scholarly journals LXR nuclear receptors prompt a pro-inflammatory gene and functional profile in human macrophages

2021 ◽  
Author(s):  
Arturo González de la Aleja1 ◽  
Mónica Torres-Torresano ◽  
Juan Vladimir de la Rosa ◽  
Barbara Alonso ◽  
Enrique Capa-Sardón ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Cholesterol Metabolism ◽  
Macrophage Polarization ◽  
Human Monocyte ◽  
Gene Signature ◽  
Human Macrophage ◽  
Human Macrophages ◽  
Inflammatory Gene ◽  
Anti Inflammatory

Abstract Liver X Receptors (LXR) control cholesterol metabolism and exert anti-inflammatory actions in activated macrophages. However, their contribution to human macrophage polarization in the absence of pathogenic stimuli remains unclear. In fact, the LXR pathway has been reported to be significantly enriched in pro-inflammatory synovial macrophages from rheumatoid arthritis patients as well as in immunosuppressive tumors-associated macrophages from human metastatic colon tumors. To determine the role of LXR on macrophage differentiation and polarization, we have analyzed the contribution of LXR to the acquisition of the inflammatory and T-cell-activating functions of human monocyte-derived macrophages. We now report that LXR activation prompts the acquisition of a pro-inflammatory gene signature in human macrophages, whereas LXR inactivation results in enrichment of an anti-inflammatory gene profile. Accordingly, activation and inhibition of LXR oppositely alter the production of cytokines (e.g., TNF, IL1b, CCL17, CCL19, IFNb1) and T cell stimulation activities associated to human macrophage polarization. Mechanistically, the LXR-stimulated macrophage polarization shift relies on their ability to modulate the expression of MAFB and MAF, which govern the acquisition of the macrophage anti-inflammatory profile. The pathological significance of the LXR-mediated macrophage polarization shift was demonstrated by the ability of LXR agonists to modulate macrophage polarization promoted by either tumor-derived ascitic fluids or by synovial fluid from rheumatoid arthritis patients. As a whole, our results demonstrate that LXR activation prompts the acquisition of a pro-inflammatory transcriptional and functional specialization in human macrophages .

scholarly journals Street RABV Induces the Cholinergic Anti-inflammatory Pathway in Human Monocyte-Derived Macrophages by Binding to nAChr α7

2021 ◽  
Vol 12 ◽  
Author(s):  
Carmen W. E. Embregts ◽  
Lineke Begeman ◽  
Cees J. Voesenek ◽  
Byron E. E. Martina ◽  
Marion P. G. Koopmans ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Macrophage Polarization ◽  
Flow Cytometric Analysis ◽  
Human Monocyte ◽  
Host Immune System ◽  
Inflammatory Pathway ◽  
Anti Inflammatory ◽  
Alpha Bungarotoxin

Rabies virus (RABV) is able to reach the central nervous system (CNS) without triggering a strong immune response, using multiple mechanisms to evade and suppress the host immune system. After infection via a bite or scratch from a rabid animal, RABV comes into contact with macrophages, which are the first antigen-presenting cells (APCs) that are recruited to the area and play an essential role in the onset of a specific immune response. It is poorly understood how RABV affects macrophages, and if the interaction contributes to the observed immune suppression. This study was undertaken to characterize the interactions between RABV and human monocyte-derived macrophages (MDMs). We showed that street RABV does not replicate in human MDMs. Using a recombinant trimeric RABV glycoprotein (rRABV-tG) we showed binding to the nicotinic acetylcholine receptor alpha 7 (nAChr α7) on MDMs, and confirmed the specificity using the nAChr α7 antagonist alpha-bungarotoxin (α-BTX). We found that this binding induced the cholinergic anti-inflammatory pathway (CAP), characterized by a significant decrease in tumor necrosis factor α (TNF-α) upon LPS challenge. Using confocal microscopy we found that induction of the CAP is associated with significant cytoplasmic retention of nuclear factor κB (NF-κB). Co-cultures of human MDMs exposed to street RABV and autologous T cells further revealed that the observed suppression of MDMs might affect their function as T cell activators as well, as we found a significant decrease in proliferation of CD8+ T cells and an increased production of the anti-inflammatory cytokine IL-10. Lastly, using flow cytometric analysis we observed a significant increase in expression of the M2-c surface marker CD163, hinting that street RABV might be able to affect macrophage polarization. Taken together, these results show that street RABV is capable of inducing an anti-inflammatory state in human macrophages, possibly affecting T cell functioning.

