Interferon Regulatory Factor-1 Mediates Alveolar Macrophage Pyroptosis During LPS-Induced Acute Lung Injury in Mice

Wu, Dongdong; Pan, Pinhua; Su, Xiaoli; Zhang, Lemeng; Qin, Qingwu; Tan, Hongyi; Huang, Li; Li, Yuanyuan

doi:10.1097/shk.0000000000000595

Cited by 68 publications

(44 citation statements)

References 25 publications

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“…Histopathological changes in the slices were observed with a microscope and pathological changes were evaluated in a double blind fashion. The severity of acute lung injury was evaluated using a semi-quantitative histological index, as described previously [ 51 ].…”

Section: Methodsmentioning

confidence: 99%

Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9

Zhang

Deng

Zhao

et al. 2016

IJMS

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The pathogenesis of sepsis is complex. Mitochondrial dysfunction, which is responsible for energy metabolism, intrinsic apoptotic pathway, oxidative stress, and systemic inflammatory responses, is closely related with severe sepsis induced death. Mitochondria DNA (mtDNA) contain un-methylated cytosine phosphate guanine (CpG) motifs, which exhibit immune stimulatory capacities. The aim of this study was to investigate the role and mechanism of mtDNA release on lipopolysaccharide (LPS) induced acute lung injury (ALI) and systemic inflammation. Following LPS injection, plasma mtDNA copies peak at 8 h. Compared with wild-type (WT) mice, mtDNA in toll like receptor 4 knockout (TLR4 KO) mice were significantly decreased. MtDNA intra-peritoneal administration causes apparent ALI as demonstrated by increased lung injury score, bronchoalveolar lavage fluid (BALF) total protein and wet/dry (W/D) ratio; mtDNA injection also directly provokes systemic inflammation, as demonstrated by increased IL-1β, IL-6, high-mobility group protein B1 (HMGB1) level; while nuclear DNA (nDNA) could not induce apparent ALI and systemic inflammation. However, compared with WT mice, TLR4 KO could not protect from mtDNA induced ALI and systemic inflammation. Specific TLR9 inhibitor, ODN 2088 pretreatment can significantly attenuate mtDNA induced ALI and systemic inflammation, as demonstrated by improved lung injury score, decreased lung wet/dry ratio, BALF total protein concentration, and decreased systemic level of IL-1β, IL-6 and HMGB1. MtDNA administration activates the expression of p-P38 mitogen-activated protein kinases (MAPK) in lung tissue and specific TLR9 inhibitor pretreatment can attenuate this activation. Thus, LPS-induced mtDNA release occurs in a TLR4-dependent manner, and mtDNA causes acute lung injury and systemic inflammation in a TLR9-dependent and TLR4-independent manner.

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Section: Methodsmentioning

confidence: 99%

Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9

Zhang

Deng

Zhao

et al. 2016

IJMS

Self Cite

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“…The inflammasome activation can cause a rapid, proinflammatory form of cell death called pyroptosis . Interestingly, IRF‐1 was shown to play a role in controlling CASP‐1‐dependent pyroptosis and inflammation during LPS‐induced acute lung injury in mice . In this respect, CASP‐1, regulated by IRF‐1, may thus represent the potential link between the death of leukocytes induced by CTX and the inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

“…40 Interestingly, IRF-1 was shown to play a role in controlling CASP-1-dependent pyroptosis and inflammation during LPSinduced acute lung injury in mice. 34 In this respect, CASP-1, regulated by IRF-1, may thus represent the potential link between the death of leukocytes induced by CTX and the inflammatory response. Moreover, previous studies have shown that IRF-1 directly mediates the IFN-g-induced apoptosis via the activation of Casp1 gene expression in ovarian cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Role of interferon regulatory factor 1 in governing Treg depletion, Th1 polarization, inflammasome activation and antitumor efficacy of cyclophosphamide

