scholarly journals Hypoxia-Inducible Factor-1α in Macrophages, but Not in Neutrophils, Is Important for Host Defense during Klebsiella pneumoniae-Induced Pneumosepsis

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Natasja A. Otto ◽  
Liza Pereverzeva ◽  
Valentine Leopold ◽  
Ivan Ramirez-Moral ◽  
Joris J. T. H. Roelofs ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Hypoxia Inducible Factor ◽  
Bacterial Pathogen ◽  
Myeloid Cell ◽  
Lung Macrophages ◽  
Cytokine Tumor Necrosis Factor ◽  
The Common ◽  
Deficient Mice ◽  
Necrosis Factor

Hypoxia-inducible factor- (HIF-) 1α has been implicated in the ability of cells to adapt to alterations in oxygen levels. Bacterial stimuli can induce HIF1α in immune cells, including those of myeloid origin. We here determined the role of myeloid cell HIF1α in the host response during pneumonia and sepsis caused by the common human pathogen Klebsiella pneumoniae. To this end, we generated mice deficient for HIF1α in myeloid cells (LysM-cre × Hif1αfl/fl) or neutrophils (Mrp8-cre × Hif1αfl/fl) and infected these with Klebsiella pneumoniae via the airways. Myeloid, but not neutrophil, HIF1α-deficient mice had increased bacterial loads in the lungs and distant organs after infection as compared to control mice, pointing at a role for HIF1α in macrophages. Myeloid HIF1α-deficient mice did not show increased bacterial growth after intravenous infection, suggesting that their phenotype during pneumonia was mediated by lung macrophages. Alveolar and lung interstitial macrophages from LysM-cre × Hif1αfl/fl mice produced lower amounts of the immune enhancing cytokine tumor necrosis factor upon stimulation with Klebsiella, while their capacity to phagocytose or to produce reactive oxygen species was unaltered. Alveolar macrophages did not upregulate glycolysis in response to lipopolysaccharide, irrespective of HIF1α presence. These data suggest a role for HIF1α expressed in lung macrophages in protective innate immunity during pneumonia caused by a common bacterial pathogen.

scholarly journals Exacerbated Imiquimod-Induced Psoriasis-Like Skin Inflammation in IRF5-Deficient Mice

2020 ◽  
Vol 21 (10) ◽  
pp. 3681
Author(s):  
Momoko Nakao ◽  
Tomomitsu Miyagaki ◽  
Makoto Sugaya ◽  
Shinichi Sato
Keyword(s):  
Critical Role ◽  
Skin Inflammation ◽  
Interferon Α ◽  
Toll Like Receptor ◽  
Adaptive Immune ◽  
Th17 Cytokines ◽  
Factor Α ◽  
Deficient Mice ◽  
Necrosis Factor

Interferon regulatory factors (IRFs) play diverse roles in the regulation of the innate and adaptive immune responses in various diseases. In psoriasis, IRF2 is known to be involved in pathogenesis, while studies on other IRFs are limited. In this study, we investigated the role of IRF5 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although IRF5 is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, IRF5 deficiency unexpectedly exacerbated psoriasiform skin inflammation. The interferon-α and tumor necrosis factor-α mRNA expression levels were decreased, while levels of Th17 cytokines including IL-17, IL-22, and IL-23 were increased in IRF5-deficient mice. Furthermore, IL-23 expression in DCs from IRF5-deficient mice was upregulated both in steady state and after toll-like receptor 7/8 agonist stimulation. Importantly, the expression of IRF4, which is also important for the IL-23 production in DCs, was augmented in DCs from IRF5-deficient mice. Taken together, our results suggest that IRF5 deficiency induces the upregulation of IRF4 in DCs followed by augmented IL-23 production, resulting in the amplification of Th17 responses and the exacerbation of imiquimod-induced psoriasis-like skin inflammation. The regulation of IRF4 or IRF5 expression may be a novel therapeutic approach to psoriasis.

scholarly journals HIF1α/TET1 Pathway Mediates Hypoxia-Induced Adipocytokine Promoter Hypomethylation in Human Adipocytes

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 134 ◽  
Author(s):  
Mohamed M. Ali ◽  
Shane A. Phillips ◽  
Abeer M. Mahmoud
Keyword(s):  
Dna Methylation ◽  
Interleukin 1 ◽  
Hypoxia Inducible Factor ◽  
Interferon Γ ◽  
The Body ◽  
Human Adipocytes ◽  
Protein Levels ◽  
Factor Α ◽  
Necrosis Factor

