Journal of Innate Immunity最新文献

{"title":"Acinetobacter baumannii clinical isolates resist complement-mediated lysis by inhibiting the complement cascade and improperly depositing MAC.","authors":"Michal Magda, Wendy Boschloo, Serena Bettoni, Derek Fairley, Thomas A Russo, Christian G Giske, Chaitanya Tellapragada, Suzan H M Rooijakkers, Kristian Riesbeck, Anna M Blom","doi":"10.1159/000543664","DOIUrl":"https://doi.org/10.1159/000543664","url":null,"abstract":"<p><p>Acinetobacter baumannii is a gram-negative opportunistic bacterium that causes life-threatening infections in immunocompromised hosts. The World Health Organization (WHO) recognizes the high mortality and increasing antimicrobial resistance of A. baumannii and calls for new treatment options. The complement system is a critical mechanism of innate immunity that protects the human body from bacterial infections. Complement activation leads to the deposition of the membrane attack complex (MAC), which can directly lyse gram-negative bacteria. However, A. baumannii has developed evasion mechanisms to protect itself from complement. Here, we examined clinical isolates of A. baumannii and found 11 isolates with MAC deposition and 5 isolates without deposition. Trypsinization of MAC-positive isolates significantly reduced MAC, indicating incorrect insertion, consistent with a lack of lysis of these strains. MAC-negative isolates inhibited alternative pathway activation and were significantly more serum-resistant. These strains were also more virulent in a Galleria mellonella infection model. Whole genome sequencing revealed that MAC-negative isolates carried more virulence genes, and both MAC-negative and MAC-positive A. baumannii significantly differed in capsule type. Importantly, a correlation was observed between complement inhibition and capsule type (e.g., capsule locus KL171) of MAC-negative bacteria, while the capsule type (e.g., KL230) of MAC-positive A. baumannii was associated with increased sensitivity to MAC-mediated lysis. Thus, our findings suggest a relationship between capsule type, complement resistance, and host virulence in A. baumannii.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"1-20"},"PeriodicalIF":4.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023805","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":"RNA viruses, TLRs, and cytokines: the perfect storm?","authors":"Sophia K Stegeman, Olena Kourko, Heather Amsden, Isabella E Pellizzari Delano, John E Mamatis, Madison Roth, Che C Colpitts, Katrina Gee","doi":"10.1159/000543608","DOIUrl":"https://doi.org/10.1159/000543608","url":null,"abstract":"<p><strong>Background: </strong>The interactions between virus and the host immune response are nuanced and intricate. The cytokine response arguably plays a central role in dictating the outcome of virus infection, balancing inflammation and healing, which is crucial to resolving infection without destructive immunopathologies.</p><p><strong>Summary: </strong>Early innate immune responses are key to the generation of a beneficial or detrimental immune response. These initial responses are regulated by a plethora of surface bound, endosomal, and cytoplasmic innate immune receptors known as pattern recognition receptors. Of these, the Toll like receptors (TLRs) play an important role in the induction of cytokines during virus infection. Recognizing pathogen-associated molecular patterns (PAMPs) such as viral proteins and/or nucleotide sequences, the TLRs act as sentinels for the initiation and propagation of immune responses.</p><p><strong>Key messages: </strong>TLRs are important receptors for initiating the innate response to single-stranded RNA (ssRNA) viruses like influenza A virus (IAV), severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1), SARS-CoV-2, Middle East respiratory syndrome coronavirus (MERS-CoV), dengue virus and Ebola virus. Infection with these viruses is also associated with aberrant expression of proinflammatory cytokines that contribute to a harmful cytokine storm response. Herein we discuss the connections between these ssRNA viruses, cytokine storm, and the roles for TLRs.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"1-39"},"PeriodicalIF":4.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006758","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":"5-methoxytryptophan protects against toll-like receptor 2 mediated renal tissue inflammation and fibrosis in a murine unilateral ureteral obstruction model.","authors":"Jing-Yiing Wu, Guan-Lin Lee, Yu-Fan Chueh, Cheng-Chin Kuo, Yu-Juei Hsu, Kenneth K Wu","doi":"10.1159/000543275","DOIUrl":"https://doi.org/10.1159/000543275","url":null,"abstract":"<p><strong>Introduction: </strong>5-methoxytryptophan (5-MTP) is an anti-inflammatory metabolite. Several recent reports indicate that 5-MTP protects against post-injury tissue fibrosis. It was unclear how 5-MTP controls tissue fibrosis. We postulated that 5-MTP attenuates renal interstitial fibrosis by blocking toll-like receptor 2 (TLR2) and transforming growth factor β (TGFβ) signaling pathways.