“…In contrast, ΔBH3-BAX restored TNF-mediated necrosis in BAX mutants, showing that BAX oligomerization and pore formation were not required (Figure 2B). Furthermore, BCB (BAX channel blocker), a small molecule inhibitor of BAX channel forming activity and cytochrome C release required for apoptosis (Cui et al., 2017), inhibited camptothecin-mediated apoptosis but not macrophage necrosis (Figures 2C and S2C). These results show that BAX functions in TNF-mediated necrosis independent of its oligomerization and pore-forming activity.Figure 2BAX Mediates Macrophage Necrosis by Promoting Mitochondrial Ca 2+ Overload Independent of BH3-Dependent Oligomerization and Interaction with the Mitochondrial Outer Membrane(A) Schematic of BAX to show BH domains.(B) Cording in 5 dpi TNF-high and control larvae that are WT, BAX mutant, or BAX mutant expressing ΔBH3-BAX.…”
SummaryNecrosis of infected macrophages constitutes a critical pathogenetic event in tuberculosis by releasing mycobacteria into the growth-permissive extracellular environment. In zebrafish infected with Mycobacterium marinum or Mycobacterium tuberculosis, excess tumor necrosis factor triggers programmed necrosis of infected macrophages through the production of mitochondrial reactive oxygen species (ROS) and the participation of cyclophilin D, a component of the mitochondrial permeability transition pore. Here, we show that this necrosis pathway is not mitochondrion-intrinsic but results from an inter-organellar circuit initiating and culminating in the mitochondrion. Mitochondrial ROS induce production of lysosomal ceramide that ultimately activates the cytosolic protein BAX. BAX promotes calcium flow from the endoplasmic reticulum into the mitochondrion through ryanodine receptors, and the resultant mitochondrial calcium overload triggers cyclophilin-D-mediated necrosis. We identify ryanodine receptors and plasma membrane L-type calcium channels as druggable targets to intercept mitochondrial calcium overload and necrosis of mycobacterium-infected zebrafish and human macrophages.
“…In contrast, ΔBH3-BAX restored TNF-mediated necrosis in BAX mutants, showing that BAX oligomerization and pore formation were not required (Figure 2B). Furthermore, BCB (BAX channel blocker), a small molecule inhibitor of BAX channel forming activity and cytochrome C release required for apoptosis (Cui et al., 2017), inhibited camptothecin-mediated apoptosis but not macrophage necrosis (Figures 2C and S2C). These results show that BAX functions in TNF-mediated necrosis independent of its oligomerization and pore-forming activity.Figure 2BAX Mediates Macrophage Necrosis by Promoting Mitochondrial Ca 2+ Overload Independent of BH3-Dependent Oligomerization and Interaction with the Mitochondrial Outer Membrane(A) Schematic of BAX to show BH domains.(B) Cording in 5 dpi TNF-high and control larvae that are WT, BAX mutant, or BAX mutant expressing ΔBH3-BAX.…”
SummaryNecrosis of infected macrophages constitutes a critical pathogenetic event in tuberculosis by releasing mycobacteria into the growth-permissive extracellular environment. In zebrafish infected with Mycobacterium marinum or Mycobacterium tuberculosis, excess tumor necrosis factor triggers programmed necrosis of infected macrophages through the production of mitochondrial reactive oxygen species (ROS) and the participation of cyclophilin D, a component of the mitochondrial permeability transition pore. Here, we show that this necrosis pathway is not mitochondrion-intrinsic but results from an inter-organellar circuit initiating and culminating in the mitochondrion. Mitochondrial ROS induce production of lysosomal ceramide that ultimately activates the cytosolic protein BAX. BAX promotes calcium flow from the endoplasmic reticulum into the mitochondrion through ryanodine receptors, and the resultant mitochondrial calcium overload triggers cyclophilin-D-mediated necrosis. We identify ryanodine receptors and plasma membrane L-type calcium channels as druggable targets to intercept mitochondrial calcium overload and necrosis of mycobacterium-infected zebrafish and human macrophages.
