scholarly journals Proteoglycan-4 is an essential regulator of synovial macrophage polarization and inflammatory macrophage joint infiltration

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Marwa Qadri ◽  
Gregory D. Jay ◽  
Ling X. Zhang ◽  
Tannin A. Schmidt ◽  
Jennifer Totonchy ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Membrane Thickness ◽  
Type I ◽  
Surface Markers ◽  
M1 Macrophages ◽  
Synovial Hyperplasia ◽  
Synovial Macrophage ◽  
Proteoglycan 4 ◽  
Inflammatory Macrophages ◽  
The Impact

Abstract Background Synovial macrophages perform a multitude of functions that include clearance of cell debris and foreign bodies, tissue immune surveillance, and resolution of inflammation. The functional diversity of macrophages is enabled by distinct subpopulations that express unique surface markers. Proteoglycan-4 (PRG4) is an important regulator of synovial hyperplasia and fibrotic remodeling, and the involvement of macrophages in PRG4’s synovial role is yet to be defined. Our objectives were to study the PRG4’s importance to macrophage homeostatic regulation in the synovium and infiltration of pro-inflammatory macrophages in acute synovitis and investigate whether macrophages mediated synovial fibrosis in Prg4 gene-trap (Prg4GT/GT) murine knee joints. Methods Macrophage phenotyping in Prg4GT/GT and Prg4+/+ joints was performed by flow cytometry using pan-macrophage markers, e.g., CD11b, F4/80, and surface markers of M1 macrophages (CD86) and M2 macrophages (CD206). Characterizations of the various macrophage subpopulations were performed in 2- and 6-month-old animals. The expression of inflammatory markers, IL-6, and iNOS in macrophages that are CD86+ and/or CD206+ was studied. The impact of Prg4 recombination on synovial macrophage populations of 2- and 6-month-old animals and infiltration of pro-inflammatory macrophages in response to a TLR2 agonist challenge was determined. Macrophages were depleted using liposomal clodronate and synovial membrane thickness, and the expression of fibrotic markers α-SMA, PLOD2, and collagen type I (COL-I) was assessed using immunohistochemistry. Results Total macrophages in Prg4GT/GT joints were higher than Prg4+/+ joints (p<0.0001) at 2 and 6 months, and the percentages of CD86+/CD206− and CD86+/CD206+ macrophages increased in Prg4GT/GT joints at 6 months (p<0.0001), whereas the percentage of CD86−/CD206+ macrophages decreased (p<0.001). CD86+/CD206− and CD86+/CD206+ macrophages expressed iNOS and IL-6 compared to CD86−/CD206+ macrophages (p<0.0001). Prg4 re-expression limited the accumulation of CD86+ macrophages (p<0.05) and increased CD86−/CD206+ macrophages (p<0.001) at 6 months. Prg4 recombination attenuated synovial recruitment of pro-inflammatory macrophages in 2-month-old animals (p<0.001). Clodronate-mediated macrophage depletion reduced synovial hyperplasia, α-SMA, PLOD2, and COL-I expressions in the synovium (p<0.0001). Conclusions PRG4 regulates the accumulation and homeostatic balance of macrophages in the synovium. In its absence, the synovium becomes populated with M1 macrophages. Furthermore, macrophages exert an effector role in synovial fibrosis in Prg4GT/GT animals.

scholarly journals Proteoglycan-4 is an Essential Regulator of Synovial Macrophage Polarization and Inflammatory Macrophage Joint Infiltration

2021 ◽  
Author(s):  
Marwa Qadri ◽  
Gregory D. Jay ◽  
Ling X. Zhang ◽  
Tannin A. Schmidt ◽  
Jennifer Totonchy ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Polarization Spectrum ◽  
Membrane Thickness ◽  
Type I ◽  
Synovial Hyperplasia ◽  
Arginase 1 ◽  
Liposomal Clodronate ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory ◽  
The Impact

Abstract Background: Synovial macrophages (SMs) perform a multitude of functions that include clearance of cell debris and foreign bodies, tissue immune surveillance, and resolution of inflammation. At one end of the macrophage polarization spectrum is the inflammatory phenotype (M1), which secretes IL-1β, IL-6 and expresses iNOS. On the opposite end of the spectrum is the anti-inflammatory phenotype (M2) which is characterized by the secretion of IL-10 and TGF-β. PRG4 is an important regulator of synovial hyperplasia and fibrotic remodeling and the involvement of SM activation in PRG4’s homeostatic role is yet to be defined. Our objectives were to study PRG4’s importance to SM homeostasis, M1 and M2 polarization and joint infiltration of bone marrow-derived macrophages (BMDMs) and investigate the role of SMs in mediating synovial fibrosis in Prg4 gene-trap (Prg4GT/GT) murine knee joints.Methods: SM phenotyping in Prg4GT/GT and Prg4+/+ joints was performed using flow cytometry and the balance between CD86+/CD206- (M1) and CD86-/CD206+ (M2) SMs was studied as animals aged. Expression of iNOS and IL-6 in CD86+ SMs, arginase-1 in CD206+ SMs and the impact of Prg4 recombination on SM polarization and BMDM infiltration following a TLR2 agonist challenge were determined. Inflammatory SMs were depleted using liposomal clodronate and synovial membrane thickness and expression of fibrotic markers: α-SMA, PLOD2 and collagen type I (COL-I) were assessed using immunohistochemistry.Results: Total macrophages in Prg4GT/GT joints were higher than corresponding age-matched Prg4+/+ joints (p<0.0001) and the percentages of CD86+/CD206- and CD86+/CD206+ SMs increased in Prg4GT/GT joints as animals aged (p<0.0001), whereas the percentage of CD86-/CD206+ SMs decreased (p<0.001). CD86+ SMs expressed iNOS and IL-6 compared to CD86- SMs (p<0.0001) while CD206+ SMs also expressed arginase-1. Prg4 re-expression limited the accumulation of CD86+ SMs, increased CD86-/CD206+ SMs and attenuated BMDM recruitment (p<0.001). Liposomal clodronate reduced inflammatory SMs and in turn reduced synovial hyperplasia, α-SMA, PLOD2 and COL-I expression in the synovium (p<0.0001).Conclusions: SM accumulation in the joint and the balance between inflammatory and anti-inflammatory SM subsets are regulated by PRG4. In the absence of PRG4’s role, the synovium is populated with inflammatory macrophages that drive synovial fibrosis.

scholarly journals Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 689 ◽  
Author(s):  
Rodrigo Berzaghi ◽  
Muhammad Asad Ahktar ◽  
Ashraful Islam ◽  
Brede D. Pedersen ◽  
Turid Hellevik ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ionizing Radiation ◽  
Inflammatory Cytokines ◽  
Macrophage Polarization ◽  
High Dose ◽  
Surface Markers ◽  
M1 Macrophages ◽  
Protein Levels ◽  
Healthy Donors

The abilities of cancer-associated fibroblasts (CAFs) to regulate immune responses in the context of radiotherapy remain largely unknown. This study was undertaken to determine whether ionizing radiation alters the CAF-mediated immunoregulatory effects on macrophages. CAFs were isolated from freshly-resected non-small cell lung cancer tumors, while monocyte-derived macrophages were prepared from peripheral blood of healthy donors. Experimental settings included both (CAF-macrophage) co-cultures and incubations of M0 and M1-macrophages in the presence of CAF-conditioned medium (CAF-CM). Functional assays to study macrophage polarization/activation included the expression of cell surface markers, production of nitric oxide, secretion of inflammatory cytokines and migratory capacity. We show that CAