Survival Following Traumatic Brain Injury in Drosophila Is Increased by Heterozygosity for a Mutation of the NF-κB Innate Immune Response Transcription Factor Relish
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE157102 | GEO | 2020/08/29
REPOSITORIES: GEO
Similar Datasets
Project description:Traumatic brain injury (TBI) pathologies are caused by primary and secondary injuries. Primary injuries result from physical damage to the brain, and secondary injuries arise from cellular responses to primary injuries. A characteristic cellular response is sustained activation of inflammatory pathways commonly mediated by NF-B transcription factors. Using a Drosophila melanogaster TBI model, we previously found that the main proximal transcriptional response to primary injuries is triggered by activation of Toll and Imd innate immune response pathways that engage NF-B factors Dif and Relish (Rel), respectively. Here, we monitor the abundance of Rel protein by mass spectrometry (MS) and observe that Rel increases in fly heads at 4-8 h after TBI. To investigate the necessity of Rel for secondary injuries, we generated a null allele, Reldel, by CRISPR/Cas9 editing. Heterozygous but not homozygous Reldel mutation reduced mortality at 24 h after TBI and increased the lifespan of injured flies. Additionally, the effect of heterozygous Reldel mutation on mortality was modulated by genetic background and diet. To identify genes that facilitate effects of heterozygous Reldel mutation on TBI outcomes, we compared genome-wide mRNA expression profiles of uninjured and injured +/+, +/Reldel, and Reldel/Reldel flies at 4 h following TBI. Only a few genes changed expression more than two-fold in +/Reldel flies relative to +/+ and Reldel/Reldel flies, and they were not canonical innate immune response genes. Therefore, Rel is necessary for TBI-induced secondary injuries but in complex ways involving Rel gene dose, genetic background, diet, and possibly small changes in expression of innate immune response genes.
2020-12-04 | PXD021869 | Pride
Project description:Traumatic brain injury (TBI) pathologies are caused by primary and secondary injuries. Primary injuries result from physical damage to the brain, and secondary injuries arise from cellular responses to primary injuries. A characteristic cellular response is sustained activation of inflammatory pathways commonly mediated by nuclear factor-κB (NF-κB) transcription factors. Using a Drosophila melanogaster TBI model, we previously found that the main proximal transcriptional response to primary injuries is triggered by activation of Toll and Imd innate immune response pathways that engage NF-κB factors Dif and Relish (Rel), respectively. Here, we found by mass spectrometry that Rel protein level increased in fly heads at 4-8 hr after TBI. To investigate the necessity of Rel for secondary injuries, we generated a null allele, Reldel , by CRISPR/Cas9 editing. When heterozygous but not homozygous, the Reldel mutation reduced mortality at 24 hr after TBI and increased the lifespan of injured flies. Additionally, the effect of heterozygosity for Reldel on mortality was modulated by genetic background and diet. To identify genes that facilitate effects of Reldel on TBI outcomes, we compared genome-wide mRNA expression profiles of uninjured and injured +/+, +/Reldel , and Reldel /Reldel flies at 4 hr following TBI. Only a few genes changed expression more than twofold in +/Reldel flies relative to +/+ and Reldel /Reldel flies, and they were not canonical innate immune response genes. Therefore, Rel is necessary for TBI-induced secondary injuries but in complex ways involving Rel gene dose, genetic background, diet, and possibly small changes in expression of innate immune response genes.
| S-EPMC7768241 | biostudies-literature
Project description:Survival Following Traumatic Brain Injury in Drosophila Is Increased by Heterozygosity for a Mutation of the NF-κB Innate Immune Response Transcription Factor Relish
| PRJNA660065 | ENA
Project description:Long noncoding RNAs (lncRNAs), as a class of emerging regulators, play crucial role in regulating the strength and duration of innate immunity. However, little is known about how these Drosophila Imd immunity-related lncRNAs are regulated. Herein, we firstly revealed that overexpression of lncRNA-CR33942 could strengthen the expression of Imd pathway antimicrobial peptides Diptericin (Dpt) and Attacin-A (AttA) after infection, and vice versa. Secondly, RNA-seq analysis of post-infected lncRNA-CR33942-overexpressing flies further confirmed that lncRNA-CR33942 positively regulates the Drosophila Imd pathway. Mechanistically, we indicated that lncRNA-CR33942 interacts with NF-κB transcription factor Relish to promote its binding to Dpt and AttA promoters, thereby facilitating Dpt and AttA expression. Interestingly, we found that Relish can also directly promote lncRNA-CR33942 transcription by binding to its promoter. Finally, rescue experiments and dynamic expression profiling post-infection demonstrated the vital role of the Relish/lncRNA-CR33942/AMPs regulatory axis in enhancing inadequate Imd immune responses and maintaining immune homeostasis. Taken together, our study not only elucidates a novel mechanism about lncRNA in Drosophila Imd immune regulation, but also has important guiding significance for elucidating the complex regulatory mechanism of animal innate immune response.
2022-03-22 | GSE198991 | GEO
Project description:Evidence supports the contribution of long non-coding RNAs (lncRNAs) and ferroptosis to traumatic brain injury (TBI) pathogenesis. However, lncRNA regulation in TBI-induced ferroptosis remains poorly understood. Herein, we identified an lncRNA, named noncoding transcript of chemokine (C-C motif) ligand 4 (Ccl4) overlapping (Ntoco), which was upregulated in TBI mice. The upregulation was initiated by hypoxia ischemia induced lower enrichment of H3K27me3 on the Ntoco promoter. Ntoco knockdown inhibited neuron ferroptosis, ameliorated spatial memory and lesion volume following TBI. Ntoco overexpression promoted neuron ferroptosis and recruited microglia to provoke an inflammatory response via Ccl4. Mechanistically, Ntoco facilitated K48-linked ubiquitination and protein degradation by binding to Hnrnpab, which suppressed NF-κB/Lcn2 signal axis activation, including decreased phosphorylation of IkBα, increased phosphorylation of IKKα/β, nuclear translocation of the NF-κB p65 subunit, and elevated Lcn2 expression. These data indicated that targeting Ntoco to mitigate ferroptosis might be a potential therapeutic strategy for TBI.