“…CsA inhibits the expression of pro-inflammatory cytokines in LPS-stimulated macrophages ( 35 ), and suppresses the inflammatory responses of neutrophils upon phorbol-12-myristate-13-acetate (PMA), ionomycin, or IL-8 stimulation ( 36 , 37 ). In some models, CsA inhibits the release of damage-associated molecular patterns and acts on the mitochondrial apoptotic pathway in acute inflammation ( 38 ). Here we show that CsA attenuates IAV-induced inflammatory responses by suppressing M1 macrophages polarization and promoting M2 macrophages polarization.…”
Cyclosporine A (CsA) is an immunosuppressive drug that suppresses T cell responses and is broadly used in transplantation. Its immunosuppressive action is closely linked to its binding of cyclophilin A (CypA), which widely distributed in different cell types. CsA also regulates the functions of innate immune cells, but the mechanism remains elusive. Here, we investigate the role of CsA in regulating macrophages polarization in influenza A virus-infected mice and mouse bone marrow-derived macrophages. CsA downregulates pro-inflammatory cytokines expression and upregulates anti-inflammatory cytokines expression. Mechanically, CsA decreases the polarization of macrophages into pro-inflammatory M1 phenotype and increases the polarization of macrophages into anti-inflammatory M2 phenotype. Further studies show that CsA regulates macrophages polarization-associated IFN-γ/STAT1 and IL-4/STAT6 signaling pathways. Meanwhile, all these roles of CsA are eliminated when CypA is absent, suggesting that CsA regulates macrophages polarization and inflammatory responses depend on its binding to CypA. Collectively, these results reveal a crucial mechanism of CsA in attenuating IAV-induced inflammatory responses by a switch in macrophages polarization.
“…Once released from Keap1, Nrf2 shifts to the nucleus and binds to antioxidant response elements (AREs) in various cellular defensive genes, including glutamate-cysteine ligase modifier subunit (GCLM), glutamate-cysteine ligase catalytic subunit (GCLC), heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase 1 (NQO1) [ 16 ]. The initiation of antioxidant pathways protects animals from oxidative damage and inflammatory responses simultaneously [ 17 , 18 ].…”
The nuclear factor (NF)-κB and NOD-like receptor protein 3 (NLRP3) pathways promote inflammatory signaling that injures the kidneys, whereas the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway promotes anti-inflammatory signaling that inhibits oxidative damage. Penehyclidine hydrochloride (PHC) inhibits NF-κB and activates Nrf2 signaling. We investigated whether PHC induces communication between the Nrf2 and NF-κB/NLRP3 pathways, thereby protecting against renal ischemia/reperfusion (rI/R)-induced lung inflammation. Rat alveolar macrophages (NR8383 cells) were stimulated for 24 h with PHC with or without brusatol (a Nrf2 antagonist), after which they were treated for 4 h with tert-butyl hydroperoxide (10 mM). PHC Nrf2-dependently alleviated tert-butyl hydroperoxide-induced reactive oxygen species production in alveolar macrophages. Additionally, wild-type and Nrf2
−/−
rats were each divided into four groups: (1) sham, (2) PHC (1 mg/kg), (3) rI/R and (4) rI/R + PHC (1 mg/kg). PHC markedly induced the Nrf2 and adenosine monophosphate-activated protein kinase pathways and suppressed rI/R-induced NF-κB and NLRP3 activation in the lungs. Nrf2 deficiency diminished the ability of PHC to ameliorate rI/R-induced histopathological alterations and reactive oxygen species release in the lungs; however, PHC inhibited NLRP3 signaling Nrf2-dependently, while it inhibited NF-κB signaling Nrf2-independently. Our findings demonstrate the beneficial effects of PHC on rI/R-induced lung inflammation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
