Innate Immune Signaling Pathways Research Articles

A molecular subtyping associated with the cGAS-STING pathway provides novel perspectives on the treatment of ulcerative colitis

Ulcerative colitis (UC) is characterized by an abnormal immune response, and the pathogenesis lacks clear understanding. The cGAS-STING pathway is an innate immune signaling pathway that plays a significant role in various pathophysiological processes. However, the role of the cGAS-STING pathway in UC remains largely unclear. In this study, we obtained transcriptome sequencing data from multiple publicly available databases. cGAS-STING related genes were obtained through literature search, and differentially expressed genes (DEGs) were analyzed using R package limma. Hub genes were identified through protein–protein interaction (PPI) network analysis and module construction. The ConsensuClusterPlus package was utilized to identify molecular subtypes based on hub genes. The therapeutic response, immune microenvironment, and biological pathways of subtypes were further investigated. A total of 18 DEGs were found in UC patients. We further identified IFI16, MB21D1 (CGAS), TMEM173 (STING) and TBK1 as the hub genes. These genes are highly expressed in UC. IFI16 exhibited the highest diagnostic value and predictive value for response to anti-TNF therapy. The expression level of IFI16 was higher in non-responders to anti-TNF therapy. Furthermore, a cluster analysis based on genes related to the cGAS-STING pathway revealed that patients with higher gene expression exhibited elevated immune burden and inflammation levels. This study is a pioneering analysis of cGAS-STING pathway-related genes in UC. These findings provide new insights for the diagnosis of UC and the prediction of therapeutic response.

JMJD2A promotes the development of castration-resistant prostate cancer by activating androgen receptor enhancer and inhibiting the cGAS-STING pathway.

Exploring targets for inhibiting androgen receptor (AR) activity is an effective strategy for suppressing the development of castration-resistant prostate cancer (CRPC). Upregulation of histone demethylase JMJD2A activity is an important factor in increasing AR expression in CRPC. Based on our research, we found that the binding affinity between JMJD2A and AR increases in CRPC, while the level of AR histone methylation decreases and the H3K27ac level increases in the AR enhancer region. Further investigations revealed that overexpression of the histone demethylase JMJD2A increased the binding affinity between JMJD2A and AR, decreased AR histone methylation levels, upregulated H3K27ac in the AR enhancer region, and increased AR activity. Conversely, knocking down JMJD2A effectively reversed these effects. Additionally, in CRPC, JMJD2A expression was upregulated, the tumor-intrinsic immune cGAS-STING signaling pathway was suppressed, the tumor microenvironment was altered, and AR expression was upregulated. However, both knocking down JMJD2A and inhibiting the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS-STING) signaling pathway reversed these effects. In summary, our study indicates that in CRPC, JMJD2A can directly bind to AR and activate residual AR enhancers through its demethylation activity, thereby promoting AR expression. Furthermore, upregulation of JMJD2A expression inhibits the innate immune cGAS-STING signaling pathway of the tumor, leading to a decrease in antitumor immune function, and further promoting AR expression.

The Chlamydia trachomatis Inc Tri1 interacts with TRAF7 to displace native TRAF7 interacting partners.

