Immune Signaling Research Articles

Integrative Analysis of ATAC-Seq and RNA-Seq through Machine Learning Identifies 10 Signature Genes for Breast Cancer Intrinsic Subtypes.

Breast cancer is a heterogeneous disease composed of various biologically distinct subtypes, each characterized by unique molecular features. Its formation and progression involve a complex, multistep process that includes the accumulation of numerous genetic and epigenetic alterations. Although integrating RNA-seq transcriptome data with ATAC-seq epigenetic information provides a more comprehensive understanding of gene regulation and its impact across different conditions, no classification model has yet been developed for breast cancer intrinsic subtypes based on such integrative analyses. In this study, we employed machine learning algorithms to predict intrinsic subtypes through the integrative analysis of ATAC-seq and RNA-seq data. We identified 10 signature genes (CDH3, ERBB2, TYMS, GREB1, OSR1, MYBL2, FAM83D, ESR1, FOXC1, and NAT1) using recursive feature elimination with cross-validation (RFECV) and a support vector machine (SVM) based on SHAP (SHapley Additive exPlanations) feature importance. Furthermore, we found that these genes were primarily associated with immune responses, hormone signaling, cancer progression, and cellular proliferation.

Effect of Moniezia Benedeni infection on ileal transcriptome profile characteristics of sheep

BackgroundThe intestinal mucosal immune system, renowned for its precise and sensitive regulation, can provide comprehensive and effective protection for the body, among which the ileum is a critical induction site for regulating mucosal immune homeostasis. Moniezia benedeni parasitizes the small intestine of sheep and can cause serious pathological damage or even death to the host when the infection is severe. In this study, 5 sheep infected with Moniezia benedeni were selected as the infected group, and 5 uninfected sheep were selected as the control group. The ileal transcriptome profile characteristics of Moniezia benedeni infection were analyzed based on RNA-seq sequencing technology, aiming to lay a foundation for further exploring the perception mechanism of sheep intestines to Moniezia benedeni infection and formulating effective prevention and control strategies.ResultsThe results showed that a total of 3,891 differentially expressed genes (DEGs) were detected in the ileum tissues of sheep between the infected and control groups with 2,429 up-regulated genes and 1,462 down-regulated genes. GO and KEGG pathway enrichment analysis of differential genes, as well as Clue GO analysis showed that differential genes were significantly enriched in immune and metabolic-related biological processes and signaling pathways. Particularly, in immune-related signaling pathways, the B cell receptor signaling pathway was significantly down-regulated, while in metabolic regulation related signaling pathways, Bile secretion, Fat digestion and absorption and Vitamin digestion and absorption were notably up-regulated. On this basis, the differential core genes related to immune metabolism were verified by qRT-PCR method. The results showed that OVAR, CD3E, CD8A, CD4 and CD28 were significantly up-regulated (P < 0.05), while CIITA, BLNK, BCL6 and CD79A were significantly down-regulated (P < 0.05), which were consistent with transcriptome sequencing data.ConclusionsThe results demonstrated that Moniezia benedeni infection significantly affected the immune and metabolic processes in sheep ileum, particularly, it significantly inhibited the activation process of host B cells, and also led to an overactive function of bile acid metabolism. This finding provides a solid foundation for further elucidating the response mechanism of Peyer's patches in sheep ileum to Moniezia tapeworm infection.

Multiplexed, image-based pooled screens in primary cells and tissues with PerturbView.

Optical pooled screening (OPS) is a scalable method for linking image-based phenotypes with cellular perturbations. However, it has thus far been restricted to relatively low-plex phenotypic readouts in cancer cell lines in culture due to limitations associated with in situ sequencing of perturbation barcodes. Here, we develop PerturbView, an OPS technology that leverages in vitro transcription to amplify barcodes before in situ sequencing, enabling screens with highly multiplexed phenotypic readouts across diverse systems, including primary cells and tissues. We demonstrate PerturbView in induced pluripotent stem cell-derived neurons, primary immune cells and tumor tissue sections from animal models. In a screen of immune signaling pathways in primary bone marrow-derived macrophages, PerturbView uncovered both known and novel regulators of NF-κB signaling. Furthermore, we combine PerturbView with spatial transcriptomics in tissue sections from a mouse xenograft model, paving the way to in situ screens with rich optical and transcriptomic phenotypes. PerturbView broadens the scope of OPS to a wide range of models and applications.

