Israel Ríos, Baltasar López-Navarro, Mónica Torres-Torresano, Blanca Soler Palacios, Miriam Simón-Fuentes, Ángeles Domínguez-Soto, Ittai B Muller, Gerrit Jansen, Ángel L Corbí, Amaya Puig-Kröger
{"title":"GSK3β Inhibition Prevents Macrophage Reprogramming by High-Dose Methotrexate.","authors":"Israel Ríos, Baltasar López-Navarro, Mónica Torres-Torresano, Blanca Soler Palacios, Miriam Simón-Fuentes, Ángeles Domínguez-Soto, Ittai B Muller, Gerrit Jansen, Ángel L Corbí, Amaya Puig-Kröger","doi":"10.1159/000526622","DOIUrl":"10.1159/000526622","url":null,"abstract":"<p><p>Methotrexate (MTX) is an antifolate drug used as a chemotherapeutic agent for acute lymphoblastic leukemia, where MTX improves patients' prognosis. Macrophage reprogramming is being increasingly assessed as an antitumor therapeutic strategy. However, and although MTX limits the pathogenic action of macrophages in chronic inflammatory diseases, its effects on tumor-promoting macrophages have not been previously explored. We now report that MTX shapes the transcriptional and functional profile of M-CSF-dependent human macrophages, whose transcriptome is highly enriched in the gene signature that defines pathogenic tumor-associated macrophages (\"large TAM\"). Specifically, MTX prompted the acquisition of the gene signature of antitumoral \"small TAM\" and skewed macrophages toward an IL-6high IFNβ1high IL-10low phenotype upon subsequent stimulation. Mechanistically, the MTX-induced macrophage reprogramming effect correlated with a reduction of the M-CSF receptor CSF1R expression and function, as well as a diminished expression of MAF and MAFB transcription factors, primary determinants of pro-tumoral macrophages whose transcriptional activity is dependent on GSK3β. Indeed, the ability of MTX to transcriptionally reprogram macrophages toward an antitumoral phenotype was abrogated by inhibition of GSK3β. Globally, our results establish MTX as a macrophage reprogramming drug and indicate that its ability to modulate macrophage polarization may also underlie its therapeutic benefits. Since GSK3β inhibition abrogates the reprogramming action of MTX, our results suggest that the GSK3β-MAFB/MAF axis constitutes a target for the macrophage-centered antitumor strategies.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40475966","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":"CLIPA7 Exhibits Pleiotropic Roles in the Anopheles gambiae Immune Response.","authors":"Renée Zakhia, Mike A Osta","doi":"10.1159/000526486","DOIUrl":"10.1159/000526486","url":null,"abstract":"<p><p>Clip domain serine proteases and clip domain serine protease homologs (cSPHs) are key components of serine protease cascades that drive the melanization response. Despite lacking catalytic activity, cSPHs play essential roles in regulating melanization, but the spectrum of functions they catalyze within and outside these cascades is not fully understood. Aside from their classical role as cofactors for PPO activation, we have previously revealed an unprecedented complexity in the function and molecular organization of these cSPHs in the immune response of the malaria vector Anopheles gambiae. Here, we add yet another dimension to the complex roles underpinning the contributions of cSPHs to mosquito immunity by showing that CLIPA7, a member of the expanded cSPH family, defines a novel branch within the cSPH network that is essential for the melanization of Escherichia coli but not Plasmodium ookinetes or Gram-positive bacteria. Despite its dispensability for the melanization of Gram-positive bacteria, we show that CLIPA7 is required for the clearance of systemic infections with Staphylococcus aureus. CLIPA7 is produced by hemocytes and associates with the surfaces of live E. coli and S. aureus cells in vivo as well as with those of melanized cells. Based on its RNAi phenotypes and its unique domain architecture among A. gambiae cSPHs including the presence of an RGD motif, we propose that CLIPA7 exhibits pleiotropic roles in mosquito immunity that extend beyond the regulation of melanization to microbial clearance.