Sectm1a deficiency aggravates inflammation-triggered cardiac dysfunction through disruption of LXRα signalling in macrophages

Abstract Aims Cardiac dysfunction is a prevalent comorbidity of disrupted inflammatory homeostasis observed in conditions such as sepsis (acute) or obesity (chronic). Secreted and transmembrane protein 1a (Sectm1a) has previously been implicated to regulate inflammatory responses, yet its role in inflammation-associated cardiac dysfunction is virtually unknown. Methods and results Using the CRISPR/Cas9 system, we generated a global Sectm1a-knockout (KO) mouse model and observed significantly increased mortality and cardiac injury after lipopolysaccharide (LPS) injection, when compared with wild-type (WT) control. Further analysis revealed significantly increased accumulation of inflammatory macrophages in hearts of LPS-treated KO mice. Accordingly, ablation of Sectm1a remarkably increased inflammatory cytokines levels both in vitro [from bone marrow-derived macrophages (BMDMs)] and in vivo (in serum and myocardium) after LPS challenge. RNA-sequencing results and bioinformatics analyses showed that the most significantly down-regulated genes in KO-BMDMs were modulated by LXRα, a nuclear receptor with robust anti-inflammatory activity in macrophages. Indeed, we identified that the nuclear translocation of LXRα was disrupted in KO-BMDMs when treated with GW3965 (LXR agonist), resulting in higher levels of inflammatory cytokines, compared to GW3965-treated WT-cells. Furthermore, using chronic inflammation model of high-fat diet (HFD) feeding, we observed that infiltration of inflammatory monocytes/macrophages into KO-hearts were greatly increased and accordingly, worsened cardiac function, compared to WT-HFD controls. Conclusion This study defines Sectm1a as a new regulator of inflammatory-induced cardiac dysfunction through modulation of LXRα signalling in macrophages. Our data suggest that augmenting Sectm1a activity may be a potential therapeutic approach to resolve inflammation and associated cardiac dysfunction.

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Macrophage-Biomimetic Porous Se@SiO2 Nanocomposites For “Dual Model” Immunotherapy Against Inflammatory Osteolysis

10.21203/rs.3.rs-885656/v1 ◽

2021 ◽

Author(s):

Cheng Ding ◽

Chuang Yang ◽

Tao Cheng ◽

Xingyan Wang ◽

Qiaojie Wang ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Total Joint Replacement ◽

Major Complication ◽

Dual Model ◽

Joint Replacement Surgery ◽

Pro Inflammatory Cytokines ◽

Macrophage Membrane

Abstract Background：Inflammatory osteolysis is a major complication of total joint replacement surgery that can cause prosthesis failure and necessitate revision surgery. Macrophages are key effector immune cells in inflammatory responses, but excessive M1-polarization of dysfunctional macrophages leads to the secretion of pro-inflammatory cytokines and severe loss of bone tissue. Here, we report the development of macrophage-biomimetic porous SiO2-coated ultrasmall Se particles (Porous Se@SiO2 nanospheres) for the management of inflammatory osteolysis. Results: Macrophage-membrane-coated porous Se@SiO2 nanospheres(M-Se@SiO2) can attenuate lipopolysaccharide (LPS)-induced inflammatory osteolysis by a dual-immunomodulatory effect. As macrophage membrane decoys, these nanoparticles reduce toxin levels and neutralize pro-inflammatory cytokines. Moreover, the release of Se can induce the polarization of macrophages toward the anti-inflammatory M2-phenotype. These effects are mediated via the inhibition of p65, p38, and extracellular signal-regulated kinase(ERK) signaling. Additionally, the immune environment created by M-Se@SiO2 reduces the inhibition of osteogenic differentiation caused by pro-inflammation cytokines, confirmed through in vitro and in vivo experiments.Conclusion: Our findings suggest that M-Se@SiO2 has an immunomodulatory role in LPS-induced inflammation and bone remodeling, which demonstrates that M-Se@SiO2 is a promising engineered nano-platform for the treatment of osteolysis arising after arthroplasty.

