scholarly journals Heme oxygenase-1 dampens the macrophage sterile inflammasome response and regulates its components in the hypoxic lung

2020 ◽  
Vol 318 (1) ◽  
pp. L125-L134 ◽  
Author(s):  
Sally H. Vitali ◽  
Angeles Fernandez-Gonzalez ◽  
Janhavi Nadkarni ◽  
April Kwong ◽  
Chase Rose ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Acute Hypoxia ◽  
Antioxidant Properties ◽  
Hypoxic Exposure ◽  
Mouse Lung ◽  
Heme Oxygenase 1 ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Domain 3 ◽  
Inflammasome Activity

Exposure to hypoxia causes an inflammatory reaction in the mouse lung, and this response can be modulated by overexpressing the hypoxia-inducible stress-response enzyme, heme oxygenase-1 (HO-1). We hypothesized that the inflammasome activity may be a central pathway by which HO-1 controls pulmonary inflammation following alveolar hypoxia. Therefore, we investigated whether HO-1 controls inflammasome activation by altering its expression in macrophages primed with classic NOD-like receptor containing a pyrin domain 3 (NLRP3) inducers, and in murine lungs lacking HO-1 and exposed to acute hypoxia. We found that lack of HO-1 activated lipopolysaccharide (LPS) and ATP-treated bone marrow-derived macrophages, causing an increase in secreted levels of cleaved interleukin (IL)-1B, IL-18, and caspase-1, markers of increased inflammasome activity, whereas HO-1 overexpression suppressed IL-1B, NLRP3, and IL-18. The production of cleaved IL-1B and the activation of caspase-1 in LPS- and ATP-primed macrophages were inhibited by hemin, an HO-1 inducer, and two HO-1 enzymatic products [bilirubin and carbon monoxide (CO)]. Exposure of mice to hypoxia induced the expression of several inflammasome mRNA components (IL-1B, Nlrp3, and caspase-1), and this was further augmented by HO-1 deficiency. This pronounced inflammasome activation was detected as increased protein levels of apoptosis-associated speck-like protein containing a COOH-terminal caspase recruitment domain, IL-18, procaspase-1, and cleaved caspase-1 in the lungs of hypoxic mice. Systemically, Hmox1-deficient mice showed increased basal levels of IL-18 that were further increased after 48 h of hypoxic exposure. Taken together, these finding point to a pivotal role for HO-1 in the control of baseline and hypoxic inflammasome signaling, perhaps through the antioxidant properties of bilirubin and CO’s pleiotropic effects.

scholarly journals Heme Oxygenase-1 in Macrophages Impairs the Perfusion Recovery After Hindlimb Ischemia by Suppressing Autolysosome-Dependent Degradation of NLRP3

2021 ◽  
Author(s):  
Yuankun Ma ◽  
Liangliang Jia ◽  
Yidong Wang ◽  
Yongli Ji ◽  
Jian Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Blood Flow ◽  
Heme Oxygenase ◽  
Tissue Damage ◽  
Molecular Mechanisms ◽  
Capillary Density ◽  
Heme Oxygenase 1 ◽  
Inflammasome Activation ◽  
Hindlimb Ischemia ◽  
Antiangiogenic Effect