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40705397","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":"Interactions between Macrophages and Biofilm during Staphylococcus aureus-Associated Implant Infection: Difficulties and Solutions.","authors":"Mingzhang Li, Jinlong Yu, Geyong Guo, Hao Shen","doi":"10.1159/000530385","DOIUrl":"10.1159/000530385","url":null,"abstract":"<p><p>Staphylococcus aureus (S. aureus) biofilm is the major cause of failure of implant infection treatment that results in heavy social and economic burden on individuals, families, and communities. Planktonic S. aureus attaches to medical implant surfaces where it proliferates and is wrapped by extracellular polymeric substances, forming a solid and complex biofilm. This provides a stable environment for bacterial growth, infection maintenance, and diffusion and protects the bacteria from antimicrobial agents and the immune system of the host. Macrophages are an important component of the innate immune system and resist pathogen invasion and infection through phagocytosis, antigen presentation, and cytokine secretion. The persistence, spread, or clearance of infection is determined by interplay between macrophages and S. aureus in the implant infection microenvironment. In this review, we discuss the interactions between S. aureus biofilm and macrophages, including the effects of biofilm-related bacteria on the macrophage immune response, roles of myeloid-derived suppressor cells during biofilm infection, regulation of immune cell metabolic patterns by the biofilm environment, and immune evasion strategies adopted by the biofilm against macrophages. Finally, we summarize the current methods that support macrophage-mediated removal of biofilms and emphasize the importance of considering multi-dimensions and factors related to implant-associated infection such as immunity, metabolism, the host, and the pathogen when developing new treatments.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10315156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9797410","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}
Linbin Zhou, Bo Man Ho, Hoi Ying Emily Chan, Yan Tong, Lin Du, Jing Na He, Danny Siu-Chun Ng, Clement C Tham, Chi Pui Pang, Wai Kit Chu
{"title":"Emerging Roles of cGAS-STING Signaling in Mediating Ocular Inflammation.","authors":"Linbin Zhou, Bo Man Ho, Hoi Ying Emily Chan, Yan Tong, Lin Du, Jing Na He, Danny Siu-Chun Ng, Clement C Tham, Chi Pui Pang, Wai Kit Chu","doi":"10.1159/000533897","DOIUrl":"10.1159/000533897","url":null,"abstract":"<p><p>Cyclic GMP-AMP (cGAMP) synthase (cGAS), a sensor of cytosolic DNA, recognizes cytoplasmic nucleic acids to activate the innate immune responses via generation of the second messenger cGAMP and subsequent activation of the stimulator of interferon genes (STINGs). The cGAS-STING signaling has multiple immunologic and physiological functions in all human vital organs. It mediates protective innate immune defense against DNA-containing pathogen infection, confers intrinsic antitumor immunity via detecting tumor-derived DNA, and gives rise to autoimmune and inflammatory diseases upon aberrant activation by cytosolic leakage of self-genomic and mitochondrial DNA. Disruptions in these functions are associated with the pathophysiology of various immunologic and neurodegenerative diseases. Recent evidence indicates important roles of the cGAS-STING signaling in mediating inflammatory responses in ocular inflammatory and inflammation-associated diseases, such as keratitis, diabetic retinopathy, age-related macular degeneration, and uveitis. In this review, we summarize the recently emerging evidence of cGAS-STING signaling in mediating ocular inflammatory responses and affecting pathogenesis of these complex eye diseases. We attempt to provide insightful perspectives on future directions of investigating cGAS-STING signaling in ocular inflammation. Understanding how cGAS-STING signaling is modulated to mediate ocular inflammatory responses would allow future development of novel therapeutic strategies to treat ocular inflammation and autoimmunity.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10616671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41135672","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}
Monika Kustermann, Prasad Dasari, Ingrid Knape, Emma Keltsch, Jianing Liu, Silvia Pflüger, Wolfram Osen, Karlheinz Holzmann, Markus Huber-Lang, Klaus-Michael Debatin, Gudrun Strauss