Extracellular vesicles in sepsis plasma mediate neuronal inflammation in the brain through miRNAs and innate immune signaling

BackgroundNeuroinflammation reportedly plays a critical role in the pathogenesis of sepsis-associated encephalopathy (SAE). We previously reported that circulating plasma extracellular vesicles (EVs) from septic mice are proinflammatory. In the current study, we tested the role of sepsis plasma EVs in neuroinflammation.MethodsTo track EVs in cells and tissues, HEK293T cell-derived EVs were labeled with the fluorescent dye PKH26. Cecal ligation and puncture (CLP) was conducted to model polymicrobial sepsis in mice. Plasma EVs were isolated by ultracentrifugation and their role in promoting neuronal inflammation was tested following intracerebroventricular (ICV) injection. miRNA inhibitors (anti-miR-146a, -122, -34a, and -145a) were applied to determine the effects of EV cargo miRNAs in the brain. A cytokine array was performed to profile microglia-released protein mediators. TLR7- or MyD88-knockout (KO) mice were utilized to determine the underlying mechanism of EVs-mediated neuroinflammation.ResultsWe observed the uptake of fluorescent PKH26-EVs inside the cell bodies of both microglia and neurons. Sepsis plasma EVs led to a dose-dependent cytokine release in cultured microglia, which was partially attenuated by miRNA inhibitors against the target miRNAs and in TLR7-KO cells. When administered via the ICV, sepsis plasma EVs resulted in a marked increase in the accumulation of innate immune cells, including monocyte and neutrophil and cytokine gene expression, in the brain. Although sepsis plasma EVs had no direct effect on cytokine production or neuronal injury in vitro, the conditioned media (CM) of microglia treated with sepsis plasma EVs induced neuronal cell death as evidenced by increased caspase-3 cleavage and Annexin-V staining. Cytokine arrays and bioinformatics analysis of the microglial CM revealed multiple cytokines/chemokines and other factors functionally linked to leukocyte chemotaxis and migration, TLR signaling, and neuronal death. Moreover, sepsis plasma EV-induced brain inflammation in vivo was significantly dependent on MyD88.ConclusionsCirculating plasma EVs in septic mice cause a microglial proinflammatory response in vitro and a brain innate immune response in vivo, some of which are in part mediated by TLR7 in vitro and MyD88 signaling in vivo. These findings highlight the importance of circulating EVs in brain inflammation during sepsis.

Genomic and Transcriptional Analysis of the Necroptosis Pathway Elements RIPK and MLKL in Sea Cucumber, Holothuria leucospilota.

Background: Receptor-interacting protein kinases (RIPKs) and mixed-lineage kinase domain-like protein (MLKL) are crucial in regulating innate immune responses and cell death signaling (necroptosis and apoptosis), and are potential candidates for genetic improvement in breeding programs. Knowledge about the RIPK family and MLKL in sea cucumber remains limited. Methods: We searched the genomes of sea cucumber Holothuria leucospilota for genes encoding RIPKs and MLKL, performed phylogenetic tree, motif and functional domain analyses, and examined tissue distribution and embryonic development patterns using qPCR. Results: RIPK5 (Hl-RIPK5), RIPK7 (Hl-RIPK7) and MLKL (Hl-MLKL) were identified in sea cucumber H. leucospilota. Hl-RIPK5 and Hl-RIPK7 were mainly expressed in coelomocytes, suggesting that they play a role in innate immunity, whereas Hl-MLKL exhibited relatively low expression across tissues. During embryonic development, Hl-MLKL was highly expressed from the 2-cell stage to the morula stage, while Hl-RIPK5 and Hl-RIPK7 were primarily expressed after the morula stage, indicating different roles in embryonic development. In primary coelomocytes, Hl-RIPK5 transcriptional activity was significantly depressed by LPS, poly(I:C), or pathogen Vibrio harveyi. Hl-RIPK7 expression levels were unchanged following the same challenges. Hl-MLKL mRNA levels were significantly decreased with poly(I:C) or V. harveyi, but did not change with LPS. Conclusions: These findings provide valuable insights into the evolutionary tree and characterization of RIPK and MLKL genes in sea cucumber, contributing to the broader understanding of the RIPK gene family and MLKL in ancient echinoderms.

