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The model of IRGM linking autophagy and autoimmunity. In the absence of IRGM, selective autophagy of nucleic acid sensors and mitophagy are diminished, resulting in an increased amount of nucleic acid sensor proteins and the accumulation of DAMPs leading to a vicious cycle of inflammation. The DAMPs are sensed by the nucleic acid-sensing pathways to activate the IFN response and production of ISGs, which in turn induce other invasive/aggressive immune reactions leading to cell death, tissue/organ damage, and more DAMPs, culminating in autoimmune-like conditions.
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IRGM is a genetic risk factor for several autoimmune diseases. However, the mechanism of IRGM-mediated protection in autoimmunity remains undetermined. The abnormal activation of type I interferon (IFN) response is one of the significant factors in the pathogenesis of several autoimmune diseases. In our recent study, we showed that IRGM is a master...
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... our recent work [1], we found that IRGM is a master suppressor of type I IFN response by controlling the CGAS-STING1 and DDX58/RIG-I-MAVS signaling pathways ( Figure 1). The global transcriptome analysis of IRGMdepleted human and mice cells shows a robust induction of type I IFN response. ...
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... understand how IRGM suppresses the type I IFN response, we determined the levels of the proteins associated with these pathways. All of the three signaling axes, CGAS-STING1, DDX58/RIG-I-IFIH1/MDA5-MAVS, and TLR3-TICAM1/TRIF, and all of the nodal adaptors and kinases are increased or activated in IRGM-depleted cells (Figure 1) Next, we wanted to understand how IRGM controls these signaling pathways. We found that IRGM interacts with CGAS, DDX58/RIG-I and TLR3, and mediates their autophagic degradation to suppress ISGs production (Figure 1). ...
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... of the three signaling axes, CGAS-STING1, DDX58/RIG-I-IFIH1/MDA5-MAVS, and TLR3-TICAM1/TRIF, and all of the nodal adaptors and kinases are increased or activated in IRGM-depleted cells (Figure 1) Next, we wanted to understand how IRGM controls these signaling pathways. We found that IRGM interacts with CGAS, DDX58/RIG-I and TLR3, and mediates their autophagic degradation to suppress ISGs production (Figure 1). To determine how IRGM mediates degradation of these cargo proteins, we screened the interaction of autophagy receptor proteins with IRGM. ...
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... IRGM deficiency results in reduced mitophagy flux, accumulation of hyperpolarized defunct mitochondria, and increased mitochondrial ROS (reactive oxygen species) (Figure 1). Further, the cytosol of these cells is soiled with nuclear and mitochondrial DAMPs, including dsDNA and dsRNA. ...
Similar publications
Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) and is considered one of the leading causes of mortality. Multiple immunological pathways are involved in the pathogenesis of SLE, which makes it imperative to deepen our knowledge about this disease's immunopathological complexity and explore new therapeutic target...
Citations
... Previous studies identified an association of IRGM/Irgm1 with autophagy. Jean et al. [29] and Nath et al. [30] claimed that IRGM/ Irgm1 interacted with nucleic acid sensor proteins, cGAS and RIG-I, to regulate P62-dependent autophagic degradation to suppress interferon signaling. Lin et al. [31] found that IRGM knockdown inhibited autophagic flux along with increased lipid droplet content in HepG2 and PLC/PRF/5 cells, which were corrected by the administration of rapamycin. ...