Objective: Macrophage-mediated inflammatory response is closely associated with the neovascularization process following hindlimb ischemia. We previously demonstrated that HO-1 (heme oxygenase-1) in macrophages evoked proinflammatory reactions and tissue damage. Here, we evaluated the role played by macrophage-derived HO-1 and elucidated its underlying molecular mechanisms in perfusion recovery after hindlimb ischemia. Approach and Results: We found significant upregulation of HO-1 in mouse ischemic muscles after hindlimb ischemia surgery and with most of this expression occurring in infiltrated macrophages. Myeloid conditional HO-1-deficient mice exhibited higher perfusion recovery, evidenced by restored blood flow, motor function and attenuated tissue damage as well as increased capillary density in the gastrocnemius muscles after hindlimb ischemia, relative to littermate controls. This protective effect was accompanied by reduced nod-like receptor family, NLRP3 (pyrin domain containing 3) inflammasome activation in the infiltrated macrophages without the alteration of macrophage infiltration and polarization. Moreover, suppressing inflammasome activation with NLRP3 inhibitor MCC950 improved blood flow and capillary density in wild-type mice compared with untreated mice. Mechanistically, suppressing HO-1 abolished TNF (tumor necrosis factor)-α-induced NLRP3 protein rather than mRNA expression in bone marrow–derived macrophages, indicating that HO-1 mediated post-transcriptional regulation of NLRP3. Furthermore, HO-1 inhibition promoted autolysosome-dependent degradation of NLRP3 in bone marrow–derived macrophages. Matrigel tube formation assay revealed that HO-1 deletion abrogated the antiangiogenic effect of inflammasome-activated macrophages. Conclusions: Taken together, these findings indicate that macrophage HO-1 deficiency promotes perfusion recovery after hindlimb ischemia by accelerating autolysosomal degradation of NLRP3. The underlying mechanism of action is a potential target for therapeutic angiogenesis in ischemic diseases.

scholarly journals Bach1 Modulates Heme Oxygenase-1 Expression in the Neonatal Mouse Lung

2009 ◽  
Vol 65 (2) ◽  
pp. 145-149 ◽  
Author(s):  
Sacha Kassovska-Bratinova ◽  
Guang Yang ◽  
Kazuhiko Igarashi ◽  
Phyllis A Dennery
Keyword(s):  
Heme Oxygenase ◽  
Neonatal Mouse ◽  
Mouse Lung ◽  
Heme Oxygenase 1

Targeting heme oxygenase-1 by quercetin ameliorates alcohol-induced acute liver injury via inhibiting NLRP3 inflammasome activation

2018 ◽  
Vol 9 (8) ◽  
pp. 4184-4193 ◽  
Author(s):  
Shu Liu ◽  
Lei Tian ◽  
Guangrui Chai ◽  
Bo Wen ◽  
Bingyuan Wang
Keyword(s):  
Liver Injury ◽  
Heme Oxygenase ◽  
Nlrp3 Inflammasome ◽  
Acute Liver Injury ◽  
Heme Oxygenase 1 ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

Quercetin can ameliorate alcohol-induced acute liver injury via inducing heme oxygenase-1 and inhibiting NLRP3 inflammasome activation.

scholarly journals Heme oxygenase-1-dependent central cardiorespiratory adaptations to chronic hypoxia in mice

2009 ◽  
Vol 297 (2) ◽  
pp. R300-R312 ◽  
Author(s):  
Jagadeeshan Sunderram ◽  
John Semmlow ◽  
Smita Thakker-Varia ◽  
Mantu Bhaumik ◽  
Oanh Hoang-Le ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Sympathetic Activity ◽  
Time Course ◽  
Chronic Hypoxia ◽  
Acute Hypoxia ◽  
Ventrolateral Medulla ◽  
Heme Oxygenase 1 ◽  
Respiratory Response ◽  
Wild Type ◽  
Sympathetic Responses

Adaptations to chronic hypoxia (CH) could reflect cellular changes within the cardiorespiratory regions of the rostral ventrolateral medulla (RVLM), the C1 region, and the pre-Bötzinger complex (pre-BötC). Previous studies have shown that the hypoxic chemosensitivity of these regions are heme oxygenase (HO) dependent and that CH induces HO-1. To determine the time course of HO-1 induction within these regions and explore its relevance to the respiratory and sympathetic responses during CH, the expression of HO-1 mRNA and protein in the RVLM and measures of respiration, sigh frequency, and sympathetic activity (spectral analysis of heart rate) were examined during 10 days of CH. Respiratory and sympathetic responses to acute hypoxia were obtained in chronically instrumented awake wild-type (WT) and HO-1 null mice. After 4 days of CH, there was a significant induction of HO-1 within the C1 region and pre-BötC. WT mice acclimated to CH by increasing peak diaphragm EMG after 10 days of CH but had no change in the respiratory response to acute hypoxia. There were no significant differences between WT and HO-1 null mice. In WT mice, hypoxic sigh frequency and hypoxic sensitivity of sympathetic activity initially declined before returning toward baseline after 5 days of CH, correlating with the induction of HO-1. In contrast, HO-1 null mice had a persistent decline in hypoxic sigh frequency and hypoxic sensitivity of sympathetic activity. We conclude that induction of HO-1 in these RVLM cardiorespiratory regions may be important for the hypoxic sensitivity of sighs and sympathetic activity during CH.