Chlamydia trachomatis is the leading cause of bacterial sexually transmitted infections in the USA and of preventable blindness worldwide. This obligate intracellular pathogen replicates within a membrane-bound inclusion, but how it acquires nutrients from the host while avoiding detection by the innate immune system is incompletely understood. C. trachomatis accomplishes this in part through the translocation of a unique set of effectors into the inclusion membrane, the inclusion membrane proteins (Incs). Incs are ideally positioned at the host-pathogen interface to reprogram host signaling by redirecting proteins or organelles to the inclusion. Using a combination of co-affinity purification, immunofluorescence confocal imaging, and proteomics, we characterize the interaction between an early-expressed Inc of unknown function, Tri1, and tumor necrosis factor receptor-associated factor 7 (TRAF7). TRAF7 is a multi-domain protein with a RING finger ubiquitin ligase domain and a C-terminal WD40 domain. TRAF7 regulates several innate immune signaling pathways associated with C. trachomatis infection and is mutated in a subset of tumors. We demonstrate that Tri1 and TRAF7 specifically interact during infection and that TRAF7 is recruited to the inclusion. We further show that the predicted coiled-coil domain of Tri1 is necessary to interact with the TRAF7 WD40 domain. Finally, we demonstrate that Tri1 displaces the native TRAF7 binding partners, mitogen-activated protein kinase kinase kinase 2 (MEKK2), and MEKK3. Together, our results suggest that by displacing TRAF7 native binding partners, Tri1 has the capacity to alter TRAF7 signaling during C. trachomatis infection.IMPORTANCEChlamydia trachomatis is the leading cause of bacterial sexually transmitted infections in the USA and preventable blindness worldwide. Although easily treated with antibiotics, the vast majority of infections are asymptomatic and therefore go untreated, leading to infertility and blindness. This obligate intracellular pathogen evades the immune response, which contributes to these outcomes. Here, we characterize the interaction between a C. trachomatis-secreted effector, Tri1, and a host protein involved in innate immune signaling, TRAF7. We identified host proteins that bind to TRAF7 and demonstrated that Tri1 can displace these proteins upon binding to TRAF7. Remarkably, the region of TRAF7 to which these host proteins bind is often mutated in a subset of human tumors. Our work suggests a mechanism by which Tri1 may alter TRAF7 signaling and has implications not only in the pathogenesis of C. trachomatis infections but also in understanding the role of TRAF7 in cancer.

The Therapeutic Target of IBD and the Mechanism of Dipyridamole in Treating IBD Explored by Geo Gene Chips, Network Pharmacology, and Molecular Docking.

Inflammatory Bowel Disease (IBD) is a refractory disease with repeated attacks, and there is no accurate treatment target at present. Dipyridamole, a phosphodiesterase (PDE) inhibitor, has been proven to be an effective treatment for IBD in a pilot study. This study explored the therapeutic target of IBD and the pharmacological mechanism of dipyridamole for the treatment of IBD. The candidate targets of dipyridamole were obtained by searching the pharmMapper online server and Swiss Target Prediction Database. The IBD-related targets were selected from four GEO chips and three databases, including Genecards, DisGeNET, and TTD database. A protein-protein interaction (PPI) network was constructed, and the core targets were identified according to the topological structure. KEGG and GO enrichment analysis and BioGPS location were performed. Finally, molecular docking was used to verify dipyridamole and the hub targets. We obtained 112 up-regulated genes and 157 down-regulated genes, as well as 105 composite targets of Dipyridamole-IBD. Through the PPI network analysis, we obtained the 7 hub targets, including SRC, EGFR, MAPK1, MAPK14, MAPK8, PTPN11, and LCK. The BioGPS showed that these genes were highly expressed in the immune system, digestive system, and endocrine system. In addition, the 7 hub targets had good intermolecular interactions with dipyridamole. The therapeutic effect of dipyridamole on IBD may involve immune system activation and regulation of inflammatory reactions involved in the regulation of extracellular matrix, perinuclear region of cytoplasm, protein kinase binding, and positive regulation of programmed cell death through cancer pathway (proteoglycans in cancer), lipid metabolism, Ras signaling pathway, MAPK signaling pathway, PI3K-AKT signaling pathway, Th17 cell differentiation, and other cellular and innate immune signaling pathways. This study predicted the therapeutic target of IBD and the molecular mechanism of dipyridamole in treating IBD, providing a new direction for the treatment of IBD and a theoretical basis for further research.

A closer look at mammalian antiviral condensates.

Several biomolecular condensates assemble in mammalian cells in response to viral infection. The most studied of these are stress granules (SGs), which have been proposed to promote antiviral innate immune signaling pathways, including the RLR-MAVS, the protein kinase R (PKR), and the OAS-RNase L pathways. However, recent studies have demonstrated that SGs either negatively regulate or do not impact antiviral signaling. Instead, the SG-nucleating protein, G3BP1, may function to perturb viral RNA biology by condensing viral RNA into viral-aggregated RNA condensates, thus explaining why viruses often antagonize G3BP1 or hijack its RNA condensing function. However, a recently identified condensate, termed double-stranded RNA-induced foci, promotes the activation of the PKR and OAS-RNase L antiviral pathways. In addition, SG-like condensates known as an RNase L-induced bodies (RLBs) have been observed during many viral infections, including SARS-CoV-2 and several flaviviruses. RLBs may function in promoting decay of cellular and viral RNA, as well as promoting ribosome-associated signaling pathways. Herein, we review these recent advances in the field of antiviral biomolecular condensates, and we provide perspective on the role of canonical SGs and G3BP1 during the antiviral response.