Immune-related GTPase M (IRGM) induces autophagy and suppresses inflammation, but its putative role and signaling mechanism remain undefined in the pathogenesis of liver failure. This study aimed to address how IRGM attenuates inflammatory injury by regulating autophagy in liver failure. In this study, a total of 10 patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) and 10 healthy controls were prospectively enrolled. Intrahepatic expression of IRGM/Irgm1, NLRP3 inflammasome (NLRP3, ASC, and caspase-1), autophagy-related proteins (LC3II, P62), and inflammatory cytokines (IL-1β, TNF-α) were measured. Autophagy was activated by rapamycin (4 mg/kg) in an acute liver failure (ALF) mouse model, which was used to further study the expression of Irgm1, NLRP3 inflammasome, autophagy-related proteins, and inflammatory cytokines using both qRT-PCR and Western blot analyses. Irgm1 expression was knocked down using Irgm1 short hairpin RNA (shRNA) in lipopolysaccharide (LPS)-induced AML12 cells to investigate the effects of Irgm1 deletion on autophagy and inflammation. We found that the expression of IRGM and autophagy-related proteins was significantly downregulated while the NLRP3 inflammasome was significantly upregulated in the livers of HBV-ACLF patients and the ALF mouse model (all P < 0.05). Rapamycin-induced autophagy ameliorated intrahepatic NLRP3 inflammasome activation and decreased inflammation and necrosis in the ALF mice. Irgm1 knockdown decreased autophagy and significantly upregulated NLRP3 inflammasome activation in AML12 cells (all P < 0.05). Rapamycin-induced autophagy also protected against hepatocyte injury following LPS stimulation in vitro by inhibiting NLRP3 inflammasome activation. Thus, IRGM/Irgm1 alleviates inflammation-mediated hepatocyte injury by regulating autophagy. This study provides new insight into potential molecular targets to treat liver failure.
... Previous studies identi ed an association of IRGM/Irgm1 with autophagy. Jean et al. 28 and Nath et al. 29 claimed that IRGM/Irgm1 interacted with nucleic acid sensor proteins, cGAS and RIG-I, to regulate P62dependent autophagic degradation to suppress interferon signaling. Lin et al. 30 found that IRGM knockdown inhibited autophagic ux along with increased lipid droplet content in HepG2 and PLC/PRF/5 cells, which were corrected by the administration of rapamycin. ...
Immune-related GTPase M (IRGM) induces autophagy and suppresses inflammation, but its putative role and signaling mechanism remain undefined in the pathogenesis of liver failure. This study aimed to address how IRGM attenuates inflammatory injury by regulating autophagy in liver failure. In this study, a total of 10 patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) and 10 healthy controls were prospectively enrolled. Intrahepatic expression of IRGM/Irgm1, NLRP3 inflammasome (NLRP3, ASC, and caspase-1), autophagy-related proteins (LC3II, P62), and inflammatory cytokines (IL-1β, TNF-α) were measured. Autophagy was activated by rapamycin (4 mg/kg) in an acute liver failure (ALF) mouse model, which was used to further study the expression of Irgm1, NLRP3 inflammasome, autophagy-related proteins, and inflammatory cytokines using both qRT-PCR and Western blot analyses. Irgm1 expression was knocked down using Irgm1 short hairpin RNA (shRNA) in lipopolysaccharide (LPS)-induced AML12 cells to investigate the effects of Irgm1 deletion on autophagy and inflammation. We found that expression of IRGM and autophagy-related proteins was significantly downregulated while the NLRP3 inflammasome was significantly upregulated in the livers of HBV-ACLF patients and the ALF mouse model (all P<0.05). Rapamycin-induced autophagy ameliorated intrahepatic NLRP3 inflammasome activation and decreased inflammation and necrosis in the ALF mice. Irgm1 knockdown decreased autophagy and significantly upregulated NLRP3 inflammasome activation in AML12 cells (all P<0.05). Rapamycin-induced autophagy also protected against hepatocyte injury following LPS stimulation in vitro by inhibiting NLRP3 inflammasome activation. Thus, IRGM/Irgm1 alleviates inflammation-mediated hepatocyte injury by regulating autophagy. This study provides new insight into potential molecular targets to treat liver failure.
... Also, IRGM has a crucial impact on mitophagy, a rather novel concept and a highly selective form of autophagy that degrades damaged mitochondria [13,14]. There is emerging evidence related to the importance of mitochondrial homeostasis in SLE [15,16] as it is linked to apoptosis, reactive oxygen species-derived neutrophil extracellular traps, and suppressing type I interferon levels [17]. IRGM gene has been shown to link autoimmunity to mitochondrial quality [13], and abnormalities of the gene lead to defective mitochondrial functions [18], and hence, disruption of the above-mentioned pathways. ...