Buccione

Fragale

Polverino

et al. 2017

Intl Journal of Cancer

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The antitumor effectiveness of cyclophosphamide (CTX) and other chemotherapeutics was shown to rely not only on direct cytotoxicity but also on immunogenic tumor cell death and systemic immunomodulatory mechanisms, including regulatory T cell (Treg) depletion, Th1 cell polarization, type I interferon (IFN) and proinflammatory cytokine production. IFN regulatory factor (IRF)-1 is a transcriptional regulator of IFNs and IFN-inducible genes, involved in the control of Th1 and Treg differentiation and in sterile inflammation. Aim of this study was to explore the role of IRF-1 in CTX-induced antitumor effects and related immune activities. This study shows for the first time that IRF-1 is important for the antitumor efficacy of CTX in mice. Moreover, experiments in tumor-bearing C57BL/6 mice showed that Irf1 gene expression in the spleen was transiently increased following CTX administration and correlated with the induction of Th1 cell expansion and of Il12p40 gene expression, which is the main Th1-driving cytokine. At the same time, CTX administration reduced both Foxp3 expression and Treg cell percentages. These effects were abrogated in Irf1 mice. Further experiments showed that the gene and/or protein expression of caspase-1, iNOS, IL-1β, IL-6 and CXCL10 and the levels of nitric oxide were modulated following CTX in an IRF-1-direct- or -indirect-dependent manner, and highlighted the importance of caspase-1 in driving the sterile inflammatory response to CTX. Our data identify IRF-1 as important for the antitumor efficacy of CTX and for the regulation of many immunomodulatory activities of CTX, such as Th1 polarization, Treg depletion and inflammation.

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“…Our findings suggest that pyroptosis and the downstream inflammatory response in AMs induced by LPS is a process that is dependent on TLR4-mediated up-regulation of IRF-1. In this way, IRF-1 plays a key role in controlling caspase-1-dependent pyroptosis and inflammation [26].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Interferon Regulatory Factor 1 Activates Autophagy to Aggravate Hepatic Ischemia-Reperfusion Injury by Increasing High Mobility Group Box 1 Release

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Interferon regulatory factor 1(IRF-1) and high mobility group box 1(HMGB1) have been independently identified as being key players in hepatic ischemia-reperfusion injury (IRI). We attempted to determine whether IRF-1 activates autophagy to aggravate hepatic IRI by increasing HMGB1 release. Methods: The hepatic IRI model was generated in C57BL/6 mice, euthanized at 2, 6, 12 or 24 h after reperfusion. To examine the effects of HMGB1 release inhibition, Glycyrrhiza acid (GA) was administered to the mice and at six hours after injectiont. AML12 cells were immersed in mineral oil for 90 min and then cultured in complete Dulbecco’s Modified Eagle’s Medium (DMEM)/F12 to simulate IRI. AML12 cells were treated with IRF-1 siRNA, Ad-IRF-1 or GA. The serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as histological changes were examined. Next, autophagic vacuoles were detected by transmission electron microscopy (TEM) or LC3 dots. The expression of IRF-1 and HMGB1 mRNA were measured by real-time polymerase chain reaction. The expression of IRF-1, microtubule-associated protein 1 light chain 3 (LC3), Bcl-2, Beclin 1, HMGB1 were detected by western blotting or immunohistochemistry. Results: The levels of hepatic IRF-1, mRNA and protein were significantly increased in livers after exposure to IRI, together with, IRI-induced increase of HMGB1 mRNA and release of HMGB1 in liver tissue. Knockout of IRF-1 decreased expression and release of HMGB1 in liver, and inhibiting the release of HMGB1 could alleviate hepatic IRI. In addition, knockout of IRF-1 downregulated LC3II and Beclin1, while number of autophagosomes or LC3 dots were increased. Up-regulating IRF-1 expression could increase the levels of LC3Ⅱ expression in AML12 cells after exposure to IRI. The levels of HMGB1 in Ad-IRF-1 transfected AML12 cell supernatants increased, together with number of LC3 dots increasing. However, GA could inhibit both Ad-IRF-1 induced HMGB1 release and the increase in the number of LC3 dots. Conclusions: IRF-1 activates autophagy to aggravate hepatic IRI by increasing HMGB1 release.

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Interferon Regulatory Factor-1 Mediates Alveolar Macrophage Pyroptosis During LPS-Induced Acute Lung Injury in Mice

Cited by 68 publications

References 25 publications

Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9

Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9

Role of interferon regulatory factor 1 in governing Treg depletion, Th1 polarization, inflammasome activation and antitumor efficacy of cyclophosphamide

Interferon Regulatory Factor 1 Activates Autophagy to Aggravate Hepatic Ischemia-Reperfusion Injury by Increasing High Mobility Group Box 1 Release

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