scholarly journals P201 Anti-inflammatory and immunologic actions of pinolenic acid in rheumatoid arthritis

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Rabaa Takala ◽  
Dipak Ramji ◽  
Ernest Choy
Keyword(s):  
Rheumatoid Arthritis ◽  
Flow Cytometry ◽  
Mononuclear Cells ◽  
Vehicle Control ◽  
Boyden Chamber ◽  
Pinolenic Acid ◽  
Human Macrophages ◽  
Monocyte Migration ◽  
Tnf Α ◽  
Anti Inflammatory

Abstract Background Rheumatoid arthritis (RA) is a common inflammatory arthritis. Although advanced targeted therapies have improved prognosis, many patients seek advice on dietary intervention that may improve symptoms. Pinolenic acid (PNLA) is a polyunsaturated fatty acid found in pine nuts. We investigated the anti-inflammatory effects of 25-100 μM PNLA on cell line, primary culture, and peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy controls (HCs). Methods 1- Migration using modified Boyden Chambers: THP-1 monocytes incubated with vehicle or PNLA were added to the apical compartment of a modified Boyden chamber. The migration of the cells through inserts of 8 μm pore size in response to the chemokine monocyte chemoattractant protein-1 (MCP-1) added to basolateral (bottom) chamber was determined. 2- Macropinocytosis using Lucifer yellow (LY): THP-1 and primary human macrophages were pre-incubated with PNLA or vehicle control followed by LY. After incubation, cells were removed, fixed and assessed by flow cytometry. 3- Lipid uptake using Dil-oxidised low-density lipoprotein (Dil-oxLDL): THP-1 and primary macrophages were pre-incubated with PNLA or vehicle control followed by Dil-oxLDL. After incubation, cells were removed, fixed and assessed by flow cytometry. 4- Cytokines release by lipopolysaccharide (LPS) stimulated PBMCs: PBMCs were isolated from blood obtained from RA patients aged ≥18 years and HCs. Monocytes were purified and cultured with PNLA or vehicle control. Cells were stimulated with LPS. IL-6, TNF-α, IL-1β and prostaglandin E2 (PGE2) in the supernatant were assessed by ELISAs. For macrophages, monocytes were left to grow and differentiate over 10 days, the differentiated macrophages were treated with PNLA or vehicle and activated with LPS and assayed in identical conditions for monocytes. Results PNLA at all concentrations reduced THP-1 monocytes migration by average of 55% (p < 0.001) when compared with vehicle controls. Macropinocytosis of THP-1 macrophages and human macrophages were reduced by almost 50% (p < 0.001) and 45% (p < 0.001) respectively by PNLA. Similarly, Dil-oxLDL uptake by THP-1 macrophages and primary macrophages were reduced by 40% (p < 0.01) and 25% (p < 0.05) respectively by 25 μM PNLA. Release of IL-6 and TNF-α by LPS stimulated monocytes in RA patients were reduced with 25 and 50 μM PNLA by 60% (p < 0.001) and in HC by 50% and 35% respectively (p < 0.01). PGE2 levels were inhibited by the same percentage in both HC and RA monocytes (p < 0.001) by 50 μM PNLA. Similarly, effects were observed with IL-6, TNF- α, and PGE2 levels in LPS-stimulated macrophages especially in RA patients 30% (p < 0.05). Conclusion Our data suggest that PNLA significantly attenuated monocyte migration, significantly reduced macropinocytosis and Dil-oxLDL uptake in macrophages. Furthermore, PNLA inhibited production of IL-6, TNF-α and PGE2 levels in LPS-stimulated monocytes and macrophages from RA patients. These data inform on the potential anti-inflammatory and analgesic effects of PNLA. Disclosures R. Takala None. D. Ramji None. E. Choy None.