Objective:
One of the potential factors that cause systemic lupus erythematosus (SLE) development is autophagy. Immunity-related GTPase family M protein (IRGM) has been shown to be linked to immune-mediated diseases. The aim of the current study was to assess the role of the IRGM-autophagy gene in SLE susceptibility in an Egyptian population and its relation to lupus nephritis.
Methods:
A case-control study was conducted in which a total of 200 subjects (100SLE and 100 healthy controls) were enrolled. Two single-nucleotide polymorphisms (SNPs) (rs10065172 and rs4958847) were genotyped. Genotypes and alleles analysis was conducted to compare between cases and controls, as well as a stratification analysis was conducted on the presence or absence of lupus nephritis.
Results:
Among selected SNPs of IRGM, no association was found between both SNPs and SLE susceptibility. For rs10065172, the major expressed genotype was CC (61% and 71%) (Adj OR= 2.9, 95%= 0.545-15.5), followed by TC (34 % and 27%) (Adj OR= 1.985, 95%= 0.357-11.041) in cases and controls, respectively. For rs4958847, AA and AG were comparably expressed in case [(43% and 39%) (Adj OR= 1.073, 95%= 0.483-2.382)] and control [(41% and 43%) (Adj OR= 1.24, 95%= 0.557- 2.763)], respectively. Additionally, no relationship among both SNPs and gender, lupus nephritis, disease activity, or disease duration, was observed.
Conclusion:
IRGM SNPs (rs10065172 and rs4958847) expression was comparable among SLE patients and controls of the Egyptian cohort. Genotype and allele frequency of IRGM SNPs did not differ in lupus nephritis and non-lupus nephritis patients.
... Other entities such as miR-142-3p, miR-93, miR-106B, miR-30C, miR-130a, miR-346, and miR-20a were reported to regulate inflammation by targeting the autophagy gene (i.e., ATG16L1) via several different molecular pathways. For example, miR-196 can downregulate the IRGM gene [28], that codes for a protein that plays an important role in immunity [29]. In addition, miR-196 suppresses autophagy by inhibiting the accumulation of LC3II [28]. ...
Inflammatory bowel diseases (IBD) are characterized by chronic inflammation and damage of colonocytes with etiology of genetic, epigenetic and environmental factors. MicroRNA-223 (miR-223) has been found to be increased in both IBD patients and animal colitis models. However, contentious opinions relevant to the roles of miR-223 in IBD have been reported. Notwithstading that most studies have described that miR-223 has anti-inflammatory effects, several reports have progressed a pro-inflammatory view. In this review, we summarise both the anti-inflammatory and pro-inflammatory effects of miR-223 on key molecules in inflammatory responses in both animal models and in patients diagnosed with IBD and objectively discuss the possible basis for the discrepancies.
... Because prolonged inflammatory responses can be detrimental to the host, mechanisms exist to dampen such responses when pathogens are being cleared and autophagy contributes to this resolution. Autophagy can thus target components of TLR-associated signaling pathways for degradation [21][22][23][24] . For example, depending on the context, the TRIF adaptor can be targeted by the autophagy receptors NDP52, TAX1BP1, or p62/SQSTM1 for lysosomal degradation subsequently to TLR3 and/or TLR4 engagement ( Figure 2). ...
... A particularly important aspect of the involvement of Irgm1/IRGM in autophagy may be in their ability to promote autophagic clearance of mitochondria, a process known as mitophagy. When Irgm1 and/or IRGM is absent, mitochondrial homeostasis is perturbed as reflected in an accumulation of defective mitochondria, altered mitochondrial fission/fusion states, and increased presence of intracellular mitochondrial DNA in the cytoplasm- 24,25,[201][202][203][204] . These alterations in mitochondria result in changes in cellular metabolism that shape immune cell function and increase inflammation 25,205 . ...
... The mitochondrial DNA/RNA soiling of the cytoplasm has profound consequences, as it activates intracellular sensors such as cGAS/STING. RIG-I-MAVS, and TLR7 that trigger a cascade of cytokine production 24,25,204 . This notably drives a type I 'interferonopathy' that significantly modulates multiple immune responses and is a key driver of disease. ...
