysin E toxins and showed that the origin of the D. ananassae hemolysin E-like genes (hl1-38) is consistent with prokaryotic horizontal gene transfer. These genes encode humoral factors, secreted into the hemolymph by the fat body and hemocytes. Their expression is induced solely by parasitoid infection and the proteins bind to the developing parasitoids.</p><p><strong>Conclusions: </strong>Hemolysin E-like proteins acquired by horizontal gene transfer and expressed by the primary immune organs may contribute to the elimination of parasitoids, as novel humoral factors in Drosophila innate immunity.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"10-28"},"PeriodicalIF":3.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769553","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}

{"title":"Does Adenosine Triphosphate via Purinergic Receptor Signalling Fuel Pulmonary Fibrosis?","authors":"Luke Forde, Debananda Gogoi, Rory Baird, Cormac McCarthy, Michael P Keane, Emer P Reeves, Emmet E McGrath","doi":"10.1159/000543083","DOIUrl":"10.1159/000543083","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Interstitial lung diseases (ILD) are poorly understood disorders characterised by diffuse damage to the lung parenchyma, with inflammation and fibrosis. Some manifest a progressive fibrotic phenotype with high fatality and limited treatment options, such as idiopathic pulmonary fibrosis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary: &lt;/strong&gt;The degree to which inflammation plays a role in fibrosis progression is unknown. However, wound healing and fibrosis are intricate processes influenced by various inflammatory factors. Extracellular nucleosides and nucleotides, including adenosine triphosphate, activate pro-inflammatory responses to innate immunity and are widely implicated in tissue fibrosis across different organs. The pro-inflammatory effects of extracellular nucleotides occur via P1 and P2 purinergic receptors, expressed across the lung and immune system, and have been implicated in various pulmonary diseases including pulmonary fibrosis. This review amalgamates available data on the complex role of P1 and P2 purinergic receptor signalling in pulmonary fibrosis and discusses perspectives for novel treatments.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Key messages: &lt;/strong&gt;Purinergic signalling plays a complex and pivotal role in pulmonary fibrosis, warranting further study. The intricate interplay between P1 and P2 receptor pathways necessitates a comprehensive approach to understand their collective impact. While evidence from preclinical models is promising, human studies are essential for further understanding of pulmonary fibrosis. Advances in receptor-specific agonists and antagonists provide novel avenues for research and may ultimately lead to new therapies for patients.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Interstitial lung diseases (ILD) are poorly understood disorders characterised by diffuse damage to the lung parenchyma, with inflammation and fibrosis. Some manifest a progressive fibrotic phenotype with high fatality and limited treatment options, such as idiopathic pulmonary fibrosis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary: &lt;/strong&gt;The degree to which inflammation plays a role in fibrosis progression is unknown. However, wound healing and fibrosis are intricate processes influenced by various inflammatory factors. Extracellular nucleosides and nucleotides, including adenosine triphosphate, activate pro-inflammatory responses to innate immunity and are widely implicated in tissue fibrosis across different organs. The pro-inflammatory effects of extracellular nucleotides occur via P1 and P2 purinergic receptors, expressed across the lung and immune system, and have been implicated in various pulmonary diseases including pulmonary fibrosis. This review amalgamates available data on the complex role of P1 and P2 purinergic receptor signalling in pulmonary fibrosis and discusses perspectives for novel treatments.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Key messages: &lt;/strong&gt;Purinergic signalling plays a complex and pivotal role in pulmonary fibrosis, warranting further study. The intricate","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"44-55"},"PeriodicalIF":3.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11779128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813592","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}