Obesity is associated with the accumulation of dysfunctional adipose tissue that secretes several pro-inflammatory cytokines (adipocytokines). Recent studies have presented evidence that adipose tissues in obese individuals and animal models are hypoxic, which may result in upregulation and stabilization of the hypoxia inducible factor HIF1α. Epigenetic mechanisms such as DNA methylation enable the body to respond to microenvironmental changes such as hypoxia and may represent a mechanistic link between obesity-associated hypoxia and upregulated inflammatory adipocytokines. The purpose of this study was to investigate the role of hypoxia in modifying adipocytokine DNA methylation and subsequently adipocytokine expression. We suggested that this mechanism is mediated via the DNA demethylase, ten-eleven translocation-1 (TET1), transcription of which has been shown to be induced by HIF1α. To this end, we studied the effect of hypoxia (2% O2) in differentiated subcutaneous human adipocytes in the presence or absence of HIF1α stabilizer (Dimethyloxalylglycine (DMOG), 500 μM), HIF1α inhibitor (methyl 3-[[2-[4-(2-adamantyl) phenoxy] acetyl] amino]-4-hydroxybenzoate, 30 μM), or TET1-specific siRNA. Subjecting the adipocytes to hypoxia significantly induced HIF1α and TET1 protein levels. Moreover, hypoxia induced global hydroxymethylation, reduced adipocytokine DNA promoter methylation, and induced adipocytokine expression. These effects were abolished by either HIF1α inhibitor or TET1 gene silencing. The major hypoxia-responsive adipocytokines were leptin, interleukin-1 (IL6), IL1β, tumor necrosis factor α (TNFα), and interferon γ (IFNγ). Overall, these data demonstrate an activation of the hydroxymethylation pathway mediated by TET1. This pathway contributes to promoter hypomethylation and gene upregulation of the inflammatory adipocytokines in adipocytes in response to hypoxia.

scholarly journals Distinct Roles of Lymphotoxin α and the Type I Tumor Necrosis Factor (TNF) Receptor in the Establishment of Follicular Dendritic Cells from Non–Bone Marrow–derived Cells

1997 ◽  
Vol 186 (12) ◽  
pp. 1997-2004 ◽  
Author(s):  
Mitsuru Matsumoto ◽  
Yang-Xin Fu ◽  
Hector Molina ◽  
Guangming Huang ◽  
Jinho Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Tumor Necrosis ◽  
Type I ◽  
Follicular Dendritic Cells ◽  
Wild Type ◽  
Lymphotoxin Α ◽  
Deficient Mice ◽  
Necrosis Factor

In mice deficient in either lymphotoxin α (LT-α) or type I tumor necrosis factor receptor (TNFR-I), organized clusters of follicular dendritic cells (FDC) and germinal centers (GC) are absent from the spleen. We investigated the role of LT-α and TNFR-I in the establishment of spleen FDC and GC structure by using reciprocal bone marrow (BM) transfer. When LT-α–deficient mice were reconstituted with wild-type BM, FDC organization and the ability to form GC were restored, indicating that the LT-α–expressing cells required to establish organized FDC are derived from BM. The role of LT-α in establishing organized FDC structure was further investigated by the transfer of complement receptor 1 and 2 (CR1/2)–deficient BM cells into LT-α–deficient mice. Organized FDC were identified with both the FDC-M1 and anti-CR1 monoclonal antibodies in these BM-chimeric mice, indicating that these cells were derived from the LT-α–deficient recipient. Thus, expression of LT-α in the BM-derived cells, but not in the non–BM-derived cells, is required for the maturation of FDC from non-BM precursor cells. In contrast, when TNFR-I–deficient mice were reconstituted with wild-type BM, they showed no detectable FDC clusters or GC formation. This indicates that TNFR-I expression on non–BM-derived cellular components is necessary for the establishment of these lymphoid structures. TNFR-I–deficient BM was able to restore FDC organization and GC formation in LT-α–deficient mice, indicating that formation of these structures does not require TNFR-I expression on BM-derived cells. The data in this study demonstrate that FDC organization and GC formation are controlled by both LT-α–expressing BM-derived cells and by TNFR-I-expressing non–BM-derived cells.