Autophagy is a highly conserved process that utilizes lysosomes to selectively degrade a variety of intracellular cargo, thus providing quality control over cellular components and maintaining cellular regulatory functions. Autophagy is triggered by multiple stimuli ranging from nutrient starvation to microbial infection. Autophagy extensively shapes and modulates the inflammatory response, the concerted action of immune cells, and secreted mediators aimed to eradicate a microbial infection or to heal sterile tissue damage. Here, we first review how autophagy affects innate immune signaling, cell-autonomous immune defense, and adaptive immunity. Then, we discuss the role of non-canonical autophagy in context of microbial infections and inflammation. Finally, we review how crosstalk between autophagy and inflammation influences infectious diseases as well as metabolic and autoimmune disorders.
... Meanwhile, it was also reported that IRGM inactivated caspase-11-dependent inflammatory response, whereas it activated autophagy via direct interaction with ATG8 (Eren et al, 2020;Finethy et al, 2020;Nath et al, 2021). ...
Significance:
Autophagy is critical to cellular homeostasis. Emergence of the concept of regulated necrosis, such as necroptosis, ferroptosis, pyroptosis, and MPT (mitochondrial membrane-permeability transition)-derived necrosis has revolutionized the research into necrosis. Both altered autophagy and regulated necrosis contribute to major human diseases. Recent studies reveal an intricate interplay between autophagy and regulated necrosis. Understanding the interplay at the molecular level will provide new insights into the pathophysiology of related diseases.
Recent advances:
Among the three forms of autophagy, macroautophagy is better studied for its crosstalk with regulated necrosis. Macroautophagy seemingly can either antagonize or promote regulated necrosis, depending upon the form of regulated necrosis, the type of cells or stimuli, and other cellular context. This review will critically analyze recent advances in the molecular mechanisms governing the intricate dialogues between macroautophagy and main forms of regulated necrosis.
Critical issues:
The dual roles of autophagy, either pro-survival or pro-death characteristics intricate the mechanistic relationship between autophagy and regulated necrosis at molecular level in various pathological conditions. Meanwhile, key components of regulated necrosis are also involved in the regulation of autophagy, which further complicates the interrelationship.
Future directions:
Resolving the controversies over causation between altered autophagy and a specific form of regulated necrosis requires approaches that are more definitive, where rigorous evaluation of autophagic flux and the development of more reliable and specific methods to quantify each form of necrosis will be essential. The relationship between chaperone-mediated autophagy or microautophagy and regulated necrosis remains largely unstudied.
... 57 IRGM encodes a member of the interferon-inducible GTPase family, which has important functions in the innate immune response by regulating autophagy formation in response to intracellular pathogens. 58 PKP3 encodes a member of the armadillo protein family with function in both signal transduction and cell adhesion, and its dysregulation has been implicated in transcriptional activation of proinflammatory cytokines. 59,60 Our finding suggested that DNA methylation of IRGM and PKP3 might contribute to ADL disability of older adults through inflammation response and autophagy induced by manganese. ...
Background:
Exposure to heavy metals has been reported to be associated with multiple diseases. However, direct associations and potential mechanisms of heavy metals with physical disability remain unclear.
Objectives:
We aimed to quantify associations of heavy metals with physical disability and further explore the potential mechanisms of DNA methylation on the genome scale.
Methods:
A cross-sectional study of 4,391 older adults was conducted and activities of daily living (ADL) disability were identified using a 14-item scale questionnaire including basic and instrumental activities to assess the presence of disability (yes or no) rated on a scale of dependence. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated to quantify associations between heavy metals and ADL disability prevalence using multivariate logistic regression and Bayesian kernel machine regression (BKMR) models. Whole blood-derived DNA methylation was measured using the HumanMethylationEPIC BeadChip array. An ADL disability-related epigenome-wide DNA methylation association study (EWAS) was performed among 212 sex-matched ADL disability cases and controls, and mediation analysis was further applied to explore potential mediators of DNA methylation.