{"title":"Unraveling the Complex Nexus of Macrophage Metabolism, Periodontitis, and Associated Comorbidities.","authors":"Zihan Zhang, Yi Liu, Tian Yu, Zhen Liu","doi":"10.1159/000542531","DOIUrl":"10.1159/000542531","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Periodontitis is recognized as one of the most prevalent oral dysbiotic inflammatory diseases, ultimately leading to the irreversible destruction of periodontal tissues. Macrophages play a pivotal role in the development and progression of periodontitis, and the feasibility of targeting them therapeutically has been established. Since metabolic switching significantly contributes to macrophage regulation, conducting an in-depth review of macrophage metabolism in periodontitis may serve as the foundation for developing innovative treatments.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary: &lt;/strong&gt;This paper has been carefully reviewed to provide a comprehensive overview of the roles played by macrophages in periodontitis and associated comorbidities. Initially, detailed presentations on the metabolic reprogramming of macrophages, including glucose, lipid, and amino acid metabolism, were provided. Subsequently, dominating macrophage phenotype and metabolism under lipopolysaccharide (LPS) stimulation or during periodontitis were presented with emphasize on critical molecules involved. Furthermore, in recognition of the close association between periodontitis and several comorbidities, the interaction among macrophage metabolism, periodontitis, and related metabolic diseases, was thoroughly discussed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Key messages: &lt;/strong&gt;Through the examination of current research on macrophage metabolic reprogramming induced by periodontitis, this review provides potential immunometabolic therapeutic targets for the future and raises many important, yet unstudied, subjects for follow-up.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Periodontitis is recognized as one of the most prevalent oral dysbiotic inflammatory diseases, ultimately leading to the irreversible destruction of periodontal tissues. Macrophages play a pivotal role in the development and progression of periodontitis, and the feasibility of targeting them therapeutically has been established. Since metabolic switching significantly contributes to macrophage regulation, conducting an in-depth review of macrophage metabolism in periodontitis may serve as the foundation for developing innovative treatments.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary: &lt;/strong&gt;This paper has been carefully reviewed to provide a comprehensive overview of the roles played by macrophages in periodontitis and associated comorbidities. Initially, detailed presentations on the metabolic reprogramming of macrophages, including glucose, lipid, and amino acid metabolism, were provided. Subsequently, dominating macrophage phenotype and metabolism under lipopolysaccharide (LPS) stimulation or during periodontitis were presented with emphasize on critical molecules involved. Furthermore, in recognition of the close association between periodontitis and several comorbidities, the interaction among macrophage metabolism, periodontitis, and related metabolic diseases, was thoroughly discussed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Key messages: &lt;/strong&gt;Through the e","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"211-225"},"PeriodicalIF":3.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585956","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}

{"title":"Inhibition of WNK kinases in NK cells disrupts cellular osmoregulation and control of tumor metastasis.","authors":"Ji Sung Kim,John H Kehrl","doi":"10.1159/000540744","DOIUrl":"https://doi.org/10.1159/000540744","url":null,"abstract":"INTRODUCTIONThe serine/threonine With-No-Lysine (WNK) kinase family function in blood pressure control, electrolyte homeostasis, and cellular osmoregulation. These kinases and their downstream effectors are considered promising therapeutic targets in hypertension and stroke. However, the role of WNK kinases in immune cells remains poorly understood.METHODSUsing the small-molecule WNK kinase inhibitors WNK463 and WNK-IN-11, we investigated how WNK kinase inhibition affects natural killer (NK) cell physiology.RESULTSWNK kinase inhibition with WNK463 or WNK-IN-11 significantly decreased IL-2-activated NK-cell volume, motility, and cytolytic activity. Treatment of NK cells with these inhibitors induced autophagy by activating AMPK and inhibiting mTOR signaling. Moreover, WNK kinase inhibition increased phosphorylation of Akt and c-Myc by misaligning activity of activating kinases and inhibitory phosphatases. Treatment of tumor-bearing mice with WNK463 impaired tumor metastasis control by adoptively transferred NK cells.CONCLUSIONThe catalytic activity of WNK kinases has a critical role of multiple aspects of NK cell physiology and their pharmacologic inhibition negatively impacts NK cell function.","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":"2 1","pages":"1-24"},"PeriodicalIF":5.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250536","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}