Activation of innate immunity selectively compromises mitochondrial complex I, proline oxidation, and flight activity in the major arbovirus vector Aedes aegypti.

Aedes aegypti females are natural vectors of important arboviruses such as dengue, zika, and yellow fever. Mosquitoes activate innate immune response signaling pathways upon infection, as a resistance mechanism to fight pathogens and limit their propagation. Despite the beneficial effects of immune activation for insect vectors, phenotypic costs ultimately affect their fitness. However, the underlying mechanisms that mediate these fitness costs remain poorly understood. Given the high energy required to mount a proper immune response, we hypothesized that systemic activation of innate immunity would impair flight muscle mitochondrial function, compromising tissue energy demand and flight activity. Here, we investigated the dynamic effects of activation of innate immunity by intra-thoracic zymosan injection on A. aegypti flight muscle mitochondrial metabolism. Zymosan injection significantly increased defensin A expression in fat bodies in a time-dependent manner that compromised flight activity. Although oxidant levels in flight muscle were hardly altered, ATP-linked respiratory rates driven by mitochondrial pyruvate+proline oxidation were significantly reduced at 24 h upon zymosan injection. Oxidative phosphorylation coupling was preserved regardless of innate immune response activation along 24 h. Importantly, rotenone-sensitive respiration and complex I-III activity were specifically reduced 24 h upon zymosan injection. Also, loss of complex I activity compromised ATP-linked and maximal respiratory rates mediated by mitochondrial proline oxidation. Finally, the magnitude of innate immune response activation negatively correlated with respiratory rates, regardless of the metabolic states. Collectively, we demonstrate that activation of innate immunity is strongly associated with reduced flight muscle complex I activity with direct consequences to mitochondrial proline oxidation and flight activity. Remarkably, our results indicate a trade-off between dispersal and immunity exists in an insect vector, underscoring the potential consequences of disrupted flight muscle mitochondrial energy metabolism to arbovirus transmission.

Neutrophil diversity is associated with T-cell immunity and clinical relevance in patients with thyroid cancer

Neutrophil heterogeneity is involved in autoimmune diseases, sepsis, and several cancers. However, the link between neutrophil heterogeneity and T-cell immunity in thyroid cancer is incompletely understood. We investigated the circulating neutrophil heterogeneity in 3 undifferentiated thyroid cancer (UTC), 14 differentiated thyroid cancer (DTC) (4 Stage IV, 10 Stage I–II), and healthy controls (n = 10) by transcriptomic data and cytometry. Participants with UTC had a significantly higher proportion of immature high-density neutrophils (HDN) and lower proportion of mature HDN in peripheral blood compared to DTC. The proportion of circulating PD-L1+ immature neutrophils were significantly increased in advanced cancer patients. Unsupervised analysis of transcriptomics data from circulating HDN revealed downregulation of innate immune response and T-cell receptor signaling pathway in cancer patients. Moreover, UTC patients revealed the upregulation of glycolytic process and glutamate receptor signaling pathway. Comparative analysis across tumor types and stages revealed the downregulation of various T-cell-related pathways, such as T-cell receptor signaling pathway and T-cell proliferation in advanced cancer patients. Moreover, the proportions of CD8+ and CD4+ T effector memory CD45RA+ (TEMRA) cells from peripheral blood were significantly decreased in UTC patients compared to DTC patients. Finally, we demonstrated that proportions of tumor-infiltrated neutrophils were increased and related with poor prognosis in advanced thyroid cancer using data from our RNA-seq and TCGA (The Cancer Genome Atlas) data. In conclusion, observed prevalence of circulating immature high-density neutrophils and their immunosuppressive features in undifferentiated thyroid cancers underscore the importance of understanding neutrophil dynamics in the context of tumor progression in thyroid cancer.