Results:
Each 1-standard deviation (SD) higher difference in log10-transformed manganese, copper, arsenic, and cadmium level was significantly associated with a 14% (95% CI: 1.05, 1.24), 16% (95% CI:1.07, 1.26), 22% (95% CI:1.13, 1.33), and 15% (95% CI:1.06, 1.26) higher odds of ADL disability, which remained significant in the multiple-metal and BKMR models. A total of 85 differential DNA methylation sites were identified to be associated with ADL disability prevalence, among which methylation level at cg220000984 and cg23012519 (annotated to IRGM and PKP3) mediated 31.0% and 31.2% of manganese-associated ADL disability prevalence, cg06723863 (annotated to ESRP2) mediated 32.4% of copper-associated ADL disability prevalence, cg24433124 (nearest to IER3) mediated 15.8% of arsenic-associated ADL disability prevalence, and cg07905190 and cg17485717 (annotated to FREM1 and TCP11L1) mediated 21.5% and 30.5% of cadmium-associated ADL disability prevalence (all p<0.05).
Discussion:
Our findings suggested that heavy metals contributed to higher prevalence of ADL disability and that locus-specific DNA methylation are partial mediators, providing potential biomarkers for further cellular mechanism studies. https://doi.org/10.1289/EHP10602.
... Cooney et al. [33] showed that the NOD2 and ATG16L1 genes together induced the autophagy of dendritic cells in CD, and this process was involved in the NOD2-mediated antigen presentation and bacterial treatment. e protein encoded by the IRGM gene plays an important role in the immunity induced by intracellular pathogens and is involved in the induction of autophagy and the maturation of autophagosomes [34]. IRGM is a key player in mediating p62-dependent selective autophagy of NLRP3 [35]. ...
Objective:
To investigate the mechanism of action of herb-partitioned moxibustion on CD from the perspective of autophagy and immunity.
Methods:
The expression of microtubule-associated protein LC3II and SQSTM1/p62 in the colon tissues was detected by immunohistochemistry. Western blot was used to detect the expression of autophagic and immune-related proteins in the colon, such as LC3II, SQSTM1/p62, Beclin1, ATG16L1, NOD2, IRGM, IL-1β, IL-17, and TNF-β. mRNA levels of immune factors, such as IL-1β, IL-17, and TNF-β, and autophagy signaling molecules, such as PI3KC, AKT1, LKB1, and mTOR, were detected by RT-qPCR.
Results:
Herb-partitioned moxibustion reduced the protein levels of ATG16L1, NOD2, IRGM, LC3II, and Beclin1 (P < 0.01) and both the protein and mRNA levels of IL-1β, IL-17, and TNF-β in CD rats (P < 0.01 or P < 0.05), and it also increased the expression of SQSTM1/p62 protein (P < 0.01). The modulatory effects of herb-partitioned moxibustion on ATG16L1, NOD2, IRGM, LC3II, TNF-β, and IL-17 protein and IL-1β protein and mRNA were better than those of mesalazine (P < 0.01 or P < 0.05). Herb-partitioned moxibustion also reduced colon PI3KC, AKT1, and LKB1 mRNA expressions in CD rats (P < 0.01 or P < 0.05) and increased mTOR protein expression (P < 0.05). And the modulatory effect of herb-partitioned moxibustion on AKT1 mRNA was better than that of mesalazine (P < 0.05).
Conclusion:
Herb-partitioned moxibustion may inhibit excessively activated autophagy and modulate the expression of immune-related factors by regulating the LKB1-mTOR-PI3KC signal transduction networks, thereby alleviating intestinal inflammation in CD rats.
... Recent research has focused on the emerging role of IRGM/Irgm1 in coordinating autophagy [47]. Oxidised low-density lipoprotein can induce autophagy to protect cells [8,[48][49][50][51], which is supported by our in vitro study results. ...
Rationale: Atherosclerosis plaque rupture (PR) is the pathological basis and chief culprit of most acute cardiovascular events and death. Given the complex and important role of macrophage apoptosis and autophagy in affecting plaque stability, an important unanswered question include is whether, and how, immunity-related GTPase family M protein (IRGM) and its mouse orthologue IRGM1 affect macrophage survival and atherosclerotic plaque stability.