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Selective induction of endothelial P2Y6 nucleotide receptor promotes vascular inflammation

Blood ◽

10.1182/blood-2010-10-313957 ◽

2011 ◽

Vol 117 (8) ◽

pp. 2548-2555 ◽

Cited By ~ 78

Author(s):

Ann-Kathrin Riegel ◽

Marion Faigle ◽

Stephanie Zug ◽

Peter Rosenberger ◽

Bernard Robaye ◽

...

Keyword(s):

Inflammatory Responses ◽

Vascular Inflammation ◽

In Vivo Studies ◽

Nucleotide Receptors ◽

Transcriptional Responses ◽

Lps Challenge ◽

Screening Experiments ◽

P2y6 Receptor

Abstract During a systemic inflammatory response endothelial-expressed surface molecules have been strongly implicated in orchestrating immune responses. Previous studies have shown enhanced extracellular nucleotide release during acute inflammatory conditions. Therefore, we hypothesized that endothelial nucleotide receptors could play a role in vascular inflammation. To address this hypothesis, we performed screening experiments and exposed human microvascular endothelia to inflammatory stimuli, followed by measurements of P2Y or P2X transcriptional responses. These studies showed a selective induction of the P2Y6 receptor (> 4-fold at 24 hours). Moreover, studies that used real-time reverse transcription–polymerase chain reaction, Western blot analysis, or immunofluorescence confirmed time- and dose-dependent induction of P2Y6 with tumor necrosis factor α or Lipopolysaccharide (LPS) stimulation in vitro and in vivo. Studies that used MRS 2578 as P2Y6 receptor antagonist showed attenuated nuclear factor κB reporter activity and proinflammatory gene expression in human microvascular endothelial cells in vitro. Moreover, pharmacologic or genetic in vivo studies showed attenuated inflammatory responses in P2Y6−/− mice or after P2Y6 antagonist treatment during LPS-induced vascular inflammation. These studies show an important contribution of P2Y6 signaling in enhancing vascular inflammation during systemic LPS challenge and implicate the P2Y6 receptor as a therapeutic target during systemic inflammatory responses.

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Extracellular vesicles from human cardiovascular progenitors trigger a reparative immune response in infarcted hearts

Cardiovascular Research ◽

10.1093/cvr/cvaa028 ◽

2020 ◽

Cited By ~ 8

Author(s):

Bruna Lima Correa ◽

Nadia El Harane ◽

Ingrid Gomez ◽

Hocine Rachid Hocine ◽

José Vilar ◽

...

Keyword(s):

Immune Response ◽

Extracellular Vesicles ◽

Inflammatory Cytokines ◽

Nk Cell ◽

Inflammatory Monocytes ◽

Ifn Γ ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Abstract Aims The cardioprotective effects of human induced pluripotent stem cell-derived cardiovascular progenitor cells (CPC) are largely mediated by the paracrine release of extracellular vesicles (EV). We aimed to assess the immunological behaviour of EV-CPC, which is a prerequisite for their clinical translation. Methods and results Flow cytometry demonstrated that EV-CPC expressed very low levels of immune relevant molecules including HLA Class I, CD80, CD274 (PD-L1), and CD275 (ICOS-L); and moderate levels of ligands of the natural killer (NK) cell activating receptor, NKG2D. In mixed lymphocyte reactions, EV-CPC neither induced nor modulated adaptive allogeneic T cell immune responses. They also failed to induce NK cell degranulation, even at high concentrations. These in vitro effects were confirmed in vivo as repeated injections of EV-CPC did not stimulate production of immunoglobulins or affect the interferon (IFN)-γ responses from primed splenocytes. In a mouse model of chronic heart failure, intra-myocardial injections of EV-CPC, 3 weeks after myocardial infarction, decreased both the number of cardiac pro-inflammatory Ly6Chigh monocytes and circulating levels of pro-inflammatory cytokines (IL-1α, TNF-α, and IFN-γ). In a model of acute infarction, direct cardiac injection of EV-CPC 2 days after infarction reduced pro-inflammatory macrophages, Ly6Chigh monocytes, and neutrophils in heart tissue as compared to controls. EV-CPC also reduced levels of pro-inflammatory cytokines IL-1α, IL-2, and IL-6, and increased levels of the anti-inflammatory cytokine IL-10. These effects on human macrophages and monocytes were reproduced in vitro; EV-CPC reduced the number of pro-inflammatory monocytes and M1 macrophages, while increasing the number of anti-inflammatory M2 macrophages. Conclusions EV-CPC do not trigger an immune response either in in vitro human allogeneic models or in immunocompetent animal models. The capacity for orienting the response of monocyte/macrophages towards resolution of inflammation strengthens the clinical attractiveness of EV-CPC as an acellular therapy for cardiac repair.