{"title":"TLR10: An Intriguing Toll-Like Receptor with Many Unanswered Questions.","authors":"Carolina Rego Rodrigues, Yadu Balachandran, Gurpreet Kaur Aulakh, Baljit Singh","doi":"10.1159/000535523","DOIUrl":"10.1159/000535523","url":null,"abstract":"<p><strong>Background: </strong>Toll-like receptors (TLRs) are one of the first pattern recognition receptors found in the innate immune system. The TLR family has 12 members (TLR1-TLR9, TLR11-TLR13) in mice and 10 members (TLR1-TLR10) in humans, with TLR10 being the latest identified.</p><p><strong>Summary: </strong>Considerable research has been performed on TLRs; however, TLR10 is known as an orphan receptor for the lack of information on its signalling, role, and ligands. Even though there are recent studies pointing towards the potential TLR10 ligands, their function and signalling pathway are yet to be determined.</p><p><strong>Key messages: </strong>This review gives an insight into recent findings on TLR10's pro- and anti-inflammatory properties, with the goal of outlining existing results and indicating future research topics on this receptor.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"96-104"},"PeriodicalIF":3.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10861218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139512730","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}

{"title":"The Role of Neutrophil in COVID-19: Positive or Negative.","authors":"Na Rong, Xiaohui Wei, Jiangning Liu","doi":"10.1159/000535541","DOIUrl":"10.1159/000535541","url":null,"abstract":"<p><strong>Background: </strong>Neutrophils are the first line of defense against pathogens. They are divided into multiple subpopulations during development and kill pathogens through various mechanisms. Neutrophils are considered one of the markers of severe COVID-19.</p><p><strong>Summary: </strong>In-depth research has revealed that neutrophil subpopulations have multiple complex functions. Different subsets of neutrophils play an important role in the progression of COVID-19.</p><p><strong>Key messages: </strong>In this review, we provide a detailed overview of the developmental processes of neutrophils at different stages and their recruitment and activation after SARS-CoV-2 infection, aiming to elucidate the changes in neutrophil subpopulations, characteristics, and functions after infection and provide a reference for mechanistic research on neutrophil subpopulations in the context of SARS-CoV-2 infection. In addition, we have also summarized research progress on potential targeted drugs for neutrophil immunotherapy, hoping to provide information that aids the development of therapeutic drugs for the clinical treatment of critically ill COVID-19 patients.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"80-95"},"PeriodicalIF":3.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10861219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472323","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}

