scholarly journals Aldose reductase deficiency inhibits LPS-induced M1 response in macrophages by activating autophagy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Peng Cheng ◽  
Jianwei Xie ◽  
Zhiyong Liu ◽  
Jian Wang
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Aldose Reductase ◽  
Macrophage Polarization ◽  
Critical Role ◽  
Transcriptional Level ◽  
Mrna Levels ◽  
M1 Polarization ◽  
M1 Macrophage ◽  
Oxide Synthase

AbstractMacrophage M1 polarization mediates inflammatory responses and tissue damage. Recently, aldose reductase (AR) has been shown to play a critical role in M1 polarization in macrophages. However, the underlying mechanisms are unknown. Here, we demonstrated, for the first time, that AR deficiency repressed the induction of inducible nitric oxide synthase in lipopolysaccharide (LPS)-stimulated macrophages via activation of autophagy. This suppression was related to a defect in the inhibitor of nuclear factor κB (NF-κB) kinase (IKK) complex in the classical NF-κB pathway. However, the mRNA levels of IKKβ and IKKγ were not reduced in LPS-treated AR knockout (KO) macrophages, indicating that their proteins were downregulated at the post-transcriptional level. We discovered that LPS stimuli induced the recruitment of more beclin1 and increased autophagosome formation in AR-deficient macrophages. Blocking autophagy through 3-methyladenine and ammonium chloride treatment restored IKKβ and IKKγ protein levels and increased nitric oxide synthase production in LPS-stimulated AR-deficient macrophages. More assembled IKKβ and IKKγ underwent ubiquitination and recruited the autophagic adaptor p62 in LPS-induced AR KO macrophages, promoting their delivery to autophagosomes and lysosomes. Collectively, these findings suggest that AR deficiency is involved in the regulation of NF-κB signaling, and extends the role of selective autophagy in fine-tuned M1 macrophage polarization.

scholarly journals AR Deficiency Inhibits LPS-induced M1 Response in Macrophages by Activating Autophagy

2020 ◽  
Author(s):  
Peng Cheng ◽  
Jianwei Xie ◽  
Zhiyong Liu ◽  
Jian Wang
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Critical Role ◽  
Transcriptional Level ◽  
Mrna Levels ◽  
M1 Polarization ◽  
M1 Macrophage ◽  
Oxide Synthase

Abstract Macrophage M1 polarization mediates inflammatory responses and tissue damage. Recently, aldose reductase (AR) has been shown to play a critical role in of M1 polarization in macrophages. However, the underlying mechanisms are unknown. Here, we demonstrated, for the first time, that AR deficiency repressed the induction of inducible nitric oxide synthase in lipopolysaccharide (LPS)-stimulated macrophages via activation of autophagy. This suppression was related to a defect in the inhibitor of nuclear factor κB (NF-κB) kinase (IKK) complex in the classical NF-κB pathway. However, the mRNA levels of the IKKβ and IKKγ were not reduced in LPS-treated AR knockout (KO) macrophages, indicating that their proteins were downregulated at the post-transcriptional level. We discovered that LPS stimuli induced the recruitment of more beclin1 and increased autophagosome formation in AR-deficient macrophages. Blocking autophagy by 3-methyladenine and ammonium chloride treatment restored IKKβ and IKKγ protein levels and increased nitric oxide synthase production in LPS-stimulated AR-deficient macrophages. More assembled IKKβ and IKKγ undergo ubiquitination and recruit the autophagic adaptor p62 in LPS-induced AR KO macrophages, promoting their delivery to autophagosomes and lysosomes. Collectively, these findings suggest that AR deficiency involves in the regulation of NF-κB signaling, and extends the role of selective autophagy in fine-tuned M1 macrophage polarization.