{"title":"Adoptively Transferred in vitro-Generated Myeloid-Derived Suppressor Cells Improve T-Cell Function and Antigen-Specific Immunity after Traumatic Lung Injury.","authors":"Monika Kustermann, Prasad Dasari, Ingrid Knape, Emma Keltsch, Jianing Liu, Silvia Pflüger, Wolfram Osen, Karlheinz Holzmann, Markus Huber-Lang, Klaus-Michael Debatin, Gudrun Strauss","doi":"10.1159/000525088","DOIUrl":"10.1159/000525088","url":null,"abstract":"<p><p>Immune reactions after trauma are characterized by immediate activation of innate immunity and simultaneously downregulation of adaptive immunity leading to a misbalanced immunohomeostasis and immunosuppression of the injured host. Therefore, the susceptibility to secondary infections is strongly increased after trauma. Immune responses are regulated by a network of immune cells influencing each other and at the same time modifying their functions dependent on the inflammatory environment. Although myeloid-derived suppressor cells (MDSCs) are initially described as T-cell suppressors, their immunomodulatory capacity after trauma is mostly undefined. Therefore, in vitro-generated MDSCs were adoptively transferred into mice after blunt chest trauma (TxT). A single MDSC treatment-induced splenic T-cell expansion decreased apoptosis sensitivity and improved proliferation in the absence of T-cell exhaustion until 2 weeks after trauma. MDSC treatment had a long-lasting effect on the genomic landscape of CD4+ T cells by upregulating primarily Th2-associated genes. Remarkably, immune-activating functions of MDSCs supported the ability of TxT mice to respond to post-traumatic secondary antigen challenge. Secondary insults were mimicked by immunizing MDSC-treated TxT mice with ovalbumin (OVA), followed by OVA restimulation in vitro. MDSC treatment significantly increased the frequency of OVA-specific T cells, enhanced their Th1/Th2 cytokine expression, and induced upregulation of cytolytic molecules finally improving OVA-specific cytotoxicity. Overall, we could show that therapeutic MDSC treatment after TxT improves post-traumatic T-cell functions, which might enable the traumatic host to counterbalance trauma-induced immunoparalysis.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47185637","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}
Kai-Chen Wu, Nicholas D Condon, Timothy A Hill, Robert C Reid, David P Fairlie, Junxian Lim
{"title":"Ras-Related Protein Rab5a Regulates Complement C5a Receptor Trafficking, Chemotaxis, and Chemokine Secretion in Human Macrophages.","authors":"Kai-Chen Wu, Nicholas D Condon, Timothy A Hill, Robert C Reid, David P Fairlie, Junxian Lim","doi":"10.1159/000530012","DOIUrl":"10.1159/000530012","url":null,"abstract":"<p><p>Complement activation and Rab GTPase trafficking are commonly observed in inflammatory responses. Recruitment of innate immune cells to sites of infection or injury and secretion of inflammatory chemokines are promoted by complement component 5a (C5a) that activates the cell surface protein C5a receptor1 (C5aR1). Persistent activation can lead to a myriad of inflammatory and autoimmune diseases. Here, we demonstrate that the mechanism of C5a induced chemotaxis of human monocyte-derived macrophages (HMDMs) and their secretion of inflammatory chemokines are controlled by Rab5a. We find that C5a activation of the G protein coupled receptor C5aR1 expressed on the surface of HMDMs, recruits β-arrestin2 via Rab5a trafficking, then activates downstream phosphatidylinositol 3-kinase (PI3K)/Akt signaling that culminates in chemotaxis and secretion of pro-inflammatory chemokines from HMDMs. High-resolution lattice light-sheet microscopy on live cells showed that C5a activates C5aR1-GFP internalization and colocalization with Rab5a-tdTomato but not with dominant negative mutant Rab5a-S34N-tdTomato in HEK293 cells. We found that Rab5a is significantly upregulated in differentiated HMDMs and internalization of C5aR1 is dependent on Rab5a. Interestingly, while knockdown of Rab5a inhibited C5aR1-mediated Akt phosphorylation, it did not affect C5aR1-mediated ERK1/2 phosphorylation or intracellular calcium mobilization in HMDMs. Functional analysis using transwell migration and µ-slide chemotaxis assays indicated that Rab5a regulates C5a-induced chemotaxis of HMDMs. Further, C5aR1 was found to mediate interaction of Rab5a with β-arrestin2 but not with G proteins in HMDMs. Furthermore, C5a-induced secretion of pro-inflammatory chemokines (CCL2, CCL3) from HMDMs was attenuated by Rab5a or β-arrestin2 knockdown or by pharmacological inhibition with a C5aR1 antagonist or a PI3K inhibitor. These findings reveal a C5a-C5aR1-β-arrestin2-Rab5a-PI3K signaling pathway that regulates chemotaxis and pro-inflammatory chemokine secretion in HMDMs and suggests new ways of selectively modulating C5a-induced inflammatory outputs.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10105068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9307960","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}
