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IRGM regulates autophagy. IRGM has been shown to be a potent autophagy regulator via five mechanisms: (1) pattern recognition receptors, including NOD2, are triggered upon bacterial infection via PAMPs. Activated NOD2 enhances IRGM binding to ATG16L1, to form a tripartite complex that induces autophagy. (2) IRGM activates AMPK, which in turn phosphorylates ULK1 and Beclin 1 to induce autophagy. (3) IRGM influences the composition of the Beclin 1 complex, by competing with the negative regulators Bcl2 and Rubicon, to trigger autophagy. (4) By binding to ATG8, IRGM induces Stx17 recruitment and stimulates autophagosome-lysosome fusion. (5) Finally, it induces TFEB translocation and lysosomal biogenesis by interacting with calcineurin. Additionally, IRGM isoforms mediate mitochondrial fission by facilitating mitochondrial depolarisation via cardiolipin, potentiating cell death. Furthermore, IRGM prevents type-1 interferon response by sequestering nucleic acid-sensing PRR and inducing their proteasomal degradation via SQSTM1-associated polyubiquitination. PAMPs, pathogen-associated molecular patterns; NOD2, nucleotide-binding oligomerization domain-containing protein 2; AMPK, 5’ AMP activated protein kinase, ATG16L1, autophagy-related gene 16-like 1; ULK1, unc-51 like autophagy activating kinase 1; Bcl2, B-cell lymphoma 2, ATG8, autophagy-related gene 8; Stx17, syntaxin 17; TFEB, transcription factor EB; Bax, Bcl2 associated X; Bak, Bcl2 homologous antagonist killer; TLR3, toll-like receptor 3; cGAS, cyclic GMP-AMP synthase; RIG-I, retinoic acid-inducible gene 1
Source publication
The human immunity-related GTPase M (IRGM) is a GTP-binding protein that regulates selective autophagy including xenophagy and mitophagy. IRGM impacts autophagy by (1) affecting mitochondrial fusion and fission, (2) promoting the co-assembly of ULK1 and Beclin 1, (3) enhancing Beclin 1 interacting partners (AMBRA1, ATG14L1, and UVRAG), (4) interact...
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Citations
... 72 Yet another study used transcriptomic datasets from SjD patients' salivary gland samples to identify three subtypes of salivary gland tissues having distinct cellular and molecular characteristics: i) oxidative phosphorylation-dominant; ii) weak inflammatory with Type I IFN signatures; or iii) B cell receptor signaling pathway-dominant. 73 Prior work has associated the autophagy-related genes ATG5, ATG7, and IRGM with autoimmunity [74][75][76][77] . ...
Objectives
Sjögren’s disease (SjD) is a common exocrine disorder typified by chronic inflammation and dryness, but also profound fatigue, suggesting a pathological basis in cellular bioenergetics. In healthy states, damaged or dysfunctional mitochondrial components are broken down and recycled by mitophagy, a specialized form of autophagy. In many autoimmune disorders, however, evidence suggests that dysfunctional mitophagy allows poorly functioning mitochondria to persist and contribute to a cellular milieu with elevated reactive oxygen species. We hypothesized that mitophagic processes are dysregulated in SjD and that dysfunctional mitochondria contribute to overall fatigue. We sought to link fatigue with mitochondrial dysfunction directly in SjD, heretofore unexamined, and further sought to assess the pathogenic extent and implications of dysregulated mitophagy in SjD.
Methods
We isolated pan T cells via negative selection from the peripheral blood mononuclear cells of 17 SjD and 8 age-matched healthy subjects, all of whom completed fatigue questionnaires prior to phlebotomy. Isolated T cells were analyzed for mitochondrial oxygen consumption rate (OCR) and glycolysis using Seahorse, and linear correlations with fatigue measures were assessed. A mitophagy transcriptional signature in SjD was identified by reanalysis of whole-blood microarray data from 190 SjD and 32 healthy subjects. Differential expression analyses were performed by case/control and subgroup analyses comparing SjD patients by mitophagy transcriptional cluster against healthy subjects followed by bioinformatic interpretation using gene set enrichment analysis.