Requirement of nuclear factor kappaB for the constitutive expression of nitric oxide synthase-2 and cyclooxygenase-2 in rat trophoblasts

1999 ◽  
Vol 112 (18) ◽  
pp. 3147-3155
Author(s):  
N.A. Callejas ◽  
M. Casado ◽  
L. Bosca ◽  
P. Martin-Sanz
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cyclooxygenase 2 ◽  
Nuclear Factor Kappab ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Cox 2 ◽  
Nf Kappab ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase

Recently isolated trophoblasts express nitric oxide synthase 2 (NOS-2) and cyclooxygenase 2 (COX-2), decreasing the levels of the corresponding mRNAs when the cells were maintained in culture. The sustained expression of COX-2 and NOS-2 in trophoblasts was dependent on the activation of nuclear factor kappaB (NF-kappaB) since proteasome inhibitors and antioxidants that abrogated NF-kappaB activity suppressed the induction of both genes. The time-dependent fall of the mRNA levels of NOS-2 and COX-2 paralleled the inhibition of NF-kappaB, determined by electrophoretic mobility shift assays, and the increase of the IkappaBalpha and IkappaBbeta inhibitory proteins. Isolated trophoblasts synthesized reactive oxygen intermediates (ROI), a process impaired after culturing the cells, and that might be involved in the NF-kappaB activation process. Moreover, treatment of recently isolated cells with ROI scavengers suppressed the expression of COX-2 and NOS-2. Challenge of trophoblasts with interleukin-1beta up-regulated the expression of both proteins, an effect that was potentiated by lipopolysaccharide. These results indicate that the physiological expression of NOS-2 and COX-2 in trophoblasts involves a sustained activation of NF-kappaB which inhibition abrogates the inducibility of both genes.

scholarly journals Dexamethasone differentially affects interleukin 1β- and cyclic AMP-induced nitric oxide synthase mRNA expression in renal mesangial cells

1994 ◽  
Vol 304 (2) ◽  
pp. 337-340 ◽  
Author(s):  
D Kunz ◽  
G Walker ◽  
J Pfeilschifter
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cyclic Amp ◽  
Mesangial Cells ◽  
Inos Mrna ◽  
Mrna Levels ◽  
Necrosis Factor Alpha ◽  
Camp Analogue ◽  
Oxide Synthase ◽  
Inos Induction

Inducible nitric oxide synthase (iNOS) is expressed in renal mesangial cells in response to two principal classes of activating signals that interact in a synergistic fashion. These two groups of activators comprise inflammatory cytokines such as interleukin (IL)-1 beta or tumour necrosis factor alpha and agents that elevate cellular levels of cyclic AMP (cAMP). We examined whether dexamethasone differentially affects iNOS induction in response to IL-1 beta and a membrane-permeable cAMP analogue, N6,O-2′-dibutyryladenosine 3′,5′-phosphate (Bt2cAMP). Nanomolar concentrations of dexamethasone suppress IL-1 beta- as well as Bt2cAMP-induced iNOS protein expression and production of nitrite, the stable end product of nitric oxide (NO) formation. In contrast, dexamethasone prevents induction of iNOS mRNA in response to Bt2cAMP without affecting IL-1 beta-triggered increase in iNOS mRNA levels. These data suggest that dexamethasone acts at different levels, depending on the stimulus used to suppress iNOS induction in mesangial cells.

Critical Role of Val567 in Substrate Recognition by Neuronal Nitric Oxide Synthase for NO Formation Activity

2003 ◽  
Vol 32 (11) ◽  
pp. 998-999 ◽  
Author(s):  
Hiroto Takahashi ◽  
Yuko Sato ◽  
Magoli Moreau ◽  
Marie-Agnes Sari ◽  
Jean-Luc Boucher ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Substrate Recognition ◽  
Critical Role ◽  
Neuronal Nitric Oxide Synthase ◽  
No Formation ◽  
Oxide Synthase

LPS-induced downregulation of MRP2 and BSEP in human liver is due to a posttranscriptional process

2004 ◽  
Vol 287 (5) ◽  
pp. G1008-G1016 ◽  
Author(s):  
Marieke G. L. Elferink ◽  
Peter Olinga ◽  
Annelies L. Draaisma ◽  
Marjolijn T. Merema ◽  
Klaas Nico Faber ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Rat Liver ◽  
Inducible Nitric Oxide Synthase ◽  
Human Liver ◽  
Mrna Levels ◽  
Liver Slices ◽  
Oxide Synthase ◽  
Human Liver Slices ◽  
Inducible Nitric Oxide

