Aging aggravated liver ischemia and reperfusion injury by promoting STING‐mediated NLRP3 activation in macrophages

Zhong, Weizhe; Rao, Zhuqing; Rao, Jianhua; Han, Guoyong; Wang, Ping; Jiang, Tao; Pan, Xiongxiong; Zhou, Shun; Zhou, Haoming; Wang, Xuehao

doi:10.1111/acel.13186

Cited by 83 publications

(68 citation statements)

References 41 publications

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“…20 During liver ischemia and reperfusion, STING suppression of macrophages inhibited the overactivation of NLRP3 inflammasome and excessive secretion of IL-1β and IL-18, eventually reducing liver injury. 44 However, to our knowledge, there is still lack of explicit data on the role of STING in ALI induced by LPS. In the present study, we discovered that STING deficiency in vivo and in vitro could relieve LPS-induced cellular injury, inflammation, oxidative stress, and pyroptosis in macrophages; however, the beneficial effects from STING deficiency were abolished after NLRP3 overexpression, indicating that the proinflammatory roles of STING relied on the activation of NLRP3.…”

Section: Discussionmentioning

confidence: 99%

Cytosolic DNA‐STING‐NLRP3 axis is involved in murine acute lung injury induced by lipopolysaccharide

Wang

Jiang

et al. 2020

Clinical & Translational Med

161

125

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Section: Discussionmentioning

confidence: 99%

Cytosolic DNA‐STING‐NLRP3 axis is involved in murine acute lung injury induced by lipopolysaccharide

Wang

Jiang

et al. 2020

Clinical & Translational Med

161

125

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“…found that activation of bile acids and TGR5 inhibits activation of the NLRP3 inflammasome via the TGR5-cAMP-PKA axis, endogenously constraining NLRP3 inflammasome-related inflammation ( 57 ). Some studies have shown that liver ischemia and reperfusion injury triggers activation of the NLRP3 inflammasome in macrophages by STING signaling ( 58 ). Our data indicated that in a mouse model of NASH with deletion of TGR5, the NLRP3 inflammasome was significantly increased, suggesting that TGR5 attenuated inflammation in NASH by inhibiting activation of NLPR3.…”

Section: Discussionmentioning

confidence: 99%

TGR5 Regulates Macrophage Inflammation in Nonalcoholic Steatohepatitis by Modulating NLRP3 Inflammasome Activation

Shi

Zhang

et al. 2021

Front. Immunol.

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Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with dysregulation of liver metabolism and inflammation. G-protein coupled bile acid receptor 1 (TGR5) is a cell surface receptor that is involved in multiple metabolic pathways. However, the functions of TGR5 in regulating macrophage innate immune activation in NASH remain unclear. Here, we found that TGR5 expression was decreased in liver tissues from humans and mice with NASH. Compared to wild type (WT) mice, TGR5-knockout (TGR5−/−) mice exhibited exacerbated liver damage, increased levels of proinflammatory factors, and enhanced M1 macrophage polarization. Moreover, TGR5 deficiency facilitated M1 macrophage polarization by promoting NLRP3 inflammasome activation and caspase-1 cleavage. Taken together, our findings revealed that TGR5 signaling attenuated liver steatosis and inflammation and inhibited NLRP3-mediated M1 macrophage polarization in NASH.

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“…However, further studies are required. Activation of STING increases liver perfusion injury, but in aged animals subjected to ischemia-reperfusion, it also activates NLRP3 inflammasome to further enhance the tissue inflammation via aggravated IL-1β and IL-18 release along with other pro-inflammatory cytokines (TNF-α and IL-6) ( 130 ). Hence, age also affects STING-mediated inflammatory diseases.…”

Section: Cgas-sting-based Host Cell Dna Recognitionmentioning

confidence: 99%

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

Kumar

2021

Front. Immunol.

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The immune system has evolved to protect the host from the pathogens and allergens surrounding their environment. The immune system develops in such a way to recognize self and non-self and develops self-tolerance against self-proteins, nucleic acids, and other larger molecules. However, the broken immunological self-tolerance leads to the development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by immunological cells on their cell membrane and in the cytosol. Different Toll-like receptors (TLRs), Nod-like receptors (NLRs) and absent in melanoma-2 (AIM-2)-like receptors (ALRs) forming inflammasomes in the cytosol, RIG (retinoic acid-inducible gene)-1-like receptors (RLRs), and C-type lectin receptors (CLRs) are some of the PRRs. The DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) is another PRR present in the cytosol and the nucleus. The present review describes the role of ALRs (AIM2), TLR9, and cGAS in recognizing the host cell DNA as a potent damage/danger-associated molecular pattern (DAMP), which moves out to the cytosol from its housing organelles (nucleus and mitochondria). The introduction opens with the concept that the immune system has evolved to recognize pathogens, the idea of horror autotoxicus, and its failure due to the emergence of autoimmune diseases (ADs), and the discovery of PRRs revolutionizing immunology. The second section describes the cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, its evolution, characteristics of self-DNAs activating it, and its role in different inflammatory conditions. The third section describes the role of TLR9 in recognizing self-DNA in the endolysosomes during infections depending on the self-DNA characteristics and various inflammatory diseases. The fourth section discusses about AIM2 (an ALR), which also binds cytosolic self-DNA (with 80–300 base pairs or bp) that inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation and pyroptosis during different inflammatory conditions. Hence, this trinity of PRRs has evolved to recognize self-DNA as a potential DAMP and comes into action to guard the cellular galaxy. However, their dysregulation proves dangerous to the host and leads to several inflammatory conditions, including sterile-inflammatory conditions autoinflammatory and ADs.

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Aging aggravated liver ischemia and reperfusion injury by promoting STING‐mediated NLRP3 activation in macrophages

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 83 publications

References 41 publications

Cytosolic DNA‐STING‐NLRP3 axis is involved in murine acute lung injury induced by lipopolysaccharide

Cytosolic DNA‐STING‐NLRP3 axis is involved in murine acute lung injury induced by lipopolysaccharide

TGR5 Regulates Macrophage Inflammation in Nonalcoholic Steatohepatitis by Modulating NLRP3 Inflammasome Activation

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

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