</p><p><strong>Methods: </strong>The effect of 5-MTP on renal fibrosis was evaluated by pretreatment of wild-type UUO mice with intraperitoneal administration of 5-MTP. To determine whether 5-MTP attenuates fibrosis by inhibiting TLR2 and TGFβ signaling pathways, we evaluated the effect of 5-MTP on TLR2-induced fibroblast phenotypic switch in NRK-49F fibroblasts and TLR2 and TGFβ signaling pathways in human proximal tubular epithelial cells (HPTEC) and RAW264.7 macrophages stimulated with Pam3CSK4 (Pam3) or TGFβ1.</p><p><strong>Results: </strong>UUO-induced renal fibrosis was abrogated in tlr2-/- mice consistent with a crucial role of TLR2 in UUO-induced renal fibrosis. UUO-induced macrophage infiltration and pro-fibrotic cytokine production in renal tissues were suppressed by tlr2 knockout. 5-MTP attenuated renal tissue fibrosis accompanied by reduction of macrophage infiltration and IL-6 and TGFβ levels. 5-MTP inhibits TLR2 upregulation and blocks TLR2-MyD88-TRAF6 signaling pathway in macrophages. Furthermore, 5-MTP blocked Pam3- and TGFβ1-induced phenotypic switch of NRK-49F to myofibroblasts and inhibited Pam3- and TGFβ1-induced signaling pathways in HPTECs and RAW264.7 cells.</p><p><strong>Conclusion: </strong>5-MTP effectively protects against UUO-induced renal interstitial fibrosis by blocking TLR2 and TGFβ signaling pathways.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"1-25"},"PeriodicalIF":4.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949968","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":"Liver X Receptors and Inflammatory-Induced C/EBPβ Selectively Cooperate to Control CD38 Transcription.","authors":"Estibaliz Glaría, Pol Rodríguez Martínez, Joan Font-Díaz, Juan Vladimir De la Rosa, Antonio Castrillo, Dylan J Crawshaw, Jose Manuel Vidal Taboada, Josep Saura, Jonathan Matalonga, Eduardo Nunes Chini, Carme Caelles, Annabel F Valledor","doi":"10.1159/000543274","DOIUrl":"10.1159/000543274","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Macrophages abundantly express liver X receptors (LXRs), which are ligand-dependent transcription factors and sensors of several cholesterol metabolites. In response to agonists, LXRs promote the expression of key lipid homeostasis regulators. Cross talk between LXRs and inflammatory signals exists in a cell type- and gene-specific manner. A common feature in the macrophage response to inflammatory mediators is the induction of CCAAT/enhancer-binding protein beta (C/EBPβ), a master transcriptional regulator and lineage-determining transcription factor in monocytes/macrophages.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Quantitative real-time PCR in control and C/EBPβ-deficient macrophages was used to explore the role of C/EBPβ in the cross talk between inflammatory mediators and the macrophage response to pharmacological LXR activation. The functional interaction between C/EBPβ and LXRs on selected genomic regions was further characterized by chromatin-immunoprecipitation (ChIP) and gene reporter studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Whereas inflammatory signaling repressed several LXR-regulated genes involved in lipid metabolism, these effects were conserved after deletion of C/EBPβ. In contrast, inflammatory mediators and LXRs synergistically induced the expression of the multifunctional protein CD38 in a C/EBPβ-dependent manner. C/EBPβ and LXRs bound to several regions with enhancer activity upstream and within the mouse Cd38 gene and their functional cooperation in macrophages required intact binding sites for LXR and C/EBPβ.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;This study reveals positive cross talk between C/EBPβ and LXRs during the macrophage inflammatory response, which selectively impacts CD38 expression.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Macrophages abundantly express liver X receptors (LXRs), which are ligand-dependent transcription factors and sensors of several cholesterol metabolites. In response to agonists, LXRs promote the expression of key lipid homeostasis regulators. Cross talk between LXRs and inflammatory signals exists in a cell type- and gene-specific manner. A common feature in the macrophage response to inflammatory mediators is the induction of CCAAT/enhancer-binding protein beta (C/EBPβ), a master transcriptional regulator and lineage-determining transcription factor in monocytes/macrophages.