Transcriptomic and Proteomic Insights into Host Immune Responses in Pediatric Severe Malarial Anemia: Dysregulation in HSP60-70-TLR2/4 Signaling and Altered Glutamine Metabolism.

Severe malarial anemia (SMA, Hb < 6.0 g/dL) is a leading cause of childhood morbidity and mortality in holoendemic Plasmodium falciparum transmission zones. This study explored the entire expressed human transcriptome in whole blood from 66 Kenyan children with non-SMA (Hb ≥ 6.0 g/dL, n = 41) and SMA (n = 25), focusing on host immune response networks. RNA-seq analysis revealed 6862 differentially expressed genes, with equally distributed up-and down-regulated genes, indicating a complex host immune response. Deconvolution analyses uncovered leukocytic immune profiles indicative of a diminished antigenic response, reduced immune priming, and polarization toward cellular repair in SMA. Weighted gene co-expression network analysis revealed that immune-regulated processes are central molecular distinctions between non-SMA and SMA. A top dysregulated immune response signaling network in SMA was the HSP60-HSP70-TLR2/4 signaling pathway, indicating altered pathogen recognition, innate immune activation, stress responses, and antigen recognition. Validation with high-throughput gene expression from a separate cohort of Kenyan children (n = 50) with varying severities of malarial anemia (n = 38 non-SMA and n = 12 SMA) confirmed the RNA-seq findings. Proteomic analyses in 35 children with matched transcript and protein abundance (n = 19 non-SMA and n = 16 SMA) confirmed dysregulation in the HSP60-HSP70-TLR2/4 signaling pathway. Additionally, glutamine transporter and glutamine synthetase genes were differentially expressed, indicating altered glutamine metabolism in SMA. This comprehensive analysis underscores complex immune dysregulation and novel pathogenic features in SMA.

Nanoenabled IL-15 Superagonist via Conditionally Stabilized Protein-Protein Interactions Eradicates Solid Tumors by Precise Immunomodulation.

Protein complexes are crucial structures that control many biological processes. Harnessing these structures could be valuable for therapeutic therapy. However, their instability and short lifespans need to be addressed for effective use. Here, we propose an innovative approach based on a functional polymeric cloak that coordinately anchors different domains of protein complexes and assembles them into a stabilized nanoformulation. As the polymer-protein association in the cloak is pH sensitive, the nanoformulation also allows targeting the release of the protein complexes to the acidic microenvironment of tumors for aiding their therapeutic performance. Building on this strategy, we developed an IL-15 nanosuperagonist (Nano-SA) by encapsulating the interleukin-15 (IL-15)/IL-15 Receptor α (IL-15Rα) complex (IL-15cx) for fostering synergistic transpresentation in tumors. Upon intravenous administration, Nano-SA stably circulated in the bloodstream, safeguarding the integrity of IL-15cx until reaching the tumor site, where it selectively released the active complex. Thus, Nano-SA significantly amplified the antitumor immune signals while diminishing systemic off-target effects. In murine colon cancer models, Nano-SA achieved potent immunotherapeutic effects, eradicating tumors without adverse side effects. These findings highlight the transformative potential of nanotechnology for advancing protein complex-based therapies.