scholarly journals Inflammasome Activation Induced by a Snake Venom Lys49-Phospholipase A2 Homologue

Toxins ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 22 ◽  
Author(s):  
Charles Nunes Boeno ◽  
Mauro Valentino Paloschi ◽  
Jéssica Amaral Lopes ◽  
Weverson Luciano Pires ◽  
Sulamita da Silva Setúbal ◽  
...  
Keyword(s):  
Snake Venom ◽  
Gastrocnemius Muscle ◽  
Inflammasome Activation ◽  
Sterile Saline ◽  
Phospholipases A2 ◽  
Caspase 1 ◽  
Domain 3 ◽  
First Time ◽  
Cytosolic Receptor ◽  
Oligomerization Domain

Background: Snake venom phospholipases A2 (PLA2s) have hemolytic, anticoagulant, myotoxic, oedematogenic, bactericidal, and inflammatory actions. BthTX-I, a Lys49-PLA2 isolated from Bothrops jararacussu venom, is an example of Lys49-PLA2 that presents such actions. NLRP3 is a cytosolic receptor from the NLR family responsible for inflammasome activation via caspase-1 activation and IL-1β liberation. The study of NLRs that recognize tissue damage and activate the inflammasome is relevant in envenomation. Methods: Male mice (18–20 g) received an intramuscular injection of BthTX-I or sterile saline. The serum was collected for creatine-kinase (CK), lactate dehydrogenase (LDH), and interleukin-1β (IL-1β) assays, and muscle was removed for inflammasome activation immunoblotting and qRT-PCR expression for nucleotide and oligomerization domain, leucine-rich repeat-containing protein family, pyrin-containing domain 3 receptor (NLRP3) inflammasome components. Results: BthTX-I-induced inflammation and myonecrosis, shown by intravital microscope, and LDH and CK release, respectively. Mouse treatment with A438079, a P2X7 receptor antagonist, did not modify these effects. BthTX-I induced inflammasome activation in muscle, but P2X7R participation in this effect was not observed. Conclusion: Together, the results showed for the first time that BthTX-I in gastrocnemius muscle induces inflammation and consequently, inflammasome activation via NLRP3 with caspase-1 activation and IL-1β liberation.

scholarly journals Heme-Oxygenase-1 Attenuates Oxidative Functions of Antigen Presenting Cells and Promotes Regulatory T Cell Differentiation during Fasciola hepatica Infection

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1938
Author(s):  
Monique Costa ◽  
Valeria da Costa ◽  
Sofía Frigerio ◽  
María Florencia Festari ◽  
Mercedes Landeira ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Molecular Mechanisms ◽  
Fasciola Hepatica ◽  
Antioxidant Properties ◽  
Antigen Presenting Cells ◽  
Parasite Infection ◽  
Economic Losses ◽  
Heme Oxygenase 1 ◽  
Host Immune System ◽  
Antigen Presenting