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A Subanesthetic Dose of Isoflurane during Postconditioning Ameliorates Zymosan-Induced Neutrophil Inflammation Lung Injury and Mortality in Mice

Mediators of Inflammation ◽

10.1155/2013/479628 ◽

2013 ◽

Vol 2013 ◽

pp. 1-14 ◽

Cited By ~ 5

Author(s):

Hui Wang ◽

Jing Fan ◽

Nan-lin Li ◽

Jun-tang Li ◽

Shi-fang Yuan ◽

...

Keyword(s):

Lung Injury ◽

Nuclear Translocation ◽

Inflammatory Responses ◽

Weight Ratio ◽

Polymorphonuclear Neutrophils ◽

Mouse Lung ◽

Endothelial Adhesion Molecule ◽

Primary Mouse

Anesthetic isoflurane (ISO) has immunomodulatory effects. In the present study, we investigated whether a subanesthetic dose of ISO (0.7%) protected against zymosan (ZY) induced inflammatory responses in the murine lung and isolated neutrophils. At 1 and 6 hrs after ZY administration intraperitoneally, ISO was inhaled for 1 hr, and 24 hrs later, lung inflammation and injury were assessed. We found that ISO improved the survival rate of mice and mitigated lung injury as characterized by the histopathology, wet-to-dry weight ratio, protein leakage, and lung function index. ISO significantly attenuated ZY-induced lung neutrophil recruitment and inflammation. This was suggested by the downregulation of (a) endothelial adhesion molecule expression and myeloperoxidase (MPO) activity in lung tissue and polymorphonuclear neutrophils (b) chemokines, and (c) proinflammatory cytokines in BALF. Furthermore, ZY-induced nuclear translocation and DNA-binding activity of NF-κB p65 were also reduced by ISO. ISO treatment inhibited iNOS expression and activity, as well as subsequent nitric oxide generation. Consistent with thesein vivoobservations,in vitrostudies confirmed that ISO blocked NF-κB and iNOS activation in primary mouse neutrophils challenged by ZY. These results provide evidence that 0.7% ISO ameliorates inflammatory responses in ZY-treated mouse lung and primary neutrophils.

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L-Theanine Reduced the Development of Knee Osteoarthritis in Rats via Its Anti-Inflammation and Anti-Matrix Degradation Actions: In Vivo and In Vitro Study

Nutrients ◽

10.3390/nu12071988 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1988 ◽

Cited By ~ 1

Author(s):

Hui Bai ◽

Zhiheng Zhang ◽

Yue Li ◽

Xiaopeng Song ◽

Tianwen Ma ◽

...

Keyword(s):

Nitric Oxide ◽

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Quantitative Polymerase Chain Reaction ◽

