scholarly journals Macrophage MST1/2 Disruption Impairs Post-Infarction Cardiac Repair via LTB4

2021 ◽  
Author(s):  
Mingming Liu ◽  
Meng Yan ◽  
Jinlong He ◽  
Huizhen Lv ◽  
Zhipeng Chen ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Bacterial Infections ◽  
Underlying Mechanism ◽  
Peritoneal Macrophages ◽  
Leukotriene B4 ◽  
Cardiac Repair ◽  
Lipid Mediator ◽  
Macrophage Phenotype ◽  
And Function ◽  
Deficient Mice

Rationale: Timely inhibition of inflammation and initiation of resolution are important to repair injured tissues. Mammalian STE20-like protein kinase 1/2 (MST1/2) acts as a regulator of macrophage-associated immune responses to bacterial infections. However, the role of MST1/2 in regulating macrophage phenotype and function in myocardial infarction (MI) remains unclear. Objective: To determine the function and underlying mechanism of macrophage MST1/2 in cardiac repair post-MI. Methods and Results: Using LysMCre-mediated Mst1/2-deficient mice, we found that MST1 deficiency exacerbated cardiac dysfunction after MI. Single-cell RNA sequencing assay indicated that the effect was attributed to a shift of macrophage subtypes from those expressing Cxcl2 and Cd163 toward Ccl2 and Ccl4 expression. Mass spectrometry identified leukotriene B4 (LTB4) as the lipid mediator that was upregulated in the absence of MST1. We found that MST1 phosphorylated 5-lipoxygenase (5-LOX) at its T218 residue, disrupting the interaction between 5-LOX and 5-LOX-activating protein, resulting in a reduction of LTB4 production. In contrast, a 5-LOXT218A variant showed no response to MST1. Moreover, treatment of peritoneal macrophages with LTB4 or medium conditioned by Mst1-deficient macrophages resulted in high Ccl2 and Ccl4 expression and low Cxcl2 and Cd163 expression, except when the cells were co-treated with the LTB4 receptor 1 (BLT1) antagonist CP105696. Furthermore, CP105696 ameliorated cardiac dysfunction in LysMCre-mediated Mst1/2-deficient mice and enhanced cardiac repair in wild-type mice treated with XMU-MP-1 after MI. Conclusions: Taken together, our results demonstrate that inhibition of MST1/2 impaired post-MI repair through activating macrophage 5-LOX-LTB4-BLT1 axis.

Abstract 11059: Role of Sirtuin 6 in Macrophage Polarization and Cardiac Repair in Diabetes

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Rajarajan A Thandavarayan ◽  
Darukeshwara Joladarashi ◽  
Sahana S Babu ◽  
Garikipati V Srikanth ◽  
Alexander R Mackie ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Experimental Studies ◽  
Peritoneal Macrophages ◽  
Left Ventricular ◽  
Cardiac Repair ◽  
Raw 264.7 Cells ◽  
Mouse Bone Marrow ◽  
Macrophage Phenotype ◽  
Intramyocardial Injection ◽  
M2 Phenotype

Clinical and experimental studies provide evidence that metabolic and inflammatory pathways are functionally interconnected to cardiovascular diseases. Dynamic changes in macrophage activation [classical M1 activation (promote inflammation) or alternative M2 activation (promote wound healing)], in response to various stress signals, modulate cardiac physiopathology in diabetes. Sirtuin 6 (SIRT6), a NAD-dependent nuclear deacetylase plays an important role in genomic stability, cellular metabolism, stress response and aging. However, the mechanism by which SIRT6 activity affects macrophage phenotype and cardiac function in diabetes is still unexplored. Mouse bone marrow-derived macrophages (BMM) exposed to high glucose (HG, 25mM D-glucose) showed reduced expression of SIRT6 as compared to low glucose (LG, 5mM D-glucose)- and osmotic control (OC, 5mM D-glucose+20mM D-mannitol)-treated cells, associated with increased expression of proinflammatory cytokine and transcription factors (NFkb, c-JUN, FOXO, SP1 and STAT1). In addition, SIRT6 level was reduced in peritoneal macrophages of both diabetic models (streptozotocin-induced and db/db mice) as compared to non-diabetic mice. SIRT6 knockdown in RAW 264.7 cells exaggerated inflammatory response when exposed to HG. In contrast, IL-4-induced increase in mRNA expression of macrophage M2 phenotype markers like Arg1, Chi4l4, Retnla and IRS-2, but not IRS-1 expression was repressed suggesting that alternative macrophage (M2) phenotype was defective in SIRT6 deficient BM-macrophages under HG condition. SIRT6 protein expression was low in myocardial infarction-induced (MI) and diabetes-affected hearts. Interestingly, mice receiving intramyocardial injection of SIRT6-deficient macrophages showed further deterioration in left ventricular function, post-MI. Taken together, these data highlight a role for SIRT6 in regulating the balance of M1/M2 polarization, therefore, modulate macrophage mediated cardiac repair and regeneration in numerous inflammatory disease states including diabetes

scholarly journals Resolution of Sterile Inflammation: Role for Vitamin C

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Bassem M. Mohammed ◽  
Bernard J. Fisher ◽  
Quoc K. Huynh ◽  
Dayanjan S. Wijesinghe ◽  
Charles E. Chalfant ◽  
...  
Keyword(s):  
Vitamin C ◽  
Sterile Inflammation ◽  
Macrophage Phenotype ◽  
Proinflammatory Response ◽  
Resolution Of Inflammation ◽  
Human Sepsis ◽  
And Function ◽  
Deficient Mice

Introduction. Macrophage reprogramming is vital for resolution of acute inflammation. Parenteral vitamin C (VitC) attenuates proinflammatory states in murine and human sepsis. However information about the mechanism by which VitC regulates resolution of inflammation is limited.Methods. To examine whether physiological levels of VitC modulate resolution of inflammation, we used transgenic mice lacking L-gulono-γ-lactone oxidase. VitC sufficient/deficient mice were subjected to a thioglycollate-elicited peritonitis model of sterile inflammation. Some VitC deficient mice received daily parenteral VitC (200 mg/kg) for 3 or 5 days following thioglycollate infusion. Peritoneal macrophages harvested on day 3 or day 5 were examined for intracellular VitC levels, pro- and anti-inflammatory protein and lipid mediators, mitochondrial function, and response to lipopolysaccharide (LPS). The THP-1 cell line was used to determine the modulatory activities of VitC in activated human macrophages.Results. VitC deficiency significantly delayed resolution of inflammation and generated an exaggerated proinflammatory response toin vitroLPS stimulation. VitC sufficiency andin vivoVitC supplementation restored macrophage phenotype and function in VitC deficient mice. VitC loading of THP-1 macrophages attenuated LPS-induced proinflammatory responses.Conclusion. VitC sufficiency favorably modulates macrophage function.In vivoorin vitroVitC supplementation restores macrophage phenotype and function leading to timely resolution of inflammation.

scholarly journals The lung–gut axis during viral respiratory infections: the impact of gut dysbiosis on secondary disease outcomes

2021 ◽  
Author(s):  
Valentin Sencio ◽  
Marina Gomes Machado ◽  
François Trottein
Keyword(s):  
Gut Microbiota ◽  
Bacterial Infections ◽  
Respiratory Infections ◽  
Critical Role ◽  
Good Health ◽  
Disease Outcomes ◽  
And Function ◽  
Viral Respiratory Infections ◽  
The Impact ◽  
Viral Respiratory

AbstractBacteria that colonize the human gastrointestinal tract are essential for good health. The gut microbiota has a critical role in pulmonary immunity and host’s defense against viral respiratory infections. The gut microbiota’s composition and function can be profoundly affected in many disease settings, including acute infections, and these changes can aggravate the severity of the disease. Here, we discuss mechanisms by which the gut microbiota arms the lung to control viral respiratory infections. We summarize the impact of viral respiratory infections on the gut microbiota and discuss the potential mechanisms leading to alterations of gut microbiota’s composition and functions. We also discuss the effects of gut microbial imbalance on disease outcomes, including gastrointestinal disorders and secondary bacterial infections. Lastly, we discuss the potential role of the lung–gut axis in coronavirus disease 2019.

Pathogenic and Compensatory Mechanisms in Epidermis of Sphingomyelin Synthase 2-Deficient Mice

2021 ◽  
pp. 1-7
Author(s):  
Shota Sakai ◽  
Asami Makino ◽  
Akihito Nishi ◽  
Takeshi Ichikawa ◽  
Tadashi Yamashita ◽  
...  
Keyword(s):  
Plasma Membranes ◽  
Lamellar Body ◽  
Lipid Mediator ◽  
Permeability Barrier ◽  
Compensatory Mechanisms ◽  
Terrestrial Environment ◽  
Sphingomyelin Synthase ◽  
Epidermal Permeability Barrier ◽  
Deficient Mice

Sphingomyelin (SM) is a constituent of cellular membranes, while ceramides (Cer) produced from SM on plasma membranes serve as a lipid mediator that regulates cell proliferation, differentiation, and apoptosis. In the skin, SM also is a precursor of Cer, an important constituent of epidermal permeability barrier. We investigated the role of epidermal SM synthase (SMS)2, an isoform of SMS, which modulates SM and Cer levels on plasma membranes. Although SMS2-knockout (SMS2-KO) mice were not neonatal lethal, an ichthyotic phenotype with epidermal hyperplasia and hyperkeratosis was evident at birth, which persisted until 2 weeks of age. These mice showed abnormal lamellar body morphology and secretion, and abnormal extracellular lamellar membranes in the stratum corneum. These abnormalities were no longer evident by 4 weeks of age in SMS2-KO mice. Our study suggests that (1) exposure to a dry terrestrial environment initiates compensatory responses, thereby normalizing epidermal ichthyotic abnormalities and (2) that a nonlethal gene abnormality can cause an ichthyotic skin phenotype.

scholarly journals Altered Expression of Peroxiredoxins in Mouse Model of Progressive Myoclonus Epilepsy upon LPS-Induced Neuroinflammation

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 357
Author(s):  
Mojca Trstenjak Prebanda ◽  
Petra Matjan-Štefin ◽  
Boris Turk ◽  
Nataša Kopitar-Jerala
Keyword(s):  
Mouse Model ◽  
Redox Homeostasis ◽  
Underlying Mechanism ◽  
Loss Of Function ◽  
Altered Expression ◽  
Lps Challenge ◽  
Progressive Myoclonus Epilepsy ◽  
Myoclonus Epilepsy ◽  
The Brain ◽  
Deficient Mice

Stefin B (cystatin B) is an inhibitor of endo-lysosomal cysteine cathepsin, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht–Lundborg disease (EPM1), a form of progressive myoclonus epilepsy. Stefin B-deficient mice, a mouse model of the disease, display key features of EPM1, including myoclonic seizures. Although the underlying mechanism is not yet completely clear, it was reported that the impaired redox homeostasis and inflammation in the brain contribute to the progression of the disease. In the present study, we investigated if lipopolysaccharide (LPS)-triggered neuroinflammation affected the protein levels of redox-sensitive proteins: thioredoxin (Trx1), thioredoxin reductase (TrxR), peroxiredoxins (Prxs) in brain and cerebella of stefin B-deficient mice. LPS challenge was found to result in a marked elevation of Trx1 and TrxR in the brain and cerebella of stefin B deficient mice, while Prx1 was upregulated only in cerebella after LPS challenge. Mitochondrial peroxiredoxin 3 (Prx3), was upregulated also in the cerebellar tissue lysates prepared from unchallenged stefin B deficient mice, while after LPS challenge Prx3 was upregulated in stefin B deficient brain and cerebella. Our results imply the role of oxidative stress in the progression of the disease.

scholarly journals Macrophage Phenotype and Function in Different Stages of Atherosclerosis