Fasciola hepatica is a fluke that infects livestock and humans causing fasciolosis, a zoonotic disease of increasing importance due to its worldwide distribution and high economic losses. The parasite regulates the host immune system by inducing a strong Th2 and regulatory T (Treg) cell immune response through mechanisms that might involve the expression or activity of heme-oxygenase-1 (HO-1), the rate-limiting enzyme in the catabolism of free heme that also has immunoregulatory and antioxidant properties. In this paper, we show that F. hepatica-infected mice upregulate HO-1 on peritoneal antigen-presenting cells (APC), which produce decreased levels of both reactive oxygen and nitrogen species (ROS/RNS). The presence of these cells was associated with increased levels of regulatory T cells (Tregs). Blocking the IL-10 receptor (IL-10R) during parasite infection demonstrated that the presence of splenic Tregs and peritoneal APC expressing HO-1 were both dependent on IL-10 activity. Furthermore, IL-10R neutralization as well as pharmacological treatment with the HO-1 inhibitor SnPP protected mice from parasite infection and allowed peritoneal APC to produce significantly higher ROS/RNS levels than those detected in cells from infected control mice. Finally, parasite infection carried out in gp91phox knockout mice with inactive NADPH oxidase was associated with decreased levels of peritoneal HO-1+ cells and splenic Tregs, and partially protected mice from the hepatic damage induced by the parasite, revealing the complexity of the molecular mechanisms involving ROS production that participate in the complex pathology induced by this helminth. Altogether, these results contribute to the elucidation of the immunoregulatory and antioxidant role of HO-1 induced by F. hepatica in the host, providing alternative checkpoints that might control fasciolosis.

scholarly journals Recruitment of pro-IL-1α to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation

2020 ◽  
Vol 118 (1) ◽  
pp. e2015632118
Author(s):  
Jargalsaikhan Dagvadorj ◽  
Karolina Mikulska-Ruminska ◽  
Gantsetseg Tumurkhuu ◽  
Rojo A. Ratsimandresy ◽  
Jessica Carriere ◽  
...  
Keyword(s):  
Computational Modeling ◽  
Nlrp3 Inflammasome ◽  
Mitochondrial Damage ◽  
Binding Motif ◽  
Inflammasome Activation ◽  
Activated Macrophages ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Interleukin 1Α ◽  
Inflammasome Activity

The balance between NLRP3 inflammasome activation and mitophagy is essential for homeostasis and cellular health, but this relationship remains poorly understood. Here we found that interleukin-1α (IL-1α)–deficient macrophages have reduced caspase-1 activity and diminished IL-1β release, concurrent with reduced mitochondrial damage, suggesting a role for IL-1α in regulating this balance. LPS priming of macrophages induced pro-IL-1α translocation to mitochondria, where it directly interacted with mitochondrial cardiolipin (CL). Computational modeling revealed a likely CL binding motif in pro-IL-1α, similar to that found in LC3b. Thus, binding of pro-IL-1α to CL in activated macrophages may interrupt CL-LC3b–dependent mitophagy, leading to enhanced Nlrp3 inflammasome activation and more robust IL-1β production. Mutation of pro-IL-1α residues predicted to be involved in CL binding resulted in reduced pro-IL-1α–CL interaction, a reduction in NLRP3 inflammasome activity, and increased mitophagy. These data identify a function for pro-IL-1α in regulating mitophagy and the potency of NLRP3 inflammasome activation.

scholarly journals Heme oxygenase-1-dependent central cardiorespiratory adaptations to chronic intermittent hypoxia in mice

2016 ◽  
Vol 121 (4) ◽  
pp. 944-952 ◽  
Author(s):  
Jag Sunderram ◽  
John Semmlow ◽  
Pranav Patel ◽  
Harshit Rao ◽  
Glen Chun ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Sympathetic Activity ◽  
Intermittent Hypoxia ◽  
Time Course ◽  
Acute Hypoxia ◽  
Chronic Intermittent Hypoxia ◽  
Heme Oxygenase 1 ◽  
Respiratory Response ◽  
Wild Type ◽  
Respiratory Parameters