Hydrolytic Enzyme ◽

Enzyme Linked Immunosorbent Assay ◽

Matrix Degradation ◽

In Vivo Animal Model

The etiology of osteoarthritis (OA) is multifactorial, with no effective disease-modifying-drugs. L-theanine has been reported to inhibit inflammatory responses in some diseases and this study aimed to investigate the effect of L-theanine on Interleukin-1(IL-1)β-stimulated chondrocytes, and in an injury-induced OA rat model. Primary chondrocytes were stimulated by IL-1β (10 ng/mL) for 24 h and then co-cultured with L-theanine for 24 h. The effects of L-theanine on IL-1β-stimulated expression of pro-inflammatory cytokines and hydrolytic enzyme were analyzed using Western blotting, quantitative polymerase chain reaction (q-PCR) and enzyme-linked immunosorbent assay (ELISA) kits. An immunofluorescence assay was used to detect nuclear factor kappa B (NF-κB) phosphorylation. OA was induced by anterior cruciate ligament transection (ACLT) surgery in rats and celecoxib was used as a positive control. OA severity was measured using the Osteoarthritis Research Society International (OARSI) grading system to describe histological changes. The results showed that L-theanine decreased the expression of pro-inflammatory mediators, including cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE-2), inducible nitric oxide synthase (iNOS), and nitric oxide (NO), both in vivo and in vitro. L-theanine treatment inhibited IL-1β-induced upregulation of matrix metalloproteinases (MMP)-3 and MMP-13, as well as inhibited NF-κB p65 activation. In vivo animal model showed that L-theanine administration (200 mg/kg) significantly alleviated OA lesions and decreased OARSI score. Our data indicated that L-theanine decreased inflammatory cytokines and protected extracellular matrix degradation through inhibition of the NF-κB pathway, and L-theanine may be considered a promising therapeutic strategy in OA prevention.

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Immune-modulating effects of alpha-1 antitrypsin

Biological Chemistry ◽

10.1515/hsz-2014-0161 ◽

2014 ◽

Vol 395 (10) ◽

pp. 1187-1193 ◽

Cited By ~ 56

Author(s):

Mario R. Ehlers

Keyword(s):

Nuclear Translocation ◽

Inflammatory Responses ◽

Graft Loss ◽

T Cell Subsets ◽

Intracellular Camp ◽

Alpha 1 Antitrypsin ◽

And Migration ◽

Pro Inflammatory Cytokines

Abstract Alpha-1 antitrypsin (AAT) is a circulating serine protease inhibitor (serpin) that inhibits neutrophil elastase in the lung, and AAT deficiency is associated with early-onset emphysema. AAT is also a liver-derived acute-phase protein that, in vitro and in vivo, reduces production of pro-inflammatory cytokines, inhibits apoptosis, blocks leukocyte degranulation and migration, and modulates local and systemic inflammatory responses. In monocytes, AAT has been shown to increase intracellular cAMP, regulate expression of CD14, and suppress NFκB nuclear translocation. These effects may be mediated by AAT’s serpin activity or by other protein-binding activities. In preclinical models of autoimmunity and transplantation, AAT therapy prevents or reverses autoimmune disease and graft loss, and these effects are accompanied by tolerogenic changes in cytokine and transcriptional profiles and T cell subsets. This review highlights advances in our understanding of the immune-modulating effects of AAT and their potential therapeutic utility.

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MiR-195-5p inhibits the development of chronic obstructive pulmonary disease via targeting siglec1

Human & Experimental Toxicology ◽

10.1177/0960327120920923 ◽

2020 ◽

Vol 39 (10) ◽

pp. 1333-1344

Author(s):

S Li ◽

L Jiang ◽

Y Yang ◽

J Cao ◽

Q Zhang ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Copd Patients ◽

Pulmonary Macrophages ◽

Pro Inflammatory Cytokines

Chronic obstructive pulmonary disease (COPD), characterized by chronic inflammation, is a recognized global health crisis. Sialic acid-binding immunoglobulin-like lectin 1 (siglec1 or CD169), mainly expressed in macrophages and dendritic cells, is markedly upregulated after encountering pathogens or under acute/chronic inflammation conditions. However, it is rarely reported that whether siglec1 plays a role in the development of COPD. In this study, we found that siglec1 had higher expression in the lungs from COPD rats and in peripheral blood mononuclear cells (PBMCs) from COPD patients. Knockdown of siglec1 in vivo and in vitro dramatically decreased pro-inflammatory cytokines production in pulmonary macrophages and alleviated pulmonary inflammatory responses in COPD rats as well as inactivated nuclear factor kappa B (NF-κB) signaling. In addition, we identified a new microRNA, miR-195-5p, which has never explored in COPD, was lower expressed in COPD rats and PBMC of COPD patients, and could negatively modulate siglec1 expression in macrophages. Moreover, overexpression of miR-195-5p via miR-195-5p mimics in vitro and in vivo could significantly alleviate pro-inflammatory cytokines production in pulmonary macrophages and pulmonary inflammatory responses in COPD rats. Together, our findings suggested that miR-195-5p inhibited the development of COPD via targeting siglec1, which might become a therapeutic target to improve COPD.