Methods: To investigate whether serum IRGM of ST-segment elevation myocardial infarction (STEMI) patients is related to plaque morphology, we divided 85 STEMI patients into those with and without plaque rupture (PR and non-PR, respectively) based on OCT image analysis, and quantified the patients' serum IRGM levels. Next, we engineered Irgm1 deficient mice (Irgm1+/-) and chimera mice with Irgm1 deficiency in the bone marrow on an ApoE-/- background, which were then fed a high-fat diet for 16 weeks. Pathological staining was used to detect necrotic plaque cores, ratios of neutral lipids and cholesterol crystal, as well as collagen fiber contents in these mice to characterize plaque stability. In addition, immunofluorescence, immunohistochemical staining and western blot were used to detect the apoptosis of macrophages in the plaques. In vitro, THP-1 and RAW264.7 cells were stimulated with ox-LDL to mimic the in vivo environment, and IRGM/IRGM1 expression were modified by specific siRNA (knockdown) or IRGM plasmid (knocked-in). The effect of IRGM/Irgm1 on autophagy and apoptosis of macrophages induced by ox-LDL was then evaluated. In addition, we introduced inhibitors of the JNK/p38/ERK signaling pathway to verify the specific mechanism by which Irgm1 regulates RAW264.7 cell apoptosis.
Results: The serum IRGM levels of PR patients is significantly higher than that of non-PR patients and healthy volunteers, which may be an effective predictor of PR. On a high-fat diet, Irgm1-deficient mice exhibit reduced necrotic plaque cores, as well as neutral lipid and cholesterol crystal ratios, with increased collagen fiber content. Additionally, macrophage apoptosis is inhibited in the plaques of Irgm1-deficient mice. In vitro, IRGM/Irgm1 deficiency rapidly inhibits ox-LDL-induced macrophage autophagy while inhibiting ox-LDL-induced macrophage apoptosis in late stages. Additionally, IRGM/Irgm1 deficiency suppresses reactive oxygen species (ROS) production in macrophages, while removal of ROS effectively inhibits macrophage apoptosis induced by IRGM overexpression. We further show that Irgm1 can affect macrophage apoptosis by regulating JNK/p38/ERK phosphorylation in the MAPK signaling pathway.
Conclusions: Serum IRGM may be related to the process of PR in STEMI patients, and IRGM/Irgm1 deficiency increases plaque stability. In addition, IRGM/Irgm1 deficiency suppresses macrophage apoptosis by inhibiting ROS generation and MAPK signaling transduction. Cumulatively, these results suggest that targeting IRGM may represent a new treatment strategy for the prevention and treatment of acute cardiovascular deaths caused by PR.
... Autophagy is a very conserved process that degrades the accumulation of toxic and necrotic substances and maintains the stability of the intracellular environment (Nath et al., 2020). Autophagy has anti-aging and anti-tumorigenic effects and inhibits neurodegeneration, degrades invading microbes, and presents intracellular antigens. ...
Random-pattern skin flap replantation is generally used in the reconstruction of surgical tissues and covering a series of skin flap defects. However, ischemia often occurs at the flap distal parts, which lead to flap necrosis. Previous studies have shown that andrographolide (Andro) protects against ischemic cardiovascular diseases, but little is known about the effect of Andro on flap viability. Thus, our study aimed to building a model of random-pattern skin flap to understand the mechanism of Andro-induced effects on flap survival. In this study, fifty-four mice were randomly categorized into the control, Andro group, and the Andro+3-methyladenine group. The skin flap samples were obtained on postoperative day 7. Subsequently, the tissue samples were underwent a series of evaluations such as changes in the appearance of flap tissue, the intensity of blood flow, and neovascularization density of skin flap. In our study, the results revealed that Andro enhanced the viability of random skin flaps by enhancing angiogenesis, inhibiting apoptosis, and reducing oxidative stress. Furthermore, our results have also demonstrated that the administration of Andro caused an elevation in the autophagy, and these remarkable impact of Andro were reversed by 3-methyladenine (3-MA), the most common autophagy inhibitor. Together, our data proves novel evidence that Andro is a potent modulator of autophagy capable of significantly increasing random-pattern skin flap survival.