Identification of tumor necrosis factor receptor 1 and its association with LPS-induced apoptosis in Onchidium reevesii

The sea slug (Onchidium reevesii) inhabits intertidal environments and face environmental pressures and disease threats. The immune system of mollusks plays a crucial role in their defense against pathogens and maintaining homeostasis. The molecular mechanisms underlying its immune defense and response to pathogens remain largely unexplored. This study aimed to isolate and identify the cDNA sequence of tumor necrosis factor receptor 1 (TNFR1) in the sea slug. The obtained cDNA sequence was named OrTNFR1. Like other members of the TNF receptor superfamily, OrTNFR1 contains a signal peptide, TNF homologous domain, and death-related domain. qPCR results showed that OrTNFR1 was highly expressed in the hepatopancreas, blood, and intestines of sea slug. This indicates that OrTNFR1 plays a role in the immune-related tissues of sea slug and is consistent with the broad expression of TNFR1 in bivalves. To investigate the inducible expression pattern and downstream effects of OrTNFR1 in response to lipopolysaccharide (LPS) stimulation, we studied the functional role of the OrTNFR1 gene by stimulating with LPS in vivo and suppressing OrTNFR1 expression using siRNA technology. Our findings demonstrate that LPS stimulation rapidly up-regulates the expression of OrTNFR1 in the hepatopancreas, blood, and intestine of the sea slug. Moreover, si-TNFR1 effectively inhibits LPS-induced TNFR1 expression and its downstream genes. Additionally, we discovered that inhibiting OrTNFR1 reduces LPS-induced cell apoptosis and the expression of apoptosis-associated protein Caspase.TNFR1 is involved in the immune defense of the sea slug, and blocking TNFR1 effectively attenuates LPS-induced cell apoptosis through the TNFR1 pathway. This finding suggests that inhibiting TNFR1 in the sea slug may serve as a potential approach to reduce cell apoptosis. As a shell-less living in harsh intertidal environments, TNFR1 likely participates in its innate immunity. Therefore, studying the TNFR1 pathway contributes to understanding the innate immune signaling pathway in the sea slug, further elucidating host defense against pathogens and apoptotic functions.

Impact of chronic muscle use and disuse on innate immune signaling in skeletal muscle

Mitochondria exhibit high levels of adaptability to various stimuli such as chronic muscle use (i.e. exercise) or disuse, such as immobilization or denervation. These changes in the mitochondrial network ultimately affect the health and functioning of skeletal muscle, which contributes to whole-body metabolism, locomotion, and postural stability. It is now acknowledged that mitochondrial dysfunction can activate inflammatory pathways through the recognition of damage-associated molecular patterns (DAMPs). The objective of this study was to examine how changes in mitochondria brought about by either chronic muscle inactivity or chronic exercise training affect innate immune system activation. We hypothesized that an inverse relationship between mitochondrial content and innate immune signaling would be evident in skeletal muscle. To investigate this, skeletal muscle from the hindlimbs of mice was collected after 7 days of sciatic muscle denervation, or after 4.5 weeks of endurance swim training involving 240 minutes of daily exercise. We analyzed the expression of the NLRP3 inflammasome, innate immune system signaling proteins, mitochondrial markers, and mitochondrial DNA (mtDNA) content using western blotting, cytochrome C oxidase (COX) activity, ELISA and qPCR. Following 7 days of denervation, there was a significant decrease in both COX-IV protein and COX activity, indicating a reduction in mitochondrial content. This was accompanied by an increase (p<0.05) in NLRP3, procaspase-1, gasdermin-D (GSDMD) and its active N-terminal fragment, GSDMD-N, as well as a notable increase in IL-1β. In addition, other possible converging pathways were also upregulated including cGAS-STING, and gasdermin-E. In comparison, following exercise training, there was a significant increase in mitochondrial content, apparent through increases in COX-IV protein, COX activity and mitochondrial RNA content. This was associated with decreases in procaspase-1 and caspase-1 protein expression alongside reduced STING activation. These findings highlight an inverse relationship between mitochondrial content and the activation of several inflammatory pathways that possibly converge upon NLRP3 inflammasome activation and pyroptotic cell death, leading to detriments in skeletal muscle health. This work aims to further the understanding of innate immune signaling pathways within muscle which can potentially highlight therapeutic targets to regulate its activation under divergent metabolic conditions. This work was supported by funds from the Natural Science and Engineering Research Council (NSERC). Priyanka Khemraj is the holder of an Ontario Graduate Scholarship. David A. Hood is the holder of a Canadian Research Chair in Cell Physiology. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

