Macrophage Regnase-3 limits tissue inflammation and injury via alternative splicing of pre-mRNA
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE236259 | GEO | 2025/08/18
REPOSITORIES: GEO
Similar Datasets
Project description:Dunster2014 - WBC Interactions (Model1)
This is a sub-model of a three-step
inflammatory response modelling study. The model includes distinct
populations of white blood cells namely, macrophages and active and
apoptotic neutrophil populations. Neutrophil apoptosis rate is
predicted to be crucial for the qualitative nature of the
system.
This model is described in the article:
The resolution of
inflammation: a mathematical model of neutrophil and macrophage
interactions.
Dunster JL, Byrne HM, King JR.
Bull. Math. Biol. 2014 Aug; 76(8):
1953-1980
Abstract:
There is growing interest in inflammation due to its
involvement in many diverse medical conditions, including
Alzheimer's disease, cancer, arthritis and asthma. The
traditional view that resolution of inflammation is a passive
process is now being superceded by an alternative hypothesis
whereby its resolution is an active, anti-inflammatory process
that can be manipulated therapeutically. This shift in mindset
has stimulated a resurgence of interest in the biological
mechanisms by which inflammation resolves. The
anti-inflammatory processes central to the resolution of
inflammation revolve around macrophages and are closely related
to pro-inflammatory processes mediated by neutrophils and their
ability to damage healthy tissue. We develop a spatially
averaged model of inflammation centring on its resolution,
accounting for populations of neutrophils and macrophages and
incorporating both pro- and anti-inflammatory processes. Our
ordinary differential equation model exhibits two outcomes that
we relate to healthy and unhealthy states. We use bifurcation
analysis to investigate how variation in the system parameters
affects its outcome. We find that therapeutic manipulation of
the rate of macrophage phagocytosis can aid in resolving
inflammation but success is critically dependent on the rate of
neutrophil apoptosis. Indeed our model predicts that an
effective treatment protocol would take a dual approach,
targeting macrophage phagocytosis alongside neutrophil
apoptosis.
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BIOMD0000000616.
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To the extent possible under law, all copyright and related or
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2024-09-02 | BIOMD0000000616 | BioModels
Project description:We studied macrophage gene expression from mice fed chow diet (C) or 60% high fat diet (HF), that phagocytized C-RBC, HFD-RBC, or no RBC. Macrophages from mice on HF diet were activated toward a pro-inflammatory phenotype. In macrophages isolated from CD mice, RBC phagocytosis yielded a gene expression pattern similar to HF macrophages. Incubation of HF-RBC with macrophages resulted in a significantly more pronounced upregulation of pro-inflammatory chemokines as compared to C-RBC. Peritoneal macrophages were obtained from C57BL/6 mice fed either C or HF diet. Phagocytosis was performed in vitro with C-RBC or HF-RBC; macrophages not exposed to RBC served as a control. Affymetrix Mouse Gene 1.0 ST microarray chips were used to assess the gene expression profile.
2013-08-28 | E-GEOD-50240 | biostudies-arrayexpress
Project description:After spinal cord injury (SCI), infiltrating macrophages undergo excessive phagocytosis of myelin and cellular debris, forming lipid-laden foamy macrophages. To understand their role in the cellular pathology of SCI, investigation of foamy macrophage phenotype in vitro revealed a unique inflammatory profile, increased reactive oxygen species (ROS) production, and mitochondrialdysfunction. Bioinformatic analysis identified PI3K as a regulator of inflammation in foamy macrophages, and pharmacological inhibition of this pathway decreased lipid content and inflammatory cytokine and ROS production in these cells. Macrophage-specific inhibition of PI3K using liposomes significantly decreased foamy macrophages at the injury site after a mid-thoracic contusive SCI in mice. RNA sequencing and in vitro analysis of foamy macrophages revealed increased autophagy after PI3K inhibition as a potential mechanism for reduced cellular lipid accumulation. Together, our data suggest that formation of pro-inflammatory foamy macrophages after SCI is due to activation of PI3K signaling that leads to decreased autophagy.
2023-12-05 | GSE237511 | GEO
Project description:Immune responses are crucial to maintaining tissue homeostasis upon tissue injury. Upon various types of challenges, macrophages play a central role in regulating inflammation and tissue repair processes. While an immunomodulatory role of Wnt antagonist Dickkopf1 (DKK1) has been implicated, the role of Wnt antagonist DKK1 in regulating macrophage polarization in inflammation and the tissue repair process remains elusive. Here we found that DKK1 induces differential gene expression profiles from type 2-cytokine-activated macrophages to promote inflammation and tissue repair. Importantly, DKK1 induced pro-inflammatory and pro-resolving gene expressions via JNK (c-jun N-terminal kinase) in macrophages. Furthermore, DKK1 potentiated IL-13-mediated macrophage polarization and activation. Co-inhibition of JNK and STAT6 markedly decreased pro-inflammatory and pro-resolving gene expressions by DKK1 and IL-13. Interestingly, thrombocyte-specific deletion of DKK1 in mice reduced monocyte-derived macrophages in the acute sterile bleomycin (BLM)-induced lung injury model, suggesting that thrombocytes communicate with macrophages via DKK1 to orchestrate inflammation-induced injury repair process. Taken together, our study demonstrates DKK1’s role as a key regulatory role in macrophage polarization in the injury-induced inflammation and repair process.