scholarly journals THE ROLE OF COMPLEMENT IN RESISTANCE TO ENDOGENOUS AND EXOGENOUS INFECTION WITH A COMMON MOUSE PATHOGEN, CORYNEBACTERIUM KUTSCHERI

1966 ◽  
Vol 124 (4) ◽  
pp. 689-699 ◽  
Author(s):  
Linda D. Caren ◽  
L. T. Rosenberg
Keyword(s):  
Survival Advantage ◽  
Mouse Serum ◽  
Equal Frequency ◽  
Laboratory Conditions ◽  
Immune Hemolysis ◽  
The Common ◽  
Deficient Mice ◽  
Normal Laboratory ◽  
Better Than

In mice, the presence or absence of a single complement (C') component, called hc1, is controlled by two alleles at the Hc locus. The sera of mice which lack this C' component do not manifest C'-mediated immune hemolysis. When challenged with the common mouse pathogen, Corynebacterium kutscheri, mice possessing hemolytic C' fare slightly better than C'-deficient mice. When mice harboring latent C. kutscheri are administered hydrocortisone, which depresses mouse serum C' levels, pseudotuberculosis is activated with equal frequency in mice of both C' types. These data suggest that in at least one situation the presence of the complete hemolytic C' system may be advantageous to the mouse. In contrast, evidence is presented which shows that under normal laboratory conditions, C'-deficient B10.D2 "old line" mice (Hc0/Hc0) have a survival advantage over C'-positive B10.D2 "new line" mice (Hc1/Hic1) during the first 3 wk of life. It is therefore concluded that mouse hemolytic C' has a balanced survival value—that is, under one set of conditions it may be advantageous, whereas in another situation, it may be disadvantageous.

scholarly journals Crucial Role of Tumor Necrosis Factor Receptor 1 Expression on Nonhematopoietic Cells for B Cell Localization within the Splenic White Pulp

1998 ◽  
Vol 187 (4) ◽  
pp. 469-477 ◽  
Author(s):  
Maria Tkachuk ◽  
Stephan Bolliger ◽  
Bernhard Ryffel ◽  
Gerd Pluschke ◽  
Theresa A. Banks ◽  
...  
Keyword(s):  
B Cells ◽  
Tumor Necrosis ◽  
Plasma Cells ◽  
Tumor Necrosis Factor Receptor ◽  
White Pulp ◽  
Splenic White Pulp ◽  
Initial Activation ◽  
Deficient Mice ◽  
Necrosis Factor

During immune responses the initial activation of B cells takes place in T cell zones of periarteriolar lymphoid sheaths (PALS) of the splenic white pulp. After initial activation, B cells migrate into the primary follicles and, in association with follicular dendritic cells (FDCs), undergo clonal expansion and differentiation giving rise to germinal centers (GCs). Peanut agglutinin binding (PNA+) cells of the GC differentiate further into memory or plasma cells. Here we report that in tumor necrosis factor receptor 1–deficient mice (TNFR1−/−), the location of B cells was altered and that plasma cells were abnormally distributed in the splenic PALS. In contrast to lymphotoxin α–deficient mice (LTα−/−), bone marrow or fetal liver transplantation did not correct the abnormal organization of the spleen, location of B cells, the lack of an FDC network, nor the antibody response in TNFR1−/− mice. These results argue for a crucial role of TNFR1 expression on nonhematopoietic cells for the maintenance of the splenic architecture and proper B cell location. In addition, the lack in development of an FDC network after adoptive transfer suggests that either FDCs are not of bone marrow origin or that they depend on signals from nonhematopoietic cells for maturation.

scholarly journals Myeloid Knockout of HIF-1αDoes Not Markedly Affect Hemorrhage/Resuscitation-Induced Inflammation and Hepatic Injury

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
G. Wetzel ◽  
B. Relja ◽  
A. Klarner ◽  
D. Henrich ◽  
N. Dehne ◽  
...  
Keyword(s):  
Hepatic Injury ◽  
Hypoxia Inducible Factor ◽  
Myeloid Cell ◽  
Vascular Endothelial ◽  
Elevated Plasma ◽  
Wild Type ◽  
Hypoxia Inducible Factor 1 ◽  
Myeloid Cell Line ◽  
Endothelial Growth Factor