416 (PB404): G protein nucleolar 3 promotes cell-cycle progression and suppresses immune response signaling in castrate-resistant prostate cancer by collaborating with the androgen-receptor

416 (PB404): G protein nucleolar 3 promotes cell-cycle progression and suppresses immune response signaling in castrate-resistant prostate cancer by collaborating with the androgen-receptor

Unraveling the Molecular Mechanisms of OSA-Related Cardiovascular Event Recurrence: A Post Hoc Analysis From the ISAACC Study

RationaleAlthough obstructive sleep apnea (OSA) is a prevalent condition among patients with acute coronary syndrome (ACS), the impact of OSA on cardiovascular event (CVE) recurrence is not homogeneous. We previously defined a specific phenotype of first-ACS patients without previous cardiovascular disease who are at increased risk of OSA-related CVE recurrence. However, the pathobiological mechanisms whereby OSA leads to adverse cardiovascular outcomes in this singular ACS phenotype remain to be investigated. ObjectiveTo characterize the molecular pathways that relate OSA with CVE recurrence. MethodsThis post hoc analysis of the ISAACC study (NCT01335087) included subjects without previous cardiovascular disease who were hospitalized for a first ACS and developed a recurrent CVE during the follow-up. Patients underwent respiratory polygraphy and fasting blood extraction during hospitalization. Two study groups were established on the basis of the apnea–hypopnea index (AHI): untreated severe OSA (AHI≥30events/h) and non-OSA (AHI<15events/h) groups. Proteomic profiling analysis included 276 cardiovascular and inflammatory-related plasma proteins via Olink® technology. ResultsProteomics was performed in 58 patients (77.6% male, median [p25;p75] age 58.0 [51.2;65.8] years, and median BMI 28.6 [25.8;31.2]kg/m2). Thirty patients had severe OSA, and 28 subjects were considered non-OSA controls. A total of 24 plasma proteins were differentially expressed between the groups. Among these proteins, 18 were significantly associated with OSA severity parameters derived from respiratory polygraphy. Further bioinformatic analyses of OSA-related proteins revealed their involvement in several molecular pathways, mostly related to immune function, cell signaling, and inflammatory processes. ConclusionA specific proteomic profile related to OSA presence and severity was identified in the plasma of ACS patients who developed recurrent CVEs. This analysis suggests the activation of key OSA-mediated molecular pathways with potential implications for cardiovascular prognosis.

Integrative Multi-Omics and Network Pharmacology Reveal the Mechanisms of Fangji Huangqi Decoction in Treating IgA Nephropathy

Ethnopharmacological relevanceFangji Huangqi Decoction (FJHQD), a classical Chinese herbal formulation, has demonstrated significant clinical efficacy in the treatment of IgA nephropathy (IgAN), although its mechanisms remain poorly understood. Aim of the studyThis study aims to investigate the renal protective mechanisms of FJHQD using an integrated approach that combines transcriptomics, proteomics, and network pharmacology. MethodsRenal glomerular structure changes were assessed via hematoxylin and eosin (H&E) and Masson staining. IgA expression in the glomeruli was quantified using immunofluorescence. Furthermore, the potential mechanisms underlying the effects of FJHQD were explored through a combined strategy of network pharmacology, transcriptomics, and proteomics. The expression of signaling pathway-related proteins was detected using Western blot. ResultsFJHQD inhibited mesangial cell proliferation and renal interstitial fibrosis, and significantly reduced excessive IgA deposition in the glomerular mesangium. Network pharmacology identified 113 important active components and 8 common active components in FJHQD, with quercetin, isorhamnetin, jaranol, and kaempferol having the highest number of target interactions. Integration of network pharmacology with multi-omics approaches revealed that 44 active components regulated numerous immune and inflammatory signaling pathways through 17 hub targets. These pathways include the Calcium signaling pathway, cAMP signaling pathway, Ras signaling pathway, MAPK signaling pathway, and PI3K-AKT signaling pathway. Subsequent in vivo experiments demonstrated that FJHQD effectively regulates the identified pathways in IgAN mice. Ultimately, molecular docking results further validated the reliability of the network pharmacology combined with multi-omics analyses. ConclusionThe findings suggest that FJHQD exerts a renal protective effect, potentially through modulation of the Calcium signaling pathway, cAMP signaling pathway, Ras signaling pathway, MAPK signaling pathway, and PI3K-AKT signaling pathway. These insights offer valuable support for the clinical use of FJHQD and open new avenues for exploring the active compounds and molecular mechanisms of Traditional Chinese Medicines (TCMs).

