IRGM links autoimmunity to autophagy

Nath, Parej; Jena, Kautilya Kumar; Mehto, Subhash; Chauhan, Nishant Ranjan; Sahu, Rinku; Dhar, Kollori; Kolapalli, Srinivasa Prasad; Chauhan, Santosh

doi:10.1080/15548627.2020.1810920

“…41,42 Moreover, it has been shown that IRGM is the negative regulator of IFN-1. 43 In a recent study, Nath et al 19 reported that IRGM expression increased in response to viral infection and they also found that IRGM depletion resulted in the robust production of various viral restriction factors that create antiviral states. Furthermore, studies have shown that autophagy acts as a suppressor during the early stages of HCC formation and as a promoter once the tumour has progressed.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study reported that reduced expression of IRGM is linked with increased inflammatory cytokines leading to cell death. 19 It has been reported that silencing of the IRGM gene impairs the conversion of the light chain (LC3) into its active form which is required for autophagosome formation. 20 IRGM is found to be involved in autophagy-mediated immunity against bacteria, but many viruses also develop strategies to manipulate autophagy for their benefit.…”

Section: Introductionmentioning

confidence: 99%

Association of IRGM gene promoter polymorphisms with hepatitis B virus infection

Sharma

¹

,

Duseja²,

Parkash

³

et al. 2022

The Journal of Gene Medicine

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Background In response to intracellular pathogens, the autophagy gene IRGM plays an essential role in the innate immune response. Various identified IRGM gene risk loci are associated with several diseases but, so far, no study is available that shows the association of IRGM with hepatitis B virus (HBV) infection. Methods We genotyped promoter variants (rs4958842, rs4958843, and rs4958846) of IRGM in HBV infected patients (551) and healthy controls (247) for their role in HBV infection. The genotyping was performed by applying methods developed in our laboratory and various biochemical parameters were assessed applying commercially available kits. Results Data analysis has shown that the mutant allele A of rs4958842 plays a role in the protection from HBV infection in various genetic models that includes allelic, co‐dominant and dominant models with the respective statistical data: allelic (odds ratio [OR] = 0.61; 95% confidence interval [CI] = 0.48–0.78; p = 0.0003), co‐dominant (OR = 0.52; 95% CI = 0.38–0.71; p = 0.0008) and dominant (OR = 0.51; 95% CI = 0.38–0.70, p = 0.0004). In chronic hepatitis B (CHB), protective association was observed in the allelic (OR = 0.48; 95% CI = 0.35–0.65, p = 0.0004), co‐dominant (OR = 0.38; 95% CI = 0.26–0.54, p = 0.0004) and dominant (OR = 0.38; 95% CI = 0.26–0.54, p = 0.0002) models. Mutant allele C of rs49598843 was associated with the risk of CHB in co‐dominant (OR = 1.52; 95% CI = 1.07–2.16, p = 0.04) and dominant (OR = 1.41; 95% CI = 1.00–2.00, p = 0.04) models. The mutant allele C of rs4958846 decreased the risk of HBV infection in allelic (OR = 0.74; 95% CI = 0.59–0.92, p = 0.01), dominant (OR = 0.72; 95% CI = 0.53–0.98, p = 0.05), homozygous (OR = 0.42; 95% CI = 0.24–0.74, p = 0.01) and recessive (OR = 0.42; 95% CI = 0.24–0.74, p = 0.0004) models. However, in the asymptomatic group, it was associated with the increased chance of HBV infection. Haplotypes, ATT (OR = 0.47; 95% CI = 0.33–0.68, p = 0.001) and GTC (OR = 0.68; 95% CI = 0.51–0.92, p = 0.01) protect, whereas GTT (OR = 2.01; 95% CI = 1.55–2.60, p < 0.0001) predisposes the individuals to HBV infection. All of these p values mentioned here were obtained after performing Bonferroni correction. Conclusions In conclusion, our findings revealed that mutant allele A of rs4958842, mutant allele C of rs4958843 and rs4958846 were associated with hepatitis B virus infection in the North Indian population.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Positive Effect of Andrographolide Induced Autophagy on Random-Pattern Skin Flaps Survival

Jiang

¹

,

Jin

²

,

Lou

³

et al. 2021

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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.

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“…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].…”

Section: Discussionmentioning

confidence: 99%

Effects of Herb-Partitioned Moxibustion on Autophagy and Immune Activity in the Colon Tissue of Rats with Crohn’s Disease

Zhao

¹

,

Ma

²

,

Zheng

³

et al. 2022

Evidence-Based Complementary and Alternative Medicine

1

0

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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.

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IRGM links autoimmunity to autophagy

Cited by 20 publications

References 1 publication

Association of IRGM gene promoter polymorphisms with hepatitis B virus infection

Association of IRGM gene promoter polymorphisms with hepatitis B virus infection

Positive Effect of Andrographolide Induced Autophagy on Random-Pattern Skin Flaps Survival

Effects of Herb-Partitioned Moxibustion on Autophagy and Immune Activity in the Colon Tissue of Rats with Crohn’s Disease

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