2024-06-21 | GSE235523 | GEO
Project description:Circular RNAs (circRNAs) are a new group of noncoding and regulatory RNAs that are particularly abundant in the nervous system, although their physiological functions are underexplored. Here we report that the brain-enriched circular RNA Edis (Ect4-derived immune suppressor) plays an essential role in neuronal development in Drosophila, as its depletion causes defective axonal projection of mushroom body (MB) neurons in the brain, as well as impaired locomotor activity and shortened lifespan of adult flies. In addition, we show that the castor gene, which encodes a transcription factor involved in neurodevelopment, is upregulated in Edis knockdown neurons. Notably, castor overexpression phenocopies Edis knockdown, and reducing castor levels suppresses the neuronal developmental phenotypes in Edis-depleted neurons. Furthermore, chromatin immunoprecipitation analysis reveals that the immune transcription factor Relish occupies two sites at the castor promoter, and that both sites are required for optimal castor gene activation induced by either immune challenge or Edis depletion. Lastly, Relish mutation rescues both the castor hyperactivation phenotype and neuronal defects in Edis knockdown animals. We conclude that the circular RNA Edis acts through Relish and castor to regulate neuronal development.
2022-10-04 | GSE196213 | GEO
Project description:Macroautophagy and cell death both contribute to innate immunity, but little is known about how these processes integrate. Drosophila larval salivary glands require autophagy for developmentally programmed cell death, and innate immune signaling factors increase in these dying cells. Here, we show that the nuclear factor κB (NF-κB) factor Relish, a component of the immune deficiency (Imd) pathway, is required for salivary gland degradation. Surprisingly, of the classic Imd pathway components, only Relish and the PGRP receptors were involved in salivary gland degradation. Significantly, Relish controls salivary gland degradation by regulating autophagy but not caspases. In addition, expression of either Relish or PGRP-LC causes premature autophagy induction and subsequent gland degradation. Relish controls autophagy by regulating the expression of Atg1, a core component and activator of the autophagy pathway. Together these findings demonstrate that a NF-κB pathway regulates autophagy during developmentally programmed cell death.
| S-EPMC6329390 | biostudies-literature
Project description:Exposure of tissues and organs to low oxygen (hypoxia) occurs in both physiological and pathological conditions in animals. Under these conditions, organisms have to adapt their physiology to ensure proper functioning and survival. Here, we define a role for the transcription factor Forkhead Box-O (FOXO) as a mediator of hypoxia tolerance in Drosophila We find that upon hypoxia exposure, FOXO transcriptional activity is rapidly induced in both larvae and adults. Moreover, we see that foxo mutant animals show misregulated glucose metabolism in low oxygen and subsequently exhibit reduced hypoxia survival. We identify the innate immune transcription factor, NF-κB/Relish, as a key FOXO target in the control of hypoxia tolerance. We find that expression of Relish and its target genes is increased in a FOXO-dependent manner in hypoxia, and that relish mutant animals show reduced survival in hypoxia. Together, these data indicate that FOXO is a hypoxia-inducible factor that mediates tolerance to low oxygen by inducing immune-like responses.
| S-EPMC7404245 | biostudies-literature
Project description:Traumatic brain injury (TBI) causes significant blood-brain barrier (BBB) breakdown, resulting in the extravasation of blood proteins into the brain. The impact of blood proteins, especially fibrinogen, on inflammation and neurodegeneration post-TBI is not fully understood, highlighting a critical gap in our comprehension of TBI pathology and its connection to innate immune activation. We combined vascular casting with 3D imaging of solvent-cleared organs (uDISCO) to study the spatial distribution of the blood coagulation protein fibrinogen in large, intact brain volumes and assessed the temporal regulation of the fibrin(ogen) deposition by immunohistochemistry in a murine model of TBI. Fibrin(ogen) deposition and innate immune cell markers were co-localized by immunohistochemistry in mouse and human brains after TBI. We assessed the role of fibrinogen in TBI using unbiased transcriptomics, flow cytometry and immunohistochemistry for innate immune and neuronal markers in Fggγ390–396A knock-in mice, which express a mutant fibrinogen that retains normal clotting function, but lacks the γ390–396 binding motif to CD11b/CD18 integrin receptor. We show that cerebral fibrinogen deposits were associated with activated innate immune cells in both human and murine TBI. Genetic elimination of fibrin-CD11b interaction reduced peripheral monocyte recruitment and the activation of inflammatory and reactive oxygen species (ROS) gene pathways in microglia and macrophages after TBI. Blockade of the fibrin-CD11b interaction was also protective from oxidative stress damage and cortical loss after TBI. These data suggest that fibrinogen is a regulator of innate immune activation and neurodegeneration in TBI. Abrogating post-injury neuroinflammation by selective blockade of fibrin’s inflammatory functions may have implications for long-term neurologic recovery following brain trauma.
2024-04-16 | GSE253476 | GEO
Project description:Adult male and female Tau-KO flies were inflicted with traumatic brain injury using high-impact trauma device. Brains were dissected at control, 1, 2 and 4 hours post-TBI. Total RNA was extracted from fly brains and 3'mRNA-seq was performed to assess gene expression changes in response to TBI in both sexes. 3 replicates were sequenced for each condition.
2021-07-15 | GSE148939 | GEO