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Deacetyl Ganoderic Acid F Inhibits LPS-Induced Neural Inflammation via NF-κB Pathway Both In Vitro and In Vivo

Nutrients ◽

10.3390/nu12010085 ◽

2019 ◽

Vol 12 (1) ◽

pp. 85 ◽

Cited By ~ 1

Author(s):

Feiya Sheng ◽

Lele Zhang ◽

Songsong Wang ◽

Lele Yang ◽

Peng Li

Keyword(s):

Inflammatory Cytokines ◽

Nuclear Translocation ◽

Therapeutic Potential ◽

Serum Levels ◽

No Production ◽

Mrna Levels ◽

Mice Model ◽

Ganoderic Acid

Microglia mediated neuronal inflammation has been widely reported to be responsible for neurodegenerative disease. Deacetyl ganoderic acid F (DeGA F) is a triterpenoid isolated from Ganoderma lucidum, which is a famous edible and medicinal mushroom used for treatment of dizziness and insomnia in traditional medicine for a long time. In this study the inhibitory effects and mechanisms of DeGA F against lipopolysaccharide (LPS)-induced inflammation both in vitro and in vivo were investigated. On murine microglial cell line BV-2 cells, DeGA F treatment inhibited LPS-triggered NO production and iNOS expression and affected the secretion and mRNA levels of relative inflammatory cytokines. DeGA F inhibited LPS-induced activation of the NF-κB pathway, as evidenced by decreased phosphorylation of IKK and IκB and the nuclear translocation of P65. In vivo, DeGA F treatment effectively inhibited NO production in zebrafish embryos. Moreover, DeGA F suppressed the serum levels of pro-inflammatory cytokines, including TNF-α and IL-6 in LPS-stimulated mice model. DeGA F reduced inflammatory response by suppressing microglia and astrocytes activation and also suppressed LPS-induced NF-κB activation in mice brains. Taken together, DeGA F exhibited remarkable anti-inflammatory effects and promising therapeutic potential for neural inflammation associated diseases.

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Immunocompatibility of Rad-PC-Rad liposomes in vitro, based on human complement activation and cytokine release

Precision Nanomedicine ◽

10.29016/180419.2 ◽

2018 ◽

Vol 1 (1) ◽

pp. 43-62 ◽

Cited By ~ 2

Author(s):

Sofiya Matviykiv ◽

Marzia Buscema ◽

Gabriela Gerganova ◽

Tamás Mészáros ◽

Gergely Tibor Kozma ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Complement Activation ◽

Inflammatory Responses ◽

Alternative Pathway ◽

White Blood Cells ◽

Membrane Attack Complex ◽

Negative Control ◽

Pro Inflammatory Cytokines

Liposomal drug delivery systems can protect pharmaceutical substances and control their release. Systemic administration of liposomes, however, often activate the innate immune system, resulting in hypersensitivity reactions. These pseudo-allergic reactions can be interpreted as activating the complement system. Complement activation destroys and eliminates foreign substances, either directly through opsonization and the formation of the membrane attack complex (MAC), or by activating leukocytes and initiating inflammatory responses via mediators, such as cytokines. In this study, we investigated the in vitro immune toxicity of the recently synthesized Rad-PC-Rad liposomes, analyzing the liposome-induced complement activation. In five human sera, Rad-PC-Rad liposomes did not induce activation, but in one serum high sensitivity via alternative pathway was detected. Such a behavior in adverse phenomena is characteristic for patient-to-patient variation and, thus, the number of donors should be in the order of hundreds rather than tens, hence the present study based on six donors is preliminary. In order to further prove the suitability of mechano-responsive Rad-PC-Rad liposomes for clinical trials, the production of pro-inflammatory cytokines was examined by human white blood cells. The concentrations of the pro-inflammatory cytokines, IL-6, IL-12p70, TNF-α, and IL-1β, induced by Rad-PC-Rad liposomal formulations, incubated with whole blood samples, were smaller or comparable to saline (negative control). Because of this favorable in vitro hemo-compatibility, in vivo investigations using these mechano-responsive liposomes should be designed.