Jian Lin, Zhanjun Lu, Gengfeng Li, Cui Zhang, Huiying Lu, Sheng Gao, Ruixin Zhu, Hailiang Huang, Konrad Aden, Jianhua Wang, Yingzi Cong, Huili Wu, Zhanju Liu
{"title":"MCPIP-1-Mediated Immunosuppression of Neutrophils Exacerbates Acute Bacterial Peritonitis and Liver Injury.","authors":"Jian Lin, Zhanjun Lu, Gengfeng Li, Cui Zhang, Huiying Lu, Sheng Gao, Ruixin Zhu, Hailiang Huang, Konrad Aden, Jianhua Wang, Yingzi Cong, Huili Wu, Zhanju Liu","doi":"10.1159/000526784","DOIUrl":"10.1159/000526784","url":null,"abstract":"<p><p>Monocyte chemotactic protein-1-induced protein-1 (MCPIP-1) is highly expressed in activated immune cells and negatively regulates immune responses, while the mechanisms underlying the immunoregulation of neutrophils in acute bacterial infection and liver injury remain elusive. Here, we examined the role of MCPIP-1 in regulating neutrophil functions during acute bacterial peritonitis and liver injury. Mice with myeloid cell-specific overexpression (McpipMye-tg) or knockout (McpipΔMye) of MCPIP-1 were generated. We found that reactive oxygen species and myeloperoxidase production, formation of neutrophil extracellular traps, and migratory capacity were deficient in McpipMye-tg neutrophils but enhanced in McpipΔMye neutrophils. The recruitment of neutrophils and pathogen clearance were markedly suppressed in McpipMye-tg mice following intraperitoneal infection with Salmonella typhimurium while intensified in McpipΔMye mice. Severe acute S. typhimurium-infected peritonitis and liver injury occurred in McpipMye-tg mice but were alleviated in McpipΔMye mice. RNA sequencing, RNA-binding protein immunoprecipitation and qPCR analysis revealed that MCPIP-1 downregulated the protective functions of neutrophils via degrading the mRNA of cold inducible RNA-binding protein. Consistently, MCPIP-1 was highly expressed in neutrophils of patients with acute infectious diseases, especially in those with liver injury. Collectively, we uncover that MCPIP-1 negatively regulates the antibacterial capacities of neutrophils, leading to exacerbating severe acute bacterial peritonitis and liver injury. It may serve as a candidate target for maintaining neutrophil homeostasis to control acute infectious diseases.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40564812","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}
Grant R Campbell, Pratima Rawat, Stephen A Spector
{"title":"Pacritinib Inhibition of IRAK1 Blocks Aberrant TLR8 Signalling by SARS-CoV-2 and HIV-1-Derived RNA.","authors":"Grant R Campbell, Pratima Rawat, Stephen A Spector","doi":"10.1159/000525292","DOIUrl":"10.1159/000525292","url":null,"abstract":"<p><p>Macrophages promote an early host response to infection by releasing pro-inflammatory cytokines such as interleukin (IL) 1β (IL-1β), tumour necrosis factor (TNF), and IL-6. One of the mechanisms through which cells sense pathogenic microorganisms is through Toll-like receptors (TLRs). IL-1 receptor-associated kinase (IRAK) 1, IRAK2, IRAK3, and IRAK4 are integral to TLR and IL-1 receptor signalling pathways. Recent studies suggest a role for aberrant TLR8 and NLRP3 inflammasome activation during both COVID-19 and HIV-1 infection. Here, we show that pacritinib inhibits the TLR8-dependent pro-inflammatory cytokine response elicited by GU-rich single-stranded RNA derived from SARS-CoV-2 and HIV-1. Using genetic and pharmacologic inhibition, we demonstrate that pacritinib inhibits IRAK1 phosphorylation and ubiquitination which then inhibits the recruitment of the TAK1 complex to IRAK1, thus inhibiting the activation of downstream signalling and the production of pro-inflammatory cytokines.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9277712","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}