{"title":"Type I Interferon, Induced by Adenovirus or Adenoviral Vector Infection, Regulates the Cytokine Response to Lipopolysaccharide in a Macrophage Type-Specific Manner.","authors":"Mareike D Maler, Sophie Zwick, Carsten Kallfass, Peggy Engelhard, Hexin Shi, Laura Hellig, Pang Zhengyang, Annika Hardt, Gernot Zissel, Zsolt Ruzsics, Willi Jahnen-Dechent, Stefan F Martin, Peter Jess Nielsen, Daiana Stolz, Justyna Lopatecka, Sarah Bastyans, Bruce Beutler, Wolfgang W Schamel, György Fejer, Marina Alexandra Freudenberg","doi":"10.1159/000538282","DOIUrl":"10.1159/000538282","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;While TLR ligands derived from microbial flora and pathogens are important activators of the innate immune system, a variety of factors such as intracellular bacteria, viruses, and parasites can induce a state of hyperreactivity, causing a dysregulated and potentially life-threatening cytokine over-response upon TLR ligand exposure. Type I interferon (IFN-αβ) is a central mediator in the induction of hypersensitivity and is strongly expressed in splenic conventional dendritic cells (cDC) and marginal zone macrophages (MZM) when mice are infected with adenovirus. This study investigates the ability of adenoviral infection to influence the activation state of the immune system and underlines the importance of considering this state when planning the treatment of patients.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Infection with adenovirus-based vectors (Ad) or pretreatment with recombinant IFN-β was used as a model to study hypersensitivity to lipopolysaccharide (LPS) in mice, murine macrophages, and human blood samples. The TNF-α, IL-6, IFN-αβ, and IL-10 responses induced by LPS after pretreatment were measured. Mouse knockout models for MARCO, IFN-αβR, CD14, IRF3, and IRF7 were used to probe the mechanisms of the hypersensitive reaction.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We show that, similar to TNF-α and IL-6 but not IL-10, the induction of IFN-αβ by LPS increases strongly after Ad infection. This is true both in mice and in human blood samples ex vivo, suggesting that the regulatory mechanisms seen in the mouse are also present in humans. In mice, the scavenger receptor MARCO on IFN-αβ-producing cDC and splenic marginal zone macrophages is important for Ad uptake and subsequent cytokine overproduction by LPS. Interestingly, not all IFN-αβ-pretreated macrophage types exposed to LPS exhibit an enhanced TNF-α and IL-6 response. Pretreated alveolar macrophages and alveolar macrophage-like murine cell lines (MPI cells) show enhanced responses, while bone marrow-derived and peritoneal macrophages show a weaker response. This correlates with the respective absence or presence of the anti-inflammatory IL-10 response in these different macrophage types. In contrast, Ad or IFN-β pretreatment enhances the subsequent induction of IFN-αβ in all macrophage types. IRF3 is dispensable for the LPS-induced IFN-αβ overproduction in infected MPI cells and partly dispensable in infected mice, while IRF7 is required. The expression of the LPS co-receptor CD14 is important but not absolutely required for the elicitation of a TNF-α over-response to LPS in Ad-infected mice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Viral infections or application of virus-based vaccines induces type I interferon and can tip the balance of the innate immune system in the direction of hyperreactivity to a subsequent exposure to TLR ligands. The adenoviral model presented here is one example of how multiple factors, both environmental and genetic, affect the physiological r","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"226-247"},"PeriodicalIF":3.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11023693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288330","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}

{"title":"Lipoteichoic Acids Are Essential for Pneumococcal Colonization and Membrane Integrity.","authors":"Max Brendel, Thomas P Kohler, Janine V Neufend, Astrid Puppe, Nicolas Gisch, Sven Hammerschmidt","doi":"10.1159/000539934","DOIUrl":"10.1159/000539934","url":null,"abstract":"<p><strong>Introduction: </strong>The hydrophilic, polymeric chain of the lipoteichoic acid (LTA) of the Gram-positive pathobiont Streptococcus pneumoniae is covalently linked to the glycosylglycerolipid α-<sc>d</sc>-glucopyranosyl-(1,3)-diacylglycerol by the LTA ligase TacL, leading to its fixation in the cytoplasmic membrane. Pneumococcal LTA, sharing identical repeating units with the wall teichoic acids (WTA), is dispensable for normal growth but required for full virulence in invasive infections.</p><p><strong>Methods: </strong>Mutants deficient in TacL and complemented strains constructed were tested for their growth, resistance against oxidative stress, and susceptibility against antimicrobial peptides. Further, the membrane fluidity of pneumococci, their capability to adhere to lung epithelial cells, and virulence in a Galleria mellonella as well as intranasal mouse infection model were assessed.</p><p><strong>Results: </strong>In the present study, we indicate that LTA is already indispensable for pneumococcal adherence to human nasopharyngeal cells and colonization in an intranasal mouse infection model. Mutants deficient for TacL did not show morphological defects. However, our analysis of pneumococcal membranes in different serotypes showed an altered membrane fluidity and surface protein abundance of lipoproteins in mutants deficient for LTA but not WTA. These mutants had a decreased membrane fluidity, exhibited higher amounts of lipoproteins, and showed an increased susceptibility to antimicrobial peptides. In complemented mutant strains, this defect was fully restored.</p><p><strong>Conclusion: </strong>Taken together, LTA is crucial for colonization and required to effectively protect pneumococci from innate immune defence mechanisms by maintaining the membrane integrity.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"370-384"},"PeriodicalIF":3.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432111","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}