IKK2 modulates the innate immune response of Zhikong scallop (Chlamys farreri) to bacterial and viral stimuli through the MyD88-dependent Toll-like receptor signaling pathway

Members of the inhibitor of nuclear factor kappa-B kinase (IKK) family are pivotal components of the innate immune signaling pathway responsible for regulating immune and inflammatory responses. Nevertheless, the various roles that IKKs play in the physiology of invertebrates, particularly marine mollusks, remain largely unexplored. In this study, an IKK gene was cloned from the Zhikong scallop, Chlamys farreri, and denoted as CfIKK2. CfIKK2 belongs to the TANK-binding kinase 1 (TBK1)/IKKε family. Real-time quantitative reverse transcription-polymerase chain reaction analysis showed that CfIKK2 was expressed in various scallop tissues and that its transcript levels substantially increased under different pathogenic stress conditions (including lipopolysaccharide, peptidoglycan, poly(I:C), acute viral necrosis virus, and Vibrio challenge). Co-immunoprecipitation experiments revealed that CfIKK2 interacts with MyD88 (a crucial adaptor in the Toll-like receptor signaling pathway) proteins through its C-terminal TBK1 coiled-coil domain 1. Moreover, CfIKK2 has been shown to interact with itself. In HEK293T cells, CfIKK2 overexpression resulted in an augmentation of mitogen-activated protein kinase phosphorylation. Furthermore, overexpression of CfIKK2 resulted in the activation of interferon reporter genes. In summary, our findings offer valuable insights into the mechanisms through which CfIKK2 responds to stress generated by pathogen-associated molecular patterns, participates in Toll-like receptor signaling, and ultimately activates some of the key cytokines involved in innate immunity in C. farreri. As a critical signaling molecule and immunoregulatory factor, CfIKK2 plays a vital role in the innate immune system of the Zhikong scallop.

RNA m5C methylation modification: a potential therapeutic target for SARS-CoV-2-associated myocarditis.

The Corona Virus Disease (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has quickly spread worldwide and resulted in significant morbidity and mortality. Although most infections are mild, some patients can also develop severe and fatal myocarditis. In eukaryotic RNAs, 5-methylcytosine (m5C) is a common kind of post-transcriptional modification, which is involved in regulating various biological processes (such as RNA export, translation, and stability maintenance). With the rapid development of m5C modification detection technology, studies related to viral m5C modification are ever-increasing. These studies have revealed that m5C modification plays an important role in various stages of viral replication, including transcription and translation. According to recent studies, m5C methylation modification can regulate SARS-CoV-2 infection by modulating innate immune signaling pathways. However, the specific role of m5C modification in SARS-CoV-2-induced myocarditis remains unclear. Therefore, this review aims to provide insights into the molecular mechanisms of m5C methylation in SARS-CoV-2 infection. Moreover, the regulatory role of NSUN2 in viral infection and host innate immune response was also highlighted. This review may provide new directions for developing therapeutic strategies for SARS-CoV-2-associated myocarditis.

MST1/2 exerts a pivotal role in inducing neuroinflammation and Coxsackievirus-A10 replication by interacting with innate immunity

Coxsackievirus-A10 (CV-A10), responsible for the hand, foot and mouth disease (HFMD) pandemic, could cause serious central nervous system (CNS) complications. The underlying molecular basis of CV-A10 and host interactions inducing neuropathogenesis is still unclear. The Hippo signaling pathway, historically known for a dominator of organ development and homeostasis, has recently been implicated as an immune regulator. However, its role in host defense against CV-A10 has not been investigated. Herein, it was found that CV-A10 proliferated in HMC3 cells and promoted the release of inflammatory cytokines. Moreover, pattern recognition receptors (PRRs)-mediated pathways, including TLR3-TRIF-TRAF3-TBK1-NF-κB axis, RIG-I/MDA5-MAVS-TRAF3-TBK1-NF-κB axis and TLR7-MyD88-IRAK1/IRAK4-TRAF6-TAK1-NF-κB axis, were examined to be elevated under CV-A10 infection. Meanwhile, it was further uncovered that Hippo signaling pathway was inhibited in HMC3 cells with CV-A10 infection. Previous studies have been reported that there exist complex relations between innate immune and Hippo signaling pathway. Then, plasmids of knockdown and overexpression of MST1/2 were transfected into HMC3 cells. Our results showed that MST1/2 suppressed the levels of inflammatory cytokines via interacting with TBK1 and IRAK1, and also enhanced virus production via restricting IRF3 and IFN-β expressions. Overall, these data obviously pointed out that CV-A10 accelerated the formation of neuroinflammation by the effect of the Hippo pathway on the PRRs-mediated pathway, which delineates a negative immunoregulatory role for MST1/2 in CV-A10 infection and the potential for this pathway to be pharmacologically targeted to treat CV-A10.