Results
Basal OCR, ATP-linked respiration, maximal respiration, and reserve capacity were significantly lower in SjD compared to healthy subjects with no observed differences in non-mitochondrial respiration, basal glycolysis, or glycolytic stress. SjD lymphocytic mitochondria show structural alterations compared to healthy subjects. Fatigue scores related to pain/discomfort in SjD correlated with the altered OCR. Results from subgroup analyses by mitophagic SjD clusters revealed highly variable inter-cluster differentially expressed genes (DEGs) and expanded the number of SjD-associated gene targets by tenfold within the same dataset.
Conclusion
Mitochondrial dysfunction, associated with fatigue, is a significant problem in SjD and warrants further investigation.
... Immunity-related GTPase M (IRGM) and its mouse orthologue Irgm1 have been proposed as key negative regulators of inflammation and autoimmunity [14,15]. Although human IRGM and mouse Irgm1 are biochemically different, they are functionally similar in regulating innate immunity and autophagy [16,17]. IRGM/Irgm1 is associated with several inflammatory and autoimmune diseases, including infectious diseases [16], Crohn's disease [18], and non-alcoholic fatty liver disease [19]. ...
... Although human IRGM and mouse Irgm1 are biochemically different, they are functionally similar in regulating innate immunity and autophagy [16,17]. IRGM/Irgm1 is associated with several inflammatory and autoimmune diseases, including infectious diseases [16], Crohn's disease [18], and non-alcoholic fatty liver disease [19]. The regulatory function of IRGM/Irgm1 in autophagy was first described in immune responses against intracellular microorganisms [20]. ...
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.
... 47 Additionally, IRGM and IRF5 are recognized as pivotal regulators of immunity and inflammation. 48,49 Therefore, these specific proteins may play a crucial role in governing mammary immunity and its associated inflammatory response. ...
Mastitis is a disease characterized by congestion, swelling, and inflammation of the mammary gland and usually caused by infection with pathogenic microorganisms. Furthermore, the development of mastitis is closely linked to the exogenous pathway of the gastrointestinal tract. However, the regulatory mechanisms governing the gut‐metabolism‐mammary axis remain incompletely understood. The present study revealed alterations in the gut microbiota of mastitis rats characterized by an increased abundance of the Proteobacteria phylum. Plasma analysis revealed significantly higher levels of L‐isoleucine and cholic acid along with 7‐ketodeoxycholic acid. Mammary tissue showed elevated levels of arachidonic acid metabolites and norlithocholic acid. Proteomic analysis showed increased levels of IFIH1, Tnfaip8l2, IRGM, and IRF5 in mastitis rats, which suggests that mastitis triggers an inflammatory response and immune stress. Follistatin (Fst) and progesterone receptor (Pgr) were significantly downregulated, raising the risk of breast cancer. Extracellular matrix (ECM) receptors and focal adhesion signaling pathways were downregulated, while blood–milk barrier integrity was disrupted. Analysis of protein‐metabolic network regulation revealed that necroptosis, protein digestion and absorption, and arachidonic acid metabolism were the principal regulatory pathways involved in the development of mastitis. In short, the onset of mastitis leads to changes in the microbiota and alterations in the metabolic profiles of various biological samples, including colonic contents, plasma, and mammary tissue. Key manifestations include disturbances in bile acid metabolism, amino acid metabolism, and arachidonic acid metabolism. At the same time, the integrity of the blood–milk barrier is compromised while inflammation is promoted, thereby reducing cell adhesion in the mammary glands. These findings contribute to a more comprehensive understanding of the metabolic status of mastitis and provide new insights into its impact on the immune system.
... Reduced autophagy is caused by the single-nucleotide mutation T300A of ATG16L1, a CD-associated gene. CD-associated variants cause reduced protein expression in immunity-related GTPase M (IRGM) encode a p47 immunity-related GTPase family (Daniel E Shumer, Natalie J Nokoff et al., 2017;Goswami et al., 2022;Ma et al., 2021). Anti-bacterial autophagy is impaired in epithelial cells and dendritic cells with ATG16L1 and NOD2 polymorphisms. ...
... The process for autophagy has three stages: initiation, maturation/nucleation, and degradation/expansion [39,40]. Various autophagy-related genes (ATG) proteins mediate this process. ...