scholarly journals Hyperoside Suppresses Renal Inflammation by Regulating Macrophage Polarization in Mice With Type 2 Diabetes Mellitus

2021 ◽  
Vol 12 ◽  
Author(s):  
Jialing Liu ◽  
Yanmei Zhang ◽  
Hongqin Sheng ◽  
Chunling Liang ◽  
Huazhen Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Macrophage Polarization ◽  
Fasting Blood Glucose ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Monocyte Chemoattractant Protein 1 ◽  
Anti Inflammatory

Accumulating evidence reveals that both inflammation and lymphocyte dysfunction play a vital role in the development of diabetic nephropathy (DN). Hyperoside (HPS) or quercetin-3-O-galactoside is an active flavonoid glycoside mainly found in the Chinese herbal medicine Tu-Si-Zi. Although HPS has a variety of pharmacological effects, including anti-oxidative and anti-apoptotic activities as well as podocyte-protective effects, its underlying anti-inflammatory mechanisms remain unclear. Herein, we investigated the therapeutic effects of HPS on murine DN and the potential mechanisms responsible for its efficacy. We used C57BLKS/6J Lepdb/db mice and a high glucose (HG)-induced bone marrow-derived macrophage (BMDM) polarization system to investigate the potentially protective effects of HPS on DN. Our results showed that HPS markedly reduced diabetes-induced albuminuria and glomerular mesangial matrix expansion, accompanied with a significant improvement of fasting blood glucose level, hyperlipidaemia and body weight. Mechanistically, pretreatment with HPS effectively regulated macrophage polarization by shifting proinflammatory M1 macrophages (F4/80+CD11b+CD86+) to anti-inflammatory M2 ones (F4/80+CD11b+CD206+) in vivo and in bone marrow-derived macrophages (BMDMs) in vitro, resulting in the inhibition of renal proinflammatory macrophage infiltration and the reduction in expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF-α) and inducible nitric oxide synthase (iNOS) while increasing expression of anti-inflammatory cytokine Arg-1 and CD163/CD206 surface molecules. Unexpectedly, pretreatment with HPS suppressed CD4+ T cell proliferation in a coculture model of IL-4-induced M2 macrophages and splenic CD4+ T cells while promoting their differentiation into CD4+IL-4+ Th2 and CD4+Foxp3+ Treg cells. Taken together, we demonstrate that HPS ameliorates murine DN via promoting macrophage polarization from an M1 to M2 phenotype and CD4+ T cell differentiation into Th2 and Treg populations. Our findings may be implicated for the treatment of DN in clinic.

scholarly journals GM-CSF Expression and Macrophage Polarization in Joints of Undifferentiated Arthritis Patients Evolving to Rheumatoid Arthritis or Psoriatic Arthritis

2020 ◽  
Author(s):  
Sara Fuentelsaz-Romero ◽  
Andrea Cuervo ◽  
Lizbeth Estrada-Capetillo ◽  
Raquel Celis ◽  
Raquel García-Campos ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
Inflammatory Marker ◽  
Macrophage Polarization ◽  
Activin A ◽  
Healthy Controls ◽  
Undifferentiated Arthritis ◽  
Gm Csf ◽  
Macrophage Density ◽  
Anti Inflammatory

Abstract Background and Aims: GM-CSF-dependent macrophage polarization hasbeen demonstrated in rheumatoid arthritis (RA). Our aim was to seek diagnostic/prognostic biomarkers for undifferentiated arthritis (UA) by analyzing GM-CSF expression and source, macrophage polarization and density in joints of patients with UA evolving to RA or PsA compared with established RA or PsA, respectively.Methods:Synovial tissue (ST)from patients with UA evolving to RA (UA>RA, n=8), PsA (UA>PsA, n=9), persistent UA (UA, n=16), established RA (n=12) and PsA (n=10), and healthy controls (n=6), were analyzed. Cell source and quantitative expression of GM-CSF and proteins associated with pro-inflammatory (GM-CSF-driven) and anti-inflammatory (M-CSF-driven) macrophage polarization (activin A, TNFα, MMP12 and CD209, respectively) were assessed in ST CD163+ macrophages by multicolor immunofluorescence. GM-CSF and activin A levels were also quantified in paired synovial fluid samples. CD163+ macrophage density was determined in all groups by immunofluorescence.Results:Synovial stromal cells (FAP+ fibroblast, CD90+ endothelial cells) and CD163+ sublining macrophages were the sources of GM-CSF. ST CD163+ macrophages from all groups expressed pro-inflammatory polarization markers (activin A, TNFα and MMP12). Expression of the M-CSF-dependent anti-inflammatory marker CD209 identified two macrophage subsets (CD163+ CD209high and CD163+ CD209low/-). CD209+ macrophages were more abundant in ST from healthy controls and PsA patients, although both macrophage subtypesshowed similar levels of pro-inflammatory markers in all groups. In paired synovial fluid samples, activin A was detected in all patients, with higher levels in UA>RA and RA, while GM-CSF was infrequently detected. ST CD163+ macrophage density was comparable between UA>RA and UA>PsA patients, but significantly higher than in persistent UA and established RA and PsA patients, respectively.Conclusions: GM-CSF is highly expressed by sublining CD90+ FAP+ synovial fibroblasts, CD90+ activated endothelium and CD163+ macrophages in different types of arthritis. The polarization state of ST macrophages was similar in all UA and established arthritis groups, with a predominance of pro-inflammatory GM-CSF-associated markers. CD163+ macrophage density was significantly higher in the UA phases of RA and PsA compared with persistent UA. Taken together, our findings support the idea that GM-CSF is a strong driver of macrophage polarization and a potential therapeutic target not only in RA but also in PsA and all types of UA.

scholarly journals The macrophage reprogramming ability of antifolates reveals soluble CD14 as a potential biomarker for methotrexate response in rheumatoid arthritis

2021 ◽  
Author(s):  
Sara Fuentelsaz-Romero ◽  
Celia Barrio Alonso ◽  
Raquel Garcia Campos ◽  
Monica Torres Torresano ◽  
Ittai Muller ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Human Monocyte ◽  
Serum Levels ◽  
Gene Signature ◽  
Soluble Cd14 ◽  
Potential Biomarker ◽  
Exogenous Addition ◽  
Proinflammatory Gene ◽  
One Carbon Metabolism ◽  
The One

The physio-pathological relevance of the one-carbon metabolism (OCM) is illustrated by the chemotherapeutic and anti-inflammatory effects of the antifolates Pemetrexed (PMX) and Methotrexate (MTX) in cancer and rheumatoid arthritis (RA). We report that OCM determines the functional and gene expression profile of human macrophages. PMX induces the acquisition of a p53-dependent proinflammatory gene signature in human monocyte-derived macrophages (GM-Mθ). Indeed, OCM blockade reprograms GM-Mθ towards a state of LPS-tolerance at the signaling and functional levels, an effect abolished by folinic acid. Importantly, OCM blockade led to reduced expression of membrane-bound and soluble CD14 (sCD14), whose exogenous addition restores LPS sensitivity. The therapeutic relevance of these results was confirmed in early RA patients, as MTX-responder RA patients exhibit lower sCD14 serum levels, with baseline sCD14 levels predicting MTX response. Our results indicate that OCM is a metabolic circuit that critically mediates the acquisition of innate immune tolerance, and positions sCD14 as a valuable tool to predict MTX-response in RA patients.

scholarly journals Translation of Collagen Ultrastructure to Biomaterial Fabrication for Material Independent but Highly Efficient Topographic Immunomodulation

2021 ◽  
Author(s):  
matthias ryma ◽  
tina tylek ◽  
julia liebscher ◽  
robin fernandez ◽  
christoph böhm ◽  
...  
Keyword(s):  
Immune Cells ◽  
Macrophage Polarization ◽  
Healing Process ◽  
Human Monocyte ◽  
Collagen Fibers ◽  
Collagen I ◽  
Human Macrophage ◽  
Type I ◽  
Native Collagen ◽  
Surface Patterns

<div>Supplement-free induction of cellular differentiation and polarization solely through the topography of materials is an auspicious strategy but has so far significantly lacked behind the efficiency and intensity of media-supplementation based protocols. For immune cells, low intensity effects were achieved on rhodent cells using standard technologically driven surface patterns and scaffold geometries, but no effects could be achieved for human immune cells. <br></div><p> </p> <p>Consistent with the idea that 3D structural motives in the extracellular matrix possess immunomodulatory capacity as part of the natural healing process, we found that human monocyte-derived macrophages show a strong M2a like pro-healing polarization when cultured on type I rat-tail collagen fibers (hereafter termed "collagen I") but not on collagen I films. <br></p><p>Therefore, we hypothesized that highly aligned nanofibrils also of synthetic polymers, if packed into larger bundles in 3D topographical similarity to native collagen I, would induce a localized macrophage polarization. <br></p> <p> </p> <p>For the automated fabrication of such bundles in a 3D printing manner, we pioneered the strategy of "Melt Electrofibrillation" by the integration of flow directed polymer phase separation into Melt Electrowriting and subsequent selective dissolution of the matrix polymer. This process yields nano-fiber bundles with a remarkable structural similarity to native collagen I fibers, particularly for medical grade polycaprolactone (PCL). </p> <p> </p> <p>These biomimetic fibrillar structures indeed induced a pronounced elongation of human monocyte-derived macrophages and unprecedentedly triggered their M2-like polarization as efficiently as IL-4 cytokine treatment.</p> <p> </p> <p>Our data evidence the biological importance of human macrophage-elongation on collagen fibers and pioneers a strategy to fabricate scaffolds that exploit this effect to drive macrophage polarization through precise and biomimetic material design. </p>

T-cell receptor- and anti-inflammatory gene-modulated T cells as therapy for autoimmune disease

2007 ◽  
Vol 3 (6) ◽  
pp. 883-890 ◽  
Author(s):  
Keishi Fujio ◽  
Tomohisa Okamura ◽  
Akiko Okamoto ◽  
Kazuhiko Yamamoto
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Disease ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Inflammatory Gene ◽  
Anti Inflammatory

scholarly journals HBEGF+ macrophages identified in rheumatoid arthritis promote joint tissue invasiveness and are reshaped differentially by medications

2019 ◽  
Author(s):  
David Kuo ◽  
Jennifer Ding ◽  
Ian Cohn ◽  
Fan Zhang ◽  
Kevin Wei ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Egf Receptor ◽  
Wide Spectrum ◽  
Joint Destruction ◽  
Human Macrophage ◽  
Dependent Manner ◽  
Human Tissues ◽  
Joint Tissue ◽  
Macrophage Phenotypes ◽  
Anti Inflammatory

AbstractMacrophages tailor their function to the signals found in tissue microenvironments, taking on a wide spectrum of phenotypes. In human tissues, a detailed understanding of macrophage phenotypes is limited. Using single-cell RNA-sequencing, we define distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF+ inflammatory macrophages is enriched in RA tissues and shaped by resident fibroblasts and the cytokine TNF. These macrophages promote fibroblast invasiveness in an EGF receptor dependent manner, indicating that inflammatory intercellular crosstalk reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo tissue assay, the HBEGF+ inflammatory macrophage is targeted by several anti-inflammatory RA medications, however, COX inhibition redirects it towards a different inflammatory phenotype that is also expected to perpetuate pathology. These data highlight advances in understanding the pathophysiology and drug mechanisms in chronic inflammatory disorders can be achieved by focusing on macrophage phenotypes in the context of complex interactions in human tissues.One Sentence SummaryA newly identified human macrophage phenotype from patients with the autoimmune condition RA is found to promote joint tissue invasiveness and demonstrates variable sensitivities to anti-inflammatory medications used to treat the disease.

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