Bifunctional HDAC and DNMT inhibitor induces viral mimicry activates the innate immune response in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a unique breast cancer subtype characterized by a lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Since TNBC lacks ER, PR, and HER2, there are currently no drugs that specifically target TNBC. Therefore, the development of new drugs or effective treatment strategies to target TNBC has become an urgent clinical need. Research has shown that the application of histone deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors leads to genomic and epigenomic instability. This, in turn, triggers the activation of pattern recognition receptors (PRRs) and subsequently activates downstream interferon (IFN) signalling pathways. In this study, the bifunctional HDAC and DNMT inhibitor J208 exhibited antitumour activity in TNBC cell lines. J208 effectively induced apoptosis and cell cycle arrest at the G0/G1 phase, inhibiting cell migration and invasion in TNBC. Moreover, this bifunctional inhibitor induced the expression of endogenous retroviruses (ERVs) and elicited a viral mimicry response, which increased the intracellular levels of double-stranded RNA (dsRNA) to activate the innate immune signalling pathway in TNBC. In summary, we demonstrated that the bifunctional inhibitor J208, which is designed to inhibit HDAC and DNMT, has potent anticancer effects, providing a new research basis for reactivating antitumour immunity by triggering innate immune signalling and offering a promising strategy for TNBC treatment.

Dietary Peppermint Extract Inhibits Chronic Heat Stress-Induced Activation of Innate Immunity and Inflammatory Response in the Spleen of Broiler Chickens.

The aim of this study was to investigate the effect of dietary peppermint extract (PE) on innate immunity and inflammatory responses in the spleen of broiler chickens under chronic heat stress. In order to further study the mechanism of the activation of innate immunity and inflammation induced by chronic heat stress and the regulatory effect of peppermint extract, we examined the spleen's histological change, the mRNA expression of major pattern recognition receptors (PRRs) (TLR2, TLR4, NOD1, MDA5 and DAI) and transcription factors (NF-κB, AP-1 and IRF3) and downstream inflammatory cytokines (IFN-α, IFN-β, IL-1β, IL-6 and TNF-α) of innate immune signaling pathways associated with heat stress in the spleen of broiler chickens. The results indicated that chronic heat stress damaged the spleen tissue. In addition, chronic heat stress induced the activation of innate immunity and inflammatory responses by increasing the mRNA expression of TLR2, TLR4 and DAI, mRNA expression of transcriptional factors (NF-κB, AP-1 and IRF3) and the concentration of downstream inflammatory cytokines in the spleen of broiler chickens. Dietary peppermint extract alleviated the damage of spleen tissue caused by chronic heat stress. In addition, peppermint extract reduced the mRNA expression of DAI, mRNA expression of transcriptional factors NF-κB, AP-1 and IRF3, and the concentration of inflammatory cytokines in the spleen of broiler chickens under chronic heat stress. In conclusion, dietary peppermint extract could have a beneficial effect on regulating inflammatory response and innate immunity via inhibiting the activation of NF-κB, AP-1 and IRF3 signaling pathways mediated by DAI in the spleen of broiler chickens induced by chronic heat stress.

The Golgi Apparatus: A Key Player in Innate Immunity.