Chronic intermittent hypoxia (CIH) increases sympathetic tone and respiratory instability. Our previous work showed that chronic hypoxia induces the oxygen-sensing enzyme heme oxygenase-1 (HO-1) within the C1 sympathoexcitatory region and the pre-Bötzinger complex (pre-BötC). We therefore examined the effect of CIH on time course of induced expression of HO-1 within these regions and determined whether the induction of HO-1 correlated with changes in respiratory, sigh frequency, and sympathetic responses (spectral analysis of heart rate) to acute hypoxia (10% O2) during 10 days of exposure to CIH in chronically instrumented awake wild-type (WT) and HO-1 null mice (HO-1−/−). HO-1 was induced within the C1 and pre-BötC regions after 1 day of CIH. There were no significant differences in the baseline respiratory parameters between WT and HO-1−/−. Prior to CIH, acute hypoxia increased respiratory frequency in both WT and HO-1−/−; however, minute diaphragm electromyogram activity increased in WT but not HO-1−/−. The hypoxic respiratory response after 1 and 10 days of CIH was restored in HO-1−/−. CIH resulted in an initial significant decline in 1) the hypoxic sigh frequency response, which was restored in WT but not HO-1−/−, and 2) the baseline sympathetic activity in WT and HO-1−/−, which remained stable subsequently in WT but not in HO-1−/−. We conclude that 1) CIH induces expression of HO-1 in the C1 and pre-BötC regions within 1 day and 2) HO-1 is necessary for hypoxia respiratory response and contributes to the maintenance of the hypoxic sigh responses and baseline sympathetic activity during CIH.

scholarly journals Pterostilbene 4′-β-Glucoside Attenuates LPS-Induced Acute Lung Injury via Induction of Heme Oxygenase-1

2018 ◽  
Vol 2018 ◽  
pp. 1-16 ◽  
Author(s):  
Jeongmin Park ◽  
Yingqing Chen ◽  
Min Zheng ◽  
Jinhyun Ryu ◽  
Gyeong Jae Cho ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Heme Oxygenase ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Mouse Lung ◽  
Heme Oxygenase 1 ◽  
Ros Production ◽  
Protective Effects ◽  
Anti Inflammatory

Heme oxygenase-1 (HO-1) can exert anti-inflammatory and antioxidant effects. Acute lung injury (ALI) is associated with increased inflammation and influx of proinflammatory cells and mediators in the airspaces and lung parenchyma. In this study, we demonstrate that pterostilbene 4′-β-glucoside (4-PG), the glycosylated form of the antioxidant pterostilbene (PTER), can protect against lipopolysaccharide- (LPS-) orPseudomonas aeruginosa- (P. aeruginosa-) induced ALI when applied as a pretreatment or therapeutic post-treatment, via the induction of HO-1. To determine whether HO-1 mediates the antioxidant and anti-inflammatory effects of 4-PG, we subjected mice genetically deficient inHmox-1to LPS-induced ALI and evaluated histological changes, HO-1 expression, and proinflammatory cytokine levels in bronchoalveolar lavage (BAL) fluid. 4-PG exhibited protective effects on LPS- orP. aeruginosa-induced ALI by ameliorating pathological changes in lung tissue and decreasing proinflammatory cytokines. In addition, HO-1 expression was significantly increased by 4-PG in cells and in mouse lung tissues. The glycosylated form of pterostilbene (4-PG) was more effective than PTER in inducing HO-1 expression. Genetic deletion ofHmox-1abolished the protective effects of 4-PG against LPS-induced inflammatory responses. Furthermore, we found that 4-PG decreased both intracellular ROS levels and mitochondrial (mt) ROS production in a manner dependent on HO-1. Pharmacological application of the HO-1 reaction product carbon monoxide (CO), but not biliverdin or iron, conferred protection inHmox-1-deficient macrophages. Taken together, these results demonstrate that 4-PG can increase HO-1 expression, which plays a critical role in ameliorating intracellular and mitochondrial ROS production, as well as in downregulating inflammatory responses induced by LPS. Therefore, these findings strongly suggest that HO-1 mediates the antioxidant and anti-inflammatory effects of 4-PG.

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