Background. Hypoxia-inducible factor-1α(HIF-1α) and NF-κB play important roles in the inflammatory response after hemorrhagic shock and resuscitation (H/R). Here, the role of myeloid HIF-1αin liver hypoxia, injury, and inflammation after H/R with special regard to NF-κB activation was studied.Methods. Mice with a conditional HIF-1αknockout (KO) in myeloid cell-line and wild-type (WT) controls were hemorrhaged for 90 min (30±2 mm Hg) and resuscitated. Controls underwent only surgical procedures.Results. After six hours, H/R enhanced the expression of HIF-1α-induced genes vascular endothelial growth factor (VEGF) and adrenomedullin (ADM). In KO mice, this was not observed. H/R-induced liver injury in HIF-1αKO was comparable to WT. Elevated plasma interleukin-6 (IL-6) levels after H/R were not reduced by HIF-1αKO. Local hepatic hypoxia was not significantly reduced in HIF-1αKO compared to controls after H/R. H/R-induced NF-κB phosphorylation in liver did not significantly differ between WT and KO.Conclusions. Here, deleting HIF-1αin myeloid cells and thereby in Kupffer cells was not protective after H/R. This data indicates that other factors, such as NF-κB, due to its upregulated phosphorylation in WT and KO mice, contrary to HIF-1α, are rather key modulators of inflammation after H/R in our model.

P3509Leukocyte derived tumour necrosis factor modulates cardiac function in health and disease

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Walker ◽  
A Gutierrez Del Arroyo ◽  
J Sanchez ◽  
G L Ackland
Keyword(s):  
Ejection Fraction ◽  
Cardiac Function ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Cardiac Injury ◽  
Cardiac Cells ◽  
Health And Disease ◽  
Deficient Mice ◽  
Necrosis Factor

Abstract Purpose Tumour necrosis factor alpha (TNFα) regulates both normal and pathophysiological cardiac function. The regulatory role of TNFα derived from different sources (leukocyte versus cardiac cells) in cardiac physiology is unclear. Deficiency of iRhom2 protein prevents circulating immune cells from shedding TNFα (and CD62L, an adhesion molecule essential for effective immune function). Here we investigated the role of leukocyte derived TNFα in constitutive cardiac function and after cardiac injury. Methods Adult iRhom2-deficient mice (KO) and wildtype (Wt) littermates, of both genders, underwent echocardiography to assess cardiac physiologic function at least 1 week before receiving a single dose of isoproterenol (300mg/kg IP) to induce cellular death in 10% of the cardiomyoctes [1]. Cardiac echocardiography was repeated 36 hours after isoproterenol. Peripheral and cardiac-resident leukocytes were phenotyped by flow cytometry and molecular markers of cardiac stress (atrial and brain natriuretic protein, ANP, BNP) and inflammation (NFkB) were quantified using RT-PCR. Results Peripheral leukocytes from iRhom2 KO mice failed to shed CD62L in response to isoproterenol induced cardiac injury (e.g. neutrophils CD62L Mean Fluorescence Intensity KO: 9149±4616, Wt: 972±558, p<0.0001, n=9). iRhom2-deficient mice had higher cardiac output at baseline (KO 23±2 mL/min, n=11) compared to their wildtype littermates (Wt 18±3 mL/min, n=9). Wild type mice increased contractility after isoproterenol (Wt ejection fraction: baseline 60±6%, isoproterenol 68±6%, n=8) whilst iRhom2-deficient mice were unable to (KO ejection fraction: baseline 66±9%, isoproterenol 61±5%, n=8). ANP and BNP mRNA were elevated in ventricular tissue of iRhom2-knockout mice after isoproterenol, when compared to naïve tissue (ANP 2ΔCT: 3x increase, BNP 2ΔCT: 1.6x increase) whereas only ANP was elevated in wildtypes (ANP 2ΔCT: 2.7x increase, BNP 2ΔCT: 0.9x increase). No difference in immune cell infiltration of ventricular cardiac tissue was observed (number of CD45+ cells KO: 3014±3482, Wt: 2555±1411, p=0.7, n=9) NFkB mRNA was upregulated at baseline (2ΔCT KO: 0.2±0.08, Wt: 0.1±0.09) suggesting constitutive cardiac inflammation in iRhom2-deficient mice. Conclusions Inability to shed CD62L and TNFα is associated with constitutive and acquired cardiac dysfunction in iRhom2-deficient mice. These data support the hypothesis that leukocyte-derived TNFα is required for maintaining cardiac function in health and disease. Acknowledgement/Funding National Institute of Academic Anaesthesia/Royal College of Anaesthetists/British Journal of Anaesthesia; National Institute for Health Research

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