The Golgi apparatus, long recognized for its roles in protein processing and vesicular trafficking, has recently been identified as a crucial contributor to innate immune signaling pathways. This review discusses our expanding understanding of the Golgi apparatus's involvement in initiating and activating these pathways. It highlights the significance of membrane connections between the Golgi and other organelles, such as the endoplasmic reticulum, mitochondria, endosomes, and autophagosomes. These connections are vital for the efficient transmission of innate immune signals and the activation of effector responses. Furthermore, the article delves into the Golgi apparatus's roles in key immune pathways, including the inflammasome-mediated activation of caspase-1, the cGAS-STING pathway, and TLR/RLR signaling. Overall, this review aims to provide insights into the multifunctional nature of the Golgi apparatus and its impact on innate immunity.

Human Plasma-Like Medium Activates Immune Elements in Glioma

INTRODUCTION: Glioma Surgically eXplanted Organoids (SXOs) are ex vivo three-dimensional models demonstrated to recapitulate the parental tumor microenvironment (TME). Human plasma-like medium (HPLM), a culture medium that mirrors physiologic nutrient conditions, has been found in other cancer subtypes to induce transcriptional differences in T-lymphocyte activation. We hypothesized that SXO culture in HPLM would maintain immune cell populations and induce physiologically relevant immune-modulatory pathways. METHODS: SXOs were established and cultured in conventional Glioma Organoid Complete medium (GOC) and transitioned to HPLM for 24 or 120 hours. Formalin-fixed paraffin-embedded samples were stained for tumor cells (GFAP), immune cells (CD45), and nucleic acid (SYTO-13) and analyzed using the Nanostring GeoMx™ Digital Spatial Profiler for spatial transcriptomics. Gene expression clustering profiles were conducted using GSEA and CIBERSORT. The gene expression differences of SXOs cultured in HPLM for 24 and 120 hours compared to those in GOC were analyzed by unpaired t-tests. RESULTS: Glioma SXOs retain diverse cell populations, with 20-30% of cells belonging to the TME. CD4+ T-cells were the most common (9.7 ± 1.0), followed by CD8+ T-cells (4.4 ± 0.6) and macrophages (3.1 ± 1.2). Following the transition to HPLM for 24 or 120 hours, there were no significant differences in tumor, immune, and stromal cell fractions. HPLM culture upregulated the immune response in SXOs, encompassing enhanced cytokine secretion, as well as improved adaptive and innate immune pathways. We particularly highlighted CD4+ T-cell activation (CD69+), Treg, and TGF-β signaling pathways as significantly increased. CONCLUSIONS: Here, we present that the culture of SXOs in physiologically similar media retains the heterogeneous TME and activates innate and adaptive immune signaling pathways. Culture in HPLM enables investigation of the glioma immune microenvironment, expanding the biological relevance of experimental results from in vitro SXO models.

Advances in the mechanism of inflammasomes activation in herpes virus infection.

Herpesviruses, prevalent DNA viruses with a double-stranded structure, establish enduring infections and play a part in various diseases. Despite their deployment of multiple tactics to evade the immune system, both localized and systemic inflammatory responses are triggered by the innate immune system's recognition of them. Recent progress has offered more profound understandings of the mechanisms behind the activation of the innate immune system by herpesviruses, specifically through inflammatory signaling. This process encompasses the initiation of an intracellular nucleoprotein complex, the inflammasome associated with inflammation.Following activation, proinflammatory cytokines such as IL-1β and IL-18 are released by the inflammasome, concurrently instigating a programmed pathway for cell death. Despite the structural resemblances between herpesviruses, the distinctive methods of inflammatory activation and the ensuing outcomes in diseases linked to the virus exhibit variations.The objective of this review is to emphasize both the similarities and differences in the mechanisms of inflammatory activation among herpesviruses, elucidating their significance in diseases resulting from these viral infections.Additionally, it identifies areas requiring further research to comprehensively grasp the impact of this crucial innate immune signaling pathway on the pathogenesis of these prevalent viruses.