Endotoxin-induced cholestasis in rodents is caused by hepatic downregulation of transporters, including the basolateral Na+-dependent taurocholate transporter (ntcp) and the canalicular bile salt export pump (bsep) and multidrug resistance-associated protein 2 (mrp2). Details about the regulation of the human transporter proteins during this process are lacking. We used precision-cut human and rat liver slices to study the regulation of transporter expression during LPS-induced cholestasis. We investigated the effect of LPS on nitrate/nitrite and cytokine production in relation to the expression of inducible nitric oxide synthase, NTCP, BSEP, and MRP2 both at the level of mRNA with RT-PCR and protein using immunofluorescence microscopy. In liver slices from both species, LPS-induced expression of inducible nitric oxide synthase was detected within 1–3 h and remained increased over 24 h. In rat liver slices, this was accompanied by a significant decrease of rat ntcp and mrp2 mRNA levels, whereas bsep levels were not affected. These results are in line with previous in vivo studies and validate our liver slice technique. In LPS-treated human liver slices, NTCP mRNA was downregulated and showed an inverse correlation with the amounts of TNF-α and Il-1β produced. In contrast, MRP2 and BSEP mRNA levels were not affected under these conditions. However, after 24-h LPS challenge, both proteins were virtually absent in human liver slices, whereas marker proteins remained detectable. In conclusion, we show that posttranscriptional mechanisms play a more prominent role in LPS-induced regulation of human MRP2 and BSEP compared with the rat transporter proteins.

scholarly journals Taurine Antagonizes Macrophages M1 Polarization by Mitophagy-Glycolysis Switch Blockage via Dragging SAM-PP2Ac Transmethylation

2021 ◽  
Vol 12 ◽  
Author(s):  
Ling Meng ◽  
Cailing Lu ◽  
Bin Wu ◽  
Chunhua Lan ◽  
Laiming Mo ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Inflammatory Diseases ◽  
Macrophage Polarization ◽  
Metabolic Adaptation ◽  
Transcriptional Level ◽  
Low Grade ◽  
Taurine Supplementation ◽  
Polarization Model ◽  
M1 Polarization ◽  
M1 Macrophage

The excessive M1 polarization of macrophages drives the occurrence and development of inflammatory diseases. The reprogramming of macrophages from M1 to M2 can be achieved by targeting metabolic events. Taurine promotes for the balance of energy metabolism and the repair of inflammatory injury, preventing chronic diseases and complications. However, little is known about the mechanisms underlying the action of taurine modulating the macrophage polarization phenotype. In this study, we constructed a low-dose LPS/IFN-γ-induced M1 polarization model to simulate a low-grade pro-inflammatory process. Our results indicate that the taurine transporter TauT/SlC6A6 is upregulated at the transcriptional level during M1 macrophage polarization. The nutrient uptake signal on the membrane supports the high abundance of taurine in macrophages after taurine supplementation, which weakens the status of methionine metabolism, resulting in insufficient S-adenosylmethionine (SAM). The low availability of SAM is directly sensed by LCMT-1 and PME-1, hindering PP2Ac methylation. PP2Ac methylation was found to be necessary for M1 polarization, including the positive regulation of VDAC1 and PINK1. Furthermore, its activation was found to promote the elimination of mitochondria by macrophages via the mitophagy pathway for metabolic adaptation. Mechanistically, taurine inhibits SAM-dependent PP2Ac methylation to block PINK1-mediated mitophagy flux, thereby maintaining a high mitochondrial density, which ultimately hinders the conversion of energy metabolism to glycolysis required for M1. Our findings reveal a novel mechanism of taurine-coupled M1 macrophage energy metabolism, providing novel insights into the occurrence and prevention of low-grade inflammation, and propose that the sensing of taurine and SAM availability may allow communication to inflammatory response in macrophages.

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