Xiaogang Luo, Ruihua Ji, Qianru Liu, Xiaoxue Xiao, Wengang Song, Huazhang An, Yingke Li, Jun Zhou
{"title":"Ste20-Like Kinase TAOK1 Positively Regulates Antiviral Responses by Controlling the TBK1-IRF3 Signaling Axis.","authors":"Xiaogang Luo, Ruihua Ji, Qianru Liu, Xiaoxue Xiao, Wengang Song, Huazhang An, Yingke Li, Jun Zhou","doi":"10.1159/000526324","DOIUrl":"10.1159/000526324","url":null,"abstract":"<p><p>The cytosolic viral nucleic acid-sensing pathways converge on the protein kinase TANK-binding kinase 1 (TBK1) and the transcription factor interferon (IFN)-regulatory factor 3 (IRF3) to induce type I IFN production and antiviral immune responses. However, the mechanism that triggers the binding of TBK1 and IRF3 after virus infection remains not fully understood. Here, we identified that thousand and one kinase 1 (TAOK1), a Ste20-like kinase, positively regulated virus-induced antiviral immune responses by controlling the TBK1-IRF3 signaling axis. Virus invasion downregulated the expression of TAOK1. TAOK1 deficiency resulted in decreased nucleic acid-mediated type I IFN production and increased susceptibility to virus infection. TAOK1 was constitutively associated with TBK1 independently of the mitochondrial antiviral signaling protein MAVS. TAOK1 promoted IRF3 activation by enhancing TBK1-IRF3 complex formation. TAOK1 enhanced virus-induced type I IFN production in a kinase activity-dependent manner. Viral infection induced TAOK1 to bind with dynein instead of microtubule-associated protein 4 (MAP4), leading to the trafficking of TBK1 to the perinuclear region to bind IRF3. Thus, the depolymerization of microtubule impaired virus-mediated IRF3 activation. Our results revealed that TAOK1 functioned as a new interaction partner and regulated antiviral signaling via trafficking TBK1 along microtubules to bind IRF3. These findings provided novel insights into the function of TAOK1 in the antiviral innate immune response and its related clinical significance.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/69/7e/jin-0015-0380.PMC10015707.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9116580","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}
Divya Narayanan, Nagaraj Moily, Hayley A McQuilten, Katherine Kedzierska, Jason M Mackenzie, Lukasz Kedzierski, John K Fazakerley
{"title":"Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections.","authors":"Divya Narayanan, Nagaraj Moily, Hayley A McQuilten, Katherine Kedzierska, Jason M Mackenzie, Lukasz Kedzierski, John K Fazakerley","doi":"10.1159/000525291","DOIUrl":"10.1159/000525291","url":null,"abstract":"<p><p>Virus infections of the central nervous system (CNS) cause important diseases of humans and animals. As in other tissues, innate antiviral responses mediated by type I interferons (IFNs) are crucially important in controlling CNS virus infections. The maturity of neuronal populations is an established critical factor determining the outcome of CNS virus infection. Using primary cultures of mouse cortical neurons, we investigated the relationships between neuronal maturation, type I IFN responses, and the outcome of Semliki Forest virus infection. The virus replicated better, infected more cells, and produced higher titres of infectious viruses in immature neurons. Complete transcriptome analysis demonstrated that resting immature neurons have low transcriptional competence to mount antiviral responses. They had no detectable transcription of the genes Ddx58 and Ifih1, which encode key RNA virus cytoplasmic sensors RIG-I and MDA5, and very low expression of genes encoding key regulators of associated signalling pathways. Upon infection, immature neurons failed to mount an antiviral response as evidenced by their failure to produce chemokines, IFNs, and other cytokines. Treatment of immature neurons with exogenous IFNβ prior to infection resulted in antiviral responses and lower levels of virus replication and infectious virus production. In contrast, resting mature neurons generated a robust antiviral response. This was augmented by pretreatment with IFNβ. Infection of mature neurons derived from IFNAR-/- mice did not make an antiviral response and replicated virus to high levels.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40324505","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}