{"title":"Dysregulation of Toll-Like Receptor Signaling-Associated Gene Expression in X-Linked Agammaglobulinemia: Implications for Correlations Genotype-Phenotype and Disease Expression.","authors":"Marcelo Teocchi, Thaís de Andrade Eugênio, Lia Furlaneto Marega, Isabella Quinti, Maria Marluce Dos Santos Vilela","doi":"10.1159/000540082","DOIUrl":"10.1159/000540082","url":null,"abstract":"<p><strong>Introduction: </strong>In X-linked agammaglobulinemia (XLA), the diversity of BTK variants complicates the study of genotype-phenotype correlations. Since BTK negatively regulates toll-like receptors (TLRs), we investigated if distinct BTK mutation types selectively modulate TLR pathways, affecting disease expression.</p><p><strong>Methods: </strong>Using reverse transcription-quantitative polymerase chain reaction, we quantified ten TLR signaling-related genes in XLA patients with missense (n = 3) and nonsense (n = 5) BTK mutations and healthy controls (n = 17).</p><p><strong>Results: </strong>BTK, IRAK2, PIK3R4, REL, TFRC, and UBE2N were predominantly downregulated, while RIPK2, TLR3, TLR10, and TLR6 showed variable regulation. The missense XLA group exhibited significant downregulation of IRAK2, PIK3R4, REL, and TFRC and upregulation of TLR3 and/or TLR6.</p><p><strong>Conclusion: </strong>Hypo-expression of TLR3, TLR6, and TLR10 may increase susceptibility to infections, while hyper-expression might contribute to chronic inflammatory conditions like arthritis or inflammatory bowel disease. Our findings shed light on the important inflammatory component characteristic of some XLA patients, even under optimal therapeutic conditions.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"425-439"},"PeriodicalIF":3.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906731","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}

{"title":"MDM2 Is Essential to Maintain the Homeostasis of Epithelial Cells by Targeting p53.","authors":"Su Wang, Shufen Zhong, Ying Huang, Songling Zhu, Shuangfeng Chen, Ran Wang, Sonam Wangmo, Bo Peng, Houkun Lv, Jichao Yang, Liyan Ma, Zhiyang Ling, Yaguang Zhang, Pengfei Sui, Bing Sun","doi":"10.1159/000539824","DOIUrl":"10.1159/000539824","url":null,"abstract":"<p><strong>Introduction: </strong>MDM2 is known as the primary negative regulator of p53, and MDM2 promotes lung cancer fibrosis and lung injury through p53-dependent and p53-independent pathways. However, the mechanism by which MDM2 influences the pathogenesis of asthma is unknown. In this study, we investigated the function of MDM2 in lung epithelial cells in type 2 lung inflammation.</p><p><strong>Methods: </strong>We used type II alveolar epithelial cell-specific heterozygous knockout of Mdm2 mice to validate its function. Then papain-induced asthma model was established, and changes in inflammation were observed by measuring immunohistochemistry and flow cytometry analysis.</p><p><strong>Results: </strong>In this study, we knockdown the mouse Mdm2 gene in type 2 alveolar epithelial cells. We demonstrated that heterozygous Mdm2 gene-deleted mice were highly susceptible to protease allergen papain-induced pulmonary inflammation characterized by increased ILC2 numbers, IL-5 and IL-13 cytokine levels, and lung pathology. A mechanistic study showed that following the decreased expression of Mdm2 in lung epithelial cells and A549 cell line, p53 was overactivated, and the expression of its downstream genes p21, Puma, and Noxa was elevated, which resulted in apoptosis. After Mdm2 knockdown, the mRNA expression of inflammation-related gene IL-25, HMGB1, and TNF-α were increased, which further amplified the downstream ILC2 response and lung inflammation.</p><p><strong>Conclusion: </strong>These results indicate that Mdm2 maintains the homeostasis of lung epithelial cells by targeting P53 and regulates the function of lung epithelial cells under type 2 lung inflammation.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"397-412"},"PeriodicalIF":3.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971294","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}