Navigating the Immune Response Landscape of Hepatitis B and Hepatitis C Virus Infections

Both the hepatitis B virus (HBV) and the hepatitis C virus (HCV) are viral pathogens that primarily target the liver and can lead to chronic liver disease. The nature of the immune response that the host mounts can vary depending on the structural differences between these two viruses. HBV is a partially double-stranded DNA virus enveloped in an outer envelope with a relatively stable genome and limited antigenic variation. It consists of an inner nucleocapsid core containing viral DNA, viral polymerase, and core antigen (HBcAg). The envelope comprises surface antigens (HBsAg) important for viral entry and immune recognition. HCV is a single-stranded RNA virus with an envelope. It has a high degree of genetic diversity due to its error-prone RNA polymerase, resulting in multiple HCV genotypes and subtypes due to its high mutation rate. Both viruses activate innate immune responses, producing type I interferons (IFNs) and pro-inflammatory cytokines. HBV can actively fight these antiviral responses in several ways, such as by making viral proteins that mess up the innate immune signalling pathways. At the same time, HCV developed strategies to evade and modulate the host's innate immune system, allowing it to establish persistent infections. The adaptive immune response against HBV and HCV involves both humoral and cellular components. Antibodies against HBsAg (anti-HBs) are critical for viral clearance and protection. CD8+ T cells are also very important for controlling HBV infection because they find and kill infected hepatocytes. During infection, HCV-specific antibodies and CD4+ and CD8+ T cells are made. However, HCV can evade immune responses by rapidly mutating its surface proteins (e.g., E2) and modulating T-cell responses. It is important to note that the immune response to HBV and HCV is a complex and dynamic process that involves various factors beyond the structural differences described above. Host factors, viral load, viral persistence, and the interplay between innate and adaptive immune responses also significantly influence the outcome of the infection

Interaction between the SFTSV envelope glycoprotein Gn and STING inhibits the formation of the STING-TBK1 complex and suppresses the NF-κB signaling pathway.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly discovered virus associated with severe hemorrhagic fever in humans. However, the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway during SFTSV infection is still unclear. We found that SFTSV infection inhibits downstream innate immune signaling pathways by activating the cytoplasmic DNA receptor cGAS. In addition, SFTSV Gn blocked the nuclear accumulation of interferon regulatory factor 3 and p65 to inhibit downstream innate immune signaling. Moreover, we determined that Gn of SFTSV inhibited K27-ubiquitin modification of STING to disrupt the assembly of the STING-TANK-binding kinase 1 complex and downstream signaling. We found that the SFTSV envelope glycoprotein Gn is a potent inhibitor of the cGAS-STING pathway. In conclusion, this study highlights the crucial function of the glycoprotein Gn in the antiviral innate immune response and reveals a new method of immune escape of SFTSV.

Implications of neonatal absence of innate immune mediated NFκB/AP1 signaling in the murine liver.

The developmental immaturity of the innate immune system helps explains the increased risk of infection in the neonatal period. Importantly, innate immune signaling pathways such as p65/NFκB and c-Jun/AP1 are responsible for the prevention of hepatocyte apoptosis in adult animals, yet whether developmental immaturity of these pathways increases the risk of hepatic injury in the neonatal period is unknown. Using a murine model of endotoxemia (LPS 5 mg/kg IP x 1) in neonatal (P3) and adult mice, we evaluated histologic evidence of hepatic injury and apoptosis, presence of p65/NFκB and c-Jun/AP1 activation and associated transcriptional regulation of apoptotic genes. We demonstrate that in contrast to adults, endotoxemic neonatal (P3) mice exhibit a significant increase in hepatic apoptosis. This is associated with absent hepatic p65/NFκB signaling and impaired expression of anti-apoptotic target genes. Hepatic c-Jun/AP1 activity was attenuated in endotoxemic P3 mice, with resulting upregulation of pro-apoptotic factors. These results demonstrate that developmental absence of innate immune p65/NFκB and c-Jun/AP1 signaling, and target gene expression is associated with apoptotic injury in neonatal mice. More work is needed to determine if this contributes to long-term hepatic dysfunction, and whether immunomodulatory approaches can prevent this injury. Various aspects of developmental immaturity of the innate immune system may help explain the increased risk of infection in the neonatal period. In adult models of inflammation and infection, innate immune signaling pathways such as p65/NFκB and c-Jun/AP1 are responsible for a protective, pro-inflammatory transcriptome and regulation of apoptosis. We demonstrate that in contrast to adults, endotoxemic neonatal (P3) mice exhibit a significant increase in hepatic apoptosis associated with absent hepatic p65/NFκB signaling and c-Jun/AP1 activity. We believe that these results may explain in part hepatic dysfunction with neonatal sepsis, and that there may be unrecognized developmental and long-term hepatic implications of early life exposure to systemic inflammatory stress.