2016 ◽  
Vol 118 (4) ◽  
pp. 653-667 ◽  
Author(s):  
Ira Tabas ◽  
Karin E. Bornfeldt
Keyword(s):  
Macrophage Phenotype ◽  
And Function

scholarly journals Critical Role for CXC Ligand 10/CXC Receptor 3 Signaling in the Murine Neonatal Response to Sepsis

2011 ◽  
Vol 79 (7) ◽  
pp. 2746-2754 ◽  
Author(s):  
Alex G. Cuenca ◽  
James L. Wynn ◽  
Kindra M. Kelly-Scumpia ◽  
Philip O. Scumpia ◽  
Lizette Vila ◽  
...  
Keyword(s):  
Neonatal Sepsis ◽  
Bacterial Infections ◽  
Critical Role ◽  
Peritoneal Macrophages ◽  
Polymicrobial Sepsis ◽  
Adjuvant Effect ◽  
Toll Like Receptor 4 ◽  
Cxcr3 Expression ◽  
Neonatal Response ◽  
Granulocyte Function

ABSTRACTPrevious studies have suggested that neonates rely heavily on innate immunity for their antimicrobial response to bacterial infections. However, the innate immune response by neonates to bacterial infection remains poorly characterized. Here, we show that in a murine model of neonatal polymicrobial sepsis, CXC ligand 10 (CXCL10) concentrations increase in the blood and peritoneum concordant with the peritoneal recruitment of granulocytes and macrophages. Additionally, CXC receptor 3 (CXCR3) expression on elicited peritoneal macrophages and granulocytes increases following sepsis. Blockade of CXCL10 worsens not only recruitment and phagocytic function of peritoneal granulocytes and macrophages but also survival. Deletion of CXCR3 also significantly increases mortality to a septic challenge. Finally, we demonstrate that the protective adjuvant effect of pretreatment with a Toll-like receptor 4 agonist to neonatal sepsis is dependent on an endogenous CXCL10 response and that pretreatment of neonates with CXCL10 can also significantly improve macrophage and granulocyte function and modestly improve outcome to polymicrobial sepsis. Together, these data suggest a critical role for CXCL10 signaling during neonatal sepsis.

scholarly journals Inositol-Requiring Enzyme 1-Dependent Activation of AMPK Promotes Brucella abortus Intracellular Growth

2016 ◽  
Vol 198 (6) ◽  
pp. 986-993 ◽  
Author(s):  
Ning Liu ◽  
Yingying Li ◽  
Chunyan Dong ◽  
Xiaohan Xu ◽  
Pan Wei ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Underlying Mechanism ◽  
Peritoneal Macrophages ◽  
Dependent Manner ◽  
Ros Production ◽  
Ampk Activation ◽  
Intracellular Growth ◽  
Serine Threonine Kinase ◽  
Content Type ◽  
Amp Activated Protein Kinase

ABSTRACTAMP-activated protein kinase (AMPK) is a serine/threonine kinase that is well conserved during evolution. AMPK activation inhibits production of reactive oxygen species (ROS) in cells via suppression of NADPH oxidase. However, the role of AMPK during the process ofBrucellainfection remains unknown. Our data demonstrate thatB. abortusinfection induces AMPK activation in HeLa cells in a time-dependent manner. The known AMPK kinases LKB1, CAMKKβ, and TAK1 are not required for the activation of AMPK byB. abortusinfection. Instead, this activation is dependent on the RNase activity of inositol-requiring enzyme 1 (IRE1). Moreover, we also found thatB. abortusinfection-induced IRE1-dependent activation of AMPK promotesB. abortusintracellular growth with peritoneal macrophages via suppression of NADPH-derived ROS production.IMPORTANCEPrevious studies showed thatB. abortusinfection does not promote any oxidative burst regulated by NADPH oxidase. However, the underlying mechanism remains elusive. We report for the first time that AMPK activation caused byB. abortusinfection plays important role in NADPH oxidase-derived ROS production.