Remote limb ischemic preconditioning alleviated spinal cord injury through inhibiting proinflammatory immune response and promoting the survival of spinal neurons.

Experimental animal study. To investigate the protective effect of remote limb ischemia preconditioning (RLPreC) on traumatic spinal cord injury (SCI) and explore the underlying biological mechanisms using RNA sequencing. China Rehabilitation Science Institute; Beijing; China. spinal cord injury was induced in mice using a force of 0.7 N. RLPreC treatment was administered. Motor function, pain behavior, and gene expression were assessed. RLPreC treatment significantly improved motor function and reduced pain-like behavior in SCI mice. RNA-Seq analysis identified 5247 differentially expressed genes (DEGs). GO analysis revealed enrichment of immune response, inflammatory signaling, and synaptic transmission pathways among these DEGs. KEGG analysis indicated suppression of inflammation and promotion of synapse-related pathways. RLPreC is a promising therapeutic strategy for improving motor function and alleviating pain after traumatic SCI. RNA-Seq analysis provides insights into potential therapeutic targets and warrants further investigation.

Transcriptome Sequencing of Gingival Tissues from Impacted Third Molars Patients Reveals the Alterations of Gene Expression.

The removal of impacted third molars by surgery may occur with a series of complications, whereas limited information about the postoperative pathogenesis is available. The objective of this study is to identify changes in gene expression after flap surgical removal of impacted third molars and provide potential information to reduce postoperative complications. The gingival tissues of twenty patients with flap surgical removal of impacted third molars and twenty healthy volunteers were collected for gene expression testing. The collected gingival tissues were used RNA sequencing technology and quantitative real-time PCR validation was performed. DEG was mapped to protein databases such as GO and KEGG for functional annotation and, based on annotation information, for mining of differential expression genes in patients with mpacted third molars. A total of 555 genes were differentially expressed. Among the top up-regulated genes, HLA-DRB4, CCL20, and CXCL8 were strongly associated with immune response and signal transduction. Among the top down-regulated genes, SPRR2B, CLDN17, LCE3D and LCE3E were related to keratinocyte differentiation, IFITM5, and BGLAP were related to bone mineralization, UGT2B17 is associated with susceptibility to osteoporosis. KEGG results showed that the DEGs were related to multiple disease-related pathways. This first transcriptome analysis of gingival tissues from patients with surgical removal of impacted third molars provides new insights into postoperative genetic changes. The results may establish a basis for future research on minimizing the incidence of complications after flap-treated third molars.

Akkermansia muciniphila administration ameliorates streptozotocin-induced hyperglycemia and muscle atrophy by promoting IGF2 secretion from mouse intestine.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease that can lead to severe diabetic complications. While the changes and correlations between gut microbiota and the pathogenesis of T1DM have been extensively studied, little is known about the benefits of interventions on gut bacterial communities, particularly using probiotics, for this disease. In the present study, we reported that the mice surviving after 5 months of streptozotocin (STZ) injection had reduced blood glucose level and recovered gut microbiota with increased Akkermansia muciniphila proportion. Gavage of heat-killed A. muciniphila increases the diversity of gut microbiota and elevated immune and metabolic signaling pathways in the intestine. Mechanistically, A. muciniphila treatment promoted the secretion of insulin-like growth factor 2 (IGF2) which subsequently activated IGF2 signaling in skeletal muscles and enhanced muscle and global metabolism. Our results suggest that the administration of heat-killed A. muciniphila could be a potential therapeutic strategy for T1DM and its associated hyperglycemia.