... IRGM controls the core autophagy machinery by interacting with NOD2 (nucleotidebinding oligomerization domain protein 2) and ATG16L1 [40]. IRGM stabilizes the Thr172 phosphorylated form of adenosine monophosphate-activated protein kinase (AMPK) [100], which is required for AMPK activation and the further phosphorylation of the ULK1 complex and Beclin-1 to induce autophagy [101,102]. ...
... IRGM stabilizes the Thr172 phosphorylated form of adenosine monophosphate-activated protein kinase (AMPK) [100], which is required for AMPK activation and the further phosphorylation of the ULK1 complex and Beclin-1 to induce autophagy [101,102]. IRGM are functionally relevant to inflammatory and autophagic responses [40]. Genetic susceptibility is a well-known factor for the risk of NAFLD [103,104]. ...
Metabolic associated fatty liver disease (MAFLD) is one of the most common causes of chronic liver disease worldwide. To date, there is no FDA-approved treatment, so there is an urgent need to determine its pathophysiology and underlying molecular mechanisms. Autophagy is a lysosomal degradation pathway that removes damaged organelles and misfolded proteins after cell injury through endoplasmic reticulum stress or starvation, which inhibits apoptosis and promotes cell survival. Recent studies have shown that autophagy plays an important role in removing lipid droplets from hepatocytes. Autophagy has also been reported to inhibit the production of pro-inflammatory cytokines and provide energy for the hepatic stellate cells activation during liver fibrosis. Thyroid hormone, irisin, melatonin, hydrogen sulfide, sulforaphane, DA-1241, vacuole membrane protein 1, nuclear factor erythroid 2-related factor 2, sodium-glucose co-transporter type-2 inhibitors, immunity-related GTPase M, and autophagy-related gene 7 have been reported to ameliorate MAFLD via autophagic induction. Lipid receptor CD36, SARS-CoV-2 Spike protein and leucine aminopeptidase 3 play a negative role in the autophagic function. This review summarizes recent advances in the role of autophagy in MAFLD. Autophagy modulates major pathological changes, including hepatic lipid metabolism, inflammation, and fibrosis, suggesting the potential of modulating autophagy for the treatment of MAFLD.
Excessive induction of inflammatory and immune responses is widely considered as one of vital factors contributing to the pathogenesis and progression of central nervous system (CNS) diseases. Neutrophils are well-studied members of inflammatory and immune cell family, contributing to the innate and adaptive immunity. Neutrophil-released neutrophil extracellular traps (NETs) play an important role in the regulation of various kinds of diseases, including CNS diseases. In this review, current knowledge on the biological features of NETs will be introduced. In addition, the role of NETs in several popular and well-studied CNS diseases including cerebral stroke, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and neurological cancers will be described and discussed through the reviewing of previous related studies.
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.
Allergic rhinitis (AR) is globally prevalent and its pathogenesis remains unclear. Alternative activation of macrophages is suggested in AR and thought to be involved in natural immunoregulatory processes in AR. Aberrant activation of Nod-like receptor protein 3 (NLRP3) inflammasome is linked with AR. Human placenta extract (HPE) is widely used in clinics due to its multiple therapeutic potential carried by diverse bioactive molecules in it. We aim to investigate the effect of HPE on AR and the possible underlying mechanism. Ovalbumin (OVA)-induced AR rat model was set up and treated by HPE or cetirizine. General manifestation of AR was evaluated along with the histological and biochemical analysis performed on rat nasal mucosa. A proteomic analysis was performed on AR rat mucosa. Mouse alveolar macrophages (MH-S cells) were cultured under OVA stimulation to investigate the regulation of macrophages polarization. The morphological changes and the expression of NLRP3 inflammasome and immunity-related GTPase M (IRGM) in nasal mucosa as well as in MH-S cells were evaluated respectively. The results of our study showed the general manifestation of AR along with the histological changes in nasal mucosa of AR rats were improved by HPE. HPE suppresses NLRP3 inflammasome and the decline of IRGM in AR rats and MH-S cells. HPE regulates macrophage polarization through IRGM/NLRP3. We demonstrated that HPE had protection for AR and the protection is achieved partly through suppressing M1 while promoting M2, the process which is mediated by IRGM via inhibiting NLRP3 inflammasome in AR.