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Quantitative real-time PCR in control and C/EBPβ-deficient macrophages was used to explore the role of C/EBPβ in the cross talk between inflammatory mediators and the macrophage response to pharmacological LXR activation. The functional interaction between C/EBPβ and LXRs on selected genomic regions was further characterized by chromatin-immunoprecipitation (ChIP) and gene reporter studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Whereas inflammatory signaling repressed several LXR-regulated genes involved in lipid metabolism, these effects were conserved after deletion of C/EBPβ.","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"56-77"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864434","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":"Human Blood Non-Classical/Classical Monocyte Cells Are Heterogeneously Presented in Severe COVID-19 and Correlate with Disease Activity.","authors":"Danhong Zhou, Yu Shen, Suxian Jing, Dong Qiu, Yang Wang, Qiuxia Qu, Cheng Chen","doi":"10.1159/000542652","DOIUrl":"10.1159/000542652","url":null,"abstract":"<p><strong>Introduction: </strong>COVID-19 is highly heterogeneous, ranging from cases with mild disease with an almost asymptomatic carrier to severe cases, in which the disease evolves rapidly. A better understanding of monocyte response during SARS-CoV-2 infection would highlight potential biomarkers and establish other possible approaches for severe cases.</p><p><strong>Methods: </strong>The study group consisted of 32 COVID-19 patients and 18 health controls from June 2023 to March 2024. The COVID-19 patients were further classified as mild and severe illnesses based on World Health Organization (WHO) criteria. For flow cytometric analysis, 50 µL of peripheral blood and 1 µL of specific monoclonal antibodies were added to each cytometric tube for surface marker detection.</p><p><strong>Results: </strong>Here, the promising finding was that the blood non-classical/classical monocyte (NC/CL) subset was skewed toward NChighCLlow and NClowCLhigh clusters among the severe COVID-19 patients. The NChighCLlow cluster in severe COVID-19 displayed a distinct clinical phenotype, implying a higher 7-day disease progression rate (p = 0.019) and a worse 28-day survival (p = 0.026). Moreover, the secretion of IL-1β and IFN-γ was primarily attributed to CL subset in monocytes, while IL-6 was secreted mainly by NC subset.</p><p><strong>Conclusion: </strong>As supported, regarding cytokine profile in context of SARS-CoV-2 infection, it was identified that circulating NC cells are proinflammatory cells most related to regulatory cells, while CL subset displayed an effective capacity to virus. These findings have implications toward optimizing evaluation in severe COVID-19, and developing strategies that target altered balance of NC/CL cell subsets.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"1-9"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716142","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":"Macrophage Evolution during Progression of Hepatitis Virus B-Related Acute-on-Chronic Liver Failure.","authors":"Jiawei Rao, Dongmei Ye, Ao Ren, Wenjin He, Xuzhi Zhang, Pengrui Chen, Qian Jian, Zongli Fu, Ronghai Deng, Yixin Hu, Yifang Gao, Yi Ma","doi":"10.1159/000542946","DOIUrl":"10.1159/000542946","url":null,"abstract":"<p><strong>Introduction: </strong>Hepatitis B virus (HBV)-related liver diseases, including hepatitis, cirrhosis, and liver failure, seriously threaten human lives and health worldwide. Innate and adaptive immune cells are all thought to participate in HBV-related diseases. However, there is a lack of information on the comprehensive landscape of the immune microenvironment.</p><p><strong>Methods: </strong>In this study, single-cell ribonucleic acid sequencing was performed on liver samples obtained from patients diagnosed with hepatitis, cirrhosis, and acute-on-chronic liver failure, which were caused by HBV. Trajectory analysis was performed to analyze the evolution of cell subsets, and branch expression analysis modeling was applied to visualize the changes in gene expression during evolution.</p><p><strong>Results: </strong>Finally, there was a significant increase in adaptive immune cells in the hepatitis and cirrhosis groups, whereas more innate immune cells were observed in the liver failure group. Furthermore, we found that monocytes underwent remarkable transcriptomic changes into FABP5+ macrophages, promoting the degranulation and chemotaxis of neutrophils through RESISTIN signaling, and LGMN+ macrophages, with the sequential activation of antigen presentation and defense to pathogens through SPP1 signaling.</p><p><strong>Conclusion: </strong>Macrophages were revealed as central to the progression of acute-on-chronic liver failure as they regulated the activation or inhibition of other immune cells, which could help in developing an effective novel therapy.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"29-43"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11753795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785975","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":"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":4.7,"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":4.7,"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":"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":5.3,"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}