NKR-P1B Receptor Expression and Function in the Different Innate Lymphoid Cells of the Lung

2021 ◽  
Author(s):  
Lucas Vajko
Keyword(s):  
Nk Cell ◽  
Γδ T Cells ◽  
Bronchial Epithelium ◽  
Lung Parenchyma ◽  
Recognition System ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Receptor Expression ◽  
And Function ◽  
Deficient Mice

Group 2 innate lymphoid cells (ILC2) are the majority of ILCs in murine lungs at steady state. ILC2s are the main producer of type-2-cytokines, IL-4, IL-5, IL-9, IL-13, and amphiregulin, playing key roles in lung tissue homeostasis, airway responses to pathogens and allergens, and in cancer-related defenses. ILC functions are regulated by cell surface receptors. NKR-P1B is an inhibitory receptor, which recognizes C-type lectin-related protein (Clr-b) as its ligand. NKR-P1B is expressed on subsets of natural killer cells, ILC2, ILC3, γδ T cells, macrophages and dendritic cells in a tissue-specific manner and regulates NK cell and ILC3 functions in the gut. Expression and function of NKR-P1B in the lung ILC populations is unexplored. Moreover, Clr-b, the ligand for NKR-P1B, is expressed in the bronchial epithelium, endothelial cells and in lung parenchyma, but its role in immune regulation in the lung is unknown. We hypothesize that ILC2s in the lung express NKR-P1B, and their function is regulated by the NKR-P1B:Clr-b recognition system. Using wild-type (WT) and NKR-P1B-deficient mice, we study the expression of NKR-P1B on lung ILC2, and the function of NKR-P1B:Clr-b recognition system in ILC2 development and function. We compare the phenotype, frequency, numbers and cytokine production by ILC2s upon stimulation between WT and NKR-P1B-deficient mice using antibody staining and flow cytometry analysis. This study will reveal the role of NKR-P1B as a model system for its human homolog, NKR-P1A, in the regulation of ILC development and function, advancing our understanding of how immune responses in the lung are regulated.

Abstract 3: Il-10 Regulated Mir-375 Enhances Endothelial Progenitor Cell Mediated Myocardial Repair And Survival After Myocardial Infarction.

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Venkata N Garikipati ◽  
Prasanna Krishnamurthy ◽  
Suresh K Verma ◽  
Alexandra R Mackie ◽  
Erin E Vaughan ◽  
...  
Keyword(s):  
Capillary Density ◽  
Tube Formation ◽  
Lv Function ◽  
Myocardial Repair ◽  
Knock Down ◽  
Cardiac Functions ◽  
Dependent Protein ◽  
And Function ◽  
Deficient Mice

We hypothesized that IL-10 regulates miR-375 signaling in EPCs to enhance their survival and function in ischemic myocardium after MI. miR-375 knock down EPC were transplanted intramyocardially after induction of MI. Mice receiving EPC treated with miR-375 inhibitor showed increased number of GFP+EPCs retention that was associated with reduced EPC apoptosis in the myocardium. The engraftment of EPC into the vascular structures and the associated capillary density was significantly higher in miR-375-treated mice. The above findings further correlated with reduced infarct size, fibrosis and enhanced LV function (echocardiography) in miR-375 knock down EPC group as compared to scrambled EPC. Our in vitro studies revealed that the knockdown of miR-375 enhanced EPC proliferation, migration; tube formation ability and inhibited cell apoptosis, while the up-regulation of miR-375 with the mimic had the opposite effects. In addition, we found that miR-375 negatively regulates the expression of 3-phosphoinositide-dependent protein kinase 1 (PDK1) by directly targeting the 3'UTR of the PDK1 transcript. Interestingly, EPC isolated from IL-10-deficient mice has elevated basal levels of miR-375 and exhibited poor proliferation and tube formation ability where as miR-375 knock down in EPC isolated from IL-10 deficient mice attenuated these effects. Furthermore, transplantation of miR-375 knock down IL-10 deficient EPC after MI resulted in attenuated cardiac functions compared to scramble IL-10 deficient EPCs. Taken together, our studies suggest that IL-10 regulated miR-375 enhances EPC survival and function, associated with efficient myocardial repair via activation of PDK-1/AKT signaling cascades.

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