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Monocyte Regulation By Soluble Uric Acid

10.26686/wgtn.17006731.v1 ◽

2021 ◽

Author(s):

◽

René Joel McLaughlin

Keyword(s):

Map Kinase ◽

Human Blood ◽

Nuclear Translocation ◽

Blood Monocytes ◽

Lps Challenge ◽

Inflammatory Stimuli ◽

Inflammatory Phenotype ◽

Inflammatory Signalling

<p>Hyperuricaemia is a chronic condition associated with diseases of the metabolic syndrome. However, the cause and effect relationship between increased serum uric acid (UA) levels and the pathophysiology of metabolic dysfunction is far from clear. From an immunological angle hyperuricaemia has been shown to modulate inflammatory signalling in both immune and nonimmune cell types. Blood monocytes are constantly exposed to soluble UA in the circulation but the direct effect of this exposure has not been examined. This research focuses on the how soluble UA alters blood monocyte responses to inflammatory stimuli using in vitro, in vivo and clinical manipulation of UA levels. The Harper group previously found that blood monocytes from hyperuricaemic individuals produced lower levels of inflammatory cytokines compared to monocytes from healthy controls when stimulated ex vivo with LPS. My research began by studying the direct effect of soluble UA on human blood monocytes in vitro. I found that soluble UA reduced monocyte production of pro-inflammatory cytokines and increased IL-10 in response to stimulation with LPS. I identified two inflammatory signalling pathways modulated by soluble UA that could be contributing to this suppressive monocyte phenotype: MAP kinase phosphorylation was reduced alongside increased expression of the regulatory protein DUSP10 and reduced ASC; there was a switch towards anti-inflammatory NFκB signalling illustrated by decreased p65 and increased p50 nuclear translocation. To study the modulation of soluble UA levels in a physiological context I raised serum UA levels in vivo with a model of acute hyperuricaemia and lowered serum UA using two clinically relevant medications: allopurinol and rasburicase. Consistent with in vitro UA treatment, raising serum UA levels in vivo suppressed pro-inflammatory cytokine responses to LPS, increased IL-10 and down-regulated monocyte MAP kinase and NFκB signalling pathways. Acute urate-lowering therapy (ULT) with allopurinol or rasburicase reversed this suppressive inflammatory cytokine and signalling pattern. The PLT2 mouse strain has had the purine metabolic pathway disrupted by random mutagenesis of the gene encoding 5-hiydroxyisourate hydrolase, the enzyme responsible for degradation of the molecule directly downstream of UA, 5-hydroxyisourate. I found that this mutation resulted in chronic hyperuricaemia with an average 2-fold increase in serum UA over C57 mice. LPS challenge resulted in increased IL-10 production in PLT2 mice compared to C57, however no differences in monocyte inflammatory signalling were observed between the two strains. Acute ULT with rasburicase reduced serum UA in the PLT2 strain and subsequent LPS challenge increased monocyte inflammatory signalling. Finally, I studied the effects of ULT on the inflammatory phenotype of human blood monocytes from patients with hyperuricaemia. ULT significantly reduced serum UA levels, which coincided with reduced blood monocyte percentages and adhesion molecule expression (CD11b and ICAM1). ULT increased the inflammatory potential of human blood monocytes: Monocytes stimulated with LPS produced less IL-10; MAP kinase phosphorylation increased alongside increased ASC expression; nuclear translocation of NFκB p65 was increased. ULT also increased expression of the NLRP3 inflammasome components procaspase1, pro-IL-1β and NLRP3. Taken together these results demonstrate a previously unidentified role for soluble UA in moderating monocyte immune responses to inflammatory stimuli. In vitro, in vivo and clinical experimentation all confirmed the immunosuppressive function of soluble UA. This potentially places UA in the centre of innate immune control through the dichotomy of its suppressive soluble effects, demonstrated herein, and the widely reported inflammatory crystalline effects. Importantly, this research illustrates that serum UA levels can be manipulated in a clinical setting to control the inflammatory phenotype of circulating immune cells.</p>

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