2023-12-06 | GSE247398 | GEO
Project description:Osteonecrosis (ON) of the femoral head (ONFH) is a devastating bone disease affecting over 20 million people worldwide. ONFH is caused by a disruption of blood supply, leading to necrotic cell death and increased inflammation. Macrophages are the key cells mediating the inflamma-tory responses in ON. It is unclear what are the dynamic phenotypes of macrophages, and what mechanisms may affect macrophage polarization and therefore the healing process. In our pre-liminary study, we found that there is an invasion of macrophages in the repair tissue during ON healing. Interestingly, in both ONFH patient and the mouse ON model, fat was co-labeled within macrophages using immunofluorescence staining, indicating phagocytosis of fat by mac-rophages. To study the effects of fat phagocytosis on macrophage phenotype, we set up an in vitro macrophage and fat co-culture system. We found that fat phagocytosis significantly de-creased M1 markers expression such as IL1β and iNOS in macrophages. Whereas the expression of M2 marker Arg1 was significantly increased with fat phagocytosis. To investigate if the polar-ization change is indeed mediated by phagocytosis, we treated the cells with Latrunculin A (LA, a phagocytosis inhibitor). LA supplement significantly reversed the polarization marker gene changes induced by fat phagocytosis. To provide an unbiased transcriptional gene analysis, we submitted the RNA for bulk RNA sequencing. Differential gene expression (DGE) analysis re-vealed top up-regulated genes were related to anti-inflammatory responses, while pro-inflammatory genes were significantly downregulated. Additionally, using the pathway en-richment and network analyses (Metascape), we confirmed that gene enriched categories related to pro-inflammatory responses were significantly downregulated in macrophages with fat phagocytosis. Finally, we validated the similar macrophage phenotype changes in vivo. To sum-marize, we discovered that fat phagocytosis occurs in both ONFH patients and the mouse ON model, which inhibits pro-inflammatory responses with increased anabolic gene expressions of macrophages. This fat phagocytosis induced macrophage phenotype is consistent with the in vivo changes shown in the ON mice model. Our study reveals a novel phagocytosis mediated macro-phage polarization mechanism in ON, which fills in our knowledge gaps of macrophage func-tions and provides new concepts in macrophage immunomodulation as a promising treatment for ON.
2024-08-02 | GSE272784 | GEO
Project description:Background: In acute kidney injury, macrophages play a major role in regulating inflammation. Classically activated macrophages (M1) undergo drastic metabolic reprogramming during their differentiation and upregulate the aerobic glycolysis pathway to fulfill their pro-inflammatory functions. NAD+ regeneration is crucial for the maintenance of glycolysis and the most direct pathway by which this occurs is via the fermentation of pyruvate to lactate, catalyzed by lactate dehydrogenase A (LDHA). Our previous study determined that LDHA is predominantly expressed in the proximal segments of the nephron in the mouse kidney and increases with hypoxia. This study investigates the potential of LDHA as a therapeutic target for inflammation by exploring its role in macrophage function in vitro. Methods: Bone-marrow-derived macrophages (BMDMs) were isolated from myeloid-specific LDHA knockout mice derived from crossbreeding LysM-Cre transgenic mice and LDHA floxed mice. RNA sequencing and LC-MS/MS metabolomics analyses were used in this study to determine the effect of LDHA deletion on BMDM following stimulation with IFN-γ. Results: LDHA deletion in IFN-γ BMDMs resulted in a significant alteration of the macrophage activation and functional pathways, and change in glycolytic, cytokine, and chemokine gene expression. Metabolite concentrations associated with pro-inflammatory macrophage profiles were diminished while anti-inflammatory-associated ones were increased in LDHA KO BMDMs. Glutamate and amino sugars metabolic pathways were significantly affected by the LDHA deletion. A combined muti-omics analysis highlighted changes in Rap1 signaling, cytokine-cytokine receptor interaction, focal adhesion, and MAPK signaling metabolism pathways. Conclusions: Deletion of LDHA in macrophages results in a notable reduction in the pro-inflammatory profile and concurrent upregulation of anti-inflammatory pathways. These findings suggest that LDHA could serve as a promising therapeutic target for inflammation, a key contributor to the pathogenesis of acute kidney injury.