RNA-seq analysis of LPS-induced immune priming in silkworms (Bombyx mori) and the role of cytochrome P450 detoxification system in the process

While immune priming has been identified in many invertebrates, the intricate mechanisms that drive this process in insects continue to be a subject of mystery. In this study, we exposed silkworm larvae to varying doses of lipopolysaccharide (LPS) to induce immune priming and assessed their survival upon challenge with Bacillus thuringiensis (Bt). Transcriptome analysis was performed to identify differentially expressed genes (DEGs) associated with immune priming. The role of CYP450 genes in this process was further explored using RNA interference (RNAi) to knockdown CYP9E2 and CYP6K1, followed by measurements of detoxification enzyme activities and reactive oxygen species (ROS) levels. We found that LPS exposure significantly increased silkworm survival rates upon Bt challenge, indicating the induction of immune priming. Transcriptome analysis revealed 549 DEGs, including a large number involved in detoxification, immunity, and metabolism, suggesting a complex regulatory network that encompasses immune responses and metabolic pathways. Functional enrichment and gene set enrichment analysis (GSEA) highlighted the activation of immune signaling pathways and the involvement of detoxification processes. Knockdown of CYP9E2 and CYP6K1 resulted in increased ROS levels, decreased detoxification enzyme activities, and reduced survival rates post-Bt challenge, implicating the critical role of these genes in immune priming and detoxification. Our findings demonstrate that LPS-induced immune priming in silkworms involves the upregulation of CYP450 genes, which play a critical role in detoxification and immune response modulation. The study provides insights into the molecular mechanisms of immune priming in insects and highlights the potential of CYP9E2 and CYP6K1 as targets for enhancing disease resistance and pest management in insects.

Drosophila Cul3 contributes to Diap2-mediated innate immune signaling for antimicrobial defense

The host antimicrobial immune response relies on a complex interplay of molecular mechanisms to effectively combat microbial infections. Herein, we investigate the functional role of Cullin-3 (Cul3), one critical constituent of cullin-RING ubiquitin ligases, in the Drosophila melanogaster (fruit fly) antimicrobial immune defense. We show that silencing of Cul3 leads to a decreased induction of antimicrobial peptides and high mortality in adult flies after bacterial infection. Through biochemical approaches, we demonstrate that Cul3 predominantly relies on its BTB-binding domain (BD) and neddylation domain (ND) to physically associate with death-associated inhibitor of apoptosis 2 (Diap2). Importantly, Cul3 ameliorates the Diap2-mediated ubiquitination of death-related ced-3/Nedd2-like caspase (Dredd), a process essential for robust immune deficiency (IMD) signaling upon bacterial infection. Taken together, our findings highlight a previously unrecognized regulatory axis of Cul3/Diap2/Dredd in the fly antimicrobial immune defense, providing potential insights into therapeutic strategies for combating bacterial infections in humans.

Mitofusins by Regulating Lung Macrophage-Derived Immune Signals Modulate Monocyte Migration and Interorgan Cross-Talk during Kidney Fibrosis

Mitofusins by Regulating Lung Macrophage-Derived Immune Signals Modulate Monocyte Migration and Interorgan Cross-Talk during Kidney Fibrosis

Duck plague virus UL24 protein initiates K48/K63-linked IRF7 polyubiquitination to antagonize the innate immune response

Duck plague virus (DPV), which is the causative agent of duck viral enteritis, is highly infectious and can cause severe disease and death in ducks, geese and other waterfowl. Several tegument proteins of DPV have been shown to affect the cyclic GMP-AMP synthase (cGAS)-STING signaling pathway to modulate host innate immune responses. DPV UL24, an important DPV tegument protein, can inhibit the activity of the IFN-β promoter. However, the mechanism by which the DPV UL24 protein regulates the host innate immune response remains unclear. In this study, we found that the UL24 protein can significantly inhibit the activity of the interferon-β promoter induced by poly(I:C) and reduce the production of IFN-β, interferon-stimulated genes (OASL, Mx), and the cellular inflammatory factor IL-6. (2) The UL24 protein can widely inhibit the mRNA level of immune signaling molecules. The UL24 protein can also downregulate the protein expression of RIG-I, MDA5, MAVS, cGAS, STING, TBK1 and IRF7 in DEFs. RT-qPCR results revealed that UL24 significantly inhibited the mRNA accumulation for the immune signaling molecules cGAS, STING, TBK1 and IRF7. (3) The UL24 protein induced the degradation of IRF7 via ubiquitination. After the DEFs were treated with the ubiquitin proteasome inhibitor MG132, the degradation of IRF7 by the UL24 protein was alleviated. Coimmunoprecipitation results revealed that DPV UL24 induced the K48/K63-linked ubiquitination of IRF7, which promoted its degradation and thus antagonized the host innate immune response.

STING induces HOIP-mediated synthesis of M1 ubiquitin chains to stimulate NFκB signaling.

STING activation by cyclic dinucleotides in mammals induces IRF3- and NFκB -mediated gene expression, and the lipidation of LC3B at Golgi-related membranes. While mechanisms of the IRF3 response are well understood, the mechanisms of NFκB activation mediated by STING remain unclear. We report that STING activation induces linear/M1-linked ubiquitin chain (M1-Ub) formation and recruitment of the LUBAC E3 ligase, HOIP, to LC3B-associated Golgi membranes where ubiquitin is also localized. Loss of HOIP prevents formation of M1-Ub ubiquitin chains and reduces STING-induced NFκB and IRF3-mediated signaling in human monocytic THP1 cells and mouse bone marrow derived macrophages, without affecting STING activation. STING-induced LC3B lipidation is not required for M1-Ub chain formation or the immune-related gene expression, however the recently reported function of STING to neutralize the pH of the Golgi may be involved. Thus, LUBAC synthesis of M1 ubiquitin chains mediates STING-induced innate immune signaling.

Dopaminergic neuronal regulation determines innate immunity of Caenorhabditis elegans during Klebsiella aerogenes infection

The innate immune signals are the front line of host defense against bacterial pathogens. Pathogen-induced harmful effects, such as reduced neuronal signals to the intestine, affect the host's food sensing and dwelling behavior. Here, we report that dopamine and kpc-1 signals control the intestinal innate immune responses through the p38/PMK-1 MAPK signaling pathway in C. elegans. K. aerogenes infection in C. elegans affects the food-dwelling behavior, which depends on dopamine regulation. The absence of the dopamine receptor (dop-1) and transporter (dat-1) increases attraction to the pathogen instead of avoidance. The K. aerogenes infection affects age-1 regulation through the furin-like proprotein convertase (kpc-1); the absence of kpc-1 affects environment-dependent dauer formation. In contrast, the dop-1 mutation antagonistically regulates intestinal immune regulation, while the kpc-1 mutation partially regulates the p38/PMK-1 MAPK pathway. Our findings indicate that dopamine and kpc-1signaling from the nervous system control intestinal immunity in an antagonistic and agonistic manner, respectively.

Unraveling the intricate link between cell death and neuroinflammation using Drosophila as a model.

Protein aggregation is a common pathological occurrence in neurodegenerative diseases. This often leads to neuroinflammation, which exacerbates the aggregation and progression of diseases like Parkinson's and Alzheimer's. Here, we focus on immune responses and neurotoxicity in a Parkinson's disease model in Drosophila. Mutations in the SNCA gene that encodes the alpha (α)-Synuclein protein have been linked to familial Parkinson's disease, disrupting autophagy regulation in neuronal cells and promoting the formation of Lewy bodies, a hallmark of Parkinson's pathology. This results in the loss of dopaminergic neurons, manifesting as movement disorders. α-Synuclein aggregation triggers innate immune responses by activating microglial cells, leading to phagocytic activity and the expression of neuroprotective antimicrobial peptides (AMPs). However, sustained AMP expression or chronic inflammation resulting from inadequate microglial phagocytosis can induce neuronal toxicity and apoptosis, leading to severe dopaminergic neuron loss. This review underscores the mechanistic connection between immune response pathways and α-Synuclein-mediated neurodegeneration using Drosophila models. Furthermore, we extensively explore factors influencing neuroinflammation and key immune signaling pathways implicated in neurodegenerative diseases, particularly Parkinson's disease. Given the limited success of traditional treatments, recent research has focused on therapies targeting inflammatory signaling pathways. Some of these approaches have shown promising results in animal models and clinical trials. We provide an overview of current therapeutic strategies showing potential in treating neurodegenerative diseases, offering new avenues for future research and treatment development.