2024-12-03 | GSE277304 | GEO
Project description:<p>Macrophages are prominent immune cells in the tumor microenvironment that can be educated into pro-tumoral phenotype by tumor cells to favor tumor growth and metastasis. The mechanisms that mediate a mutualistic relationship between tumor cells and macrophages remain poorly characterized. Here, we have shown <em>in vitro</em> that different human and murine cancer cell lines release branched‐chain α‐ketoacids (BCKAs) into the extracellular milieu, which influence macrophage polarization in an monocarboxylate transporter 1 (MCT1)‐dependent manner. We found that α‐ketoisocaproate (KIC) and α‐keto‐β‐methylvalerate (KMV) induced a pro‐tumoral macrophage state, whereas α‐ketoisovalerate (KIV) exerted a pro‐inflammatory effect on macrophages. This process was further investigated by a combined metabolomics/proteomics platform. KMV and KIC altered macrophage tricarboxylic acid (TCA) cycle intermediates and increased polyamine metabolism. Proteomic and pathway analyses revealed that the three BCKAs, especially KMV, exhibited divergent effects on the inflammatory signal pathways, phagocytosis, apoptosis and redox balance. These findings uncover cancer‐derived BCKAs as novel determinants for macrophage polarization with potential to be selectively exploited for optimizing antitumor immune responses.</p>
2022-10-03 | MTBLS4497 | MetaboLights
Project description:The mechanisms that mediate inflammatory macrophages in intestinal inflammation are incompletely understood. Here, using merged analysis of RNA sequences and mass spectrometry (MS)-based quantitative proteomics, we report the distinction of proteomics and transcriptomics in activated macrophage. Dipeptidase-2 (DPEP2), belonging to DPEP family, is highly expressed and downregulated sharply at protein level but not mRNA level in macrophages responding to inflammatory stimulations. Repression of DPEP2 not only enhances macrophage-mediated intestinal inflammation in vivo but also promotes the production of ROS and the transduction of inflammatory pathways in macrophages in vitro. Mechanistically, DPEP2 inhibits recruitment of inactivated macrophages to inflammatory sites by impairing activation of vimentin (VIM), and DPEP2 downregulation promotes the infiltration of pro-inflammatory macrophages through enhancing the activation of VIM by Akt1. Besides, overexpressed DPEP2 inhibits the transduction of inflammatory signals by resisting MAK3K7 in inactivated macrophages, and DPEP2 is degraded by activated Trim32 resulting in sharp activation of NF-κB and p38 MAPK signals by released MAK3K7 in pro-inflammatory macrophages during the development of intestinal inflammation. Trim32-DPEP2 axis accumulates potential energy of inflammation for macrophages. These results identify DPEP2 as a key regulator of macrophage-mediated intestinal inflammation. Thus, Trim32-DPEP2 axis may be a potential therapeutic target for intestinal inflammation.
2025-07-28 | PXD057405 | Pride
Project description:Infiltrating monocyte derived macrophages (MDMs) and resident microglia dominate CNS injury sites. We show that MDMs and microglia can directly communicate to modulate each other’s function. Also, the presence of MDMs in CNS injury suppresses microglia-mediated phagocytosis and inflammation. We suggest that macrophages infiltrating the injured CNS provide a mechanism to control acute and chronic microglia-mediated inflammation, which could otherwise drive damage in a variety of CNS conditions. To understand the global effects of macrophage communication to microglia, we transcriptionally profiled activated adult mouse microglia in the presence or absence of macrophages with and without an inflammatory stiumulus (LPS)
2018-08-01 | GSE102482 | GEO
Project description:The proprotein convertase enzyme FURIN processes immature pro-proteins into functional end- products. FURIN is upregulated in activated immune cells and it regulates T-cell dependent peripheral tolerance and the Th1/Th2 balance. FURIN also promotes the infectivity of pathogens by activating bacterial toxins and by processing viral proteins. Here, we evaluated the role of FURIN in LysM+ myeloid cells in vivo. Mice with a conditional deletion of FURIN in their myeloid cells (LysMCre-fur(fl/fl)) were healthy and showed unchanged proportions of neutrophils and macrophages. Instead, LysMCre-fur(fl/fl) mice had elevated serum IL-1β levels and reduced numbers of splenocytes. An LPS injection resulted in accelerated mortality, elevated serum pro-inflammatory cytokines and upregulated numbers of pro-inflammatory macrophages. A genome-wide gene expression analysis revealed the overexpression of several pro-inflammatory genes in resting FURIN-deficient macrophages. Moreover, FURIN inhibited Nos2 and promoted the expression of Arg1, which implies that FURIN regulates the M1/M2-type macrophage balance. FURIN was required for the normal production of the bioactive TGF-β1 cytokine, but it inhibited the maturation of the inflammation-provoking TACE and Caspase-1 enzymes. In conclusion, FURIN has an anti-inflammatory function in LysM+ myeloid cells in vivo.
2016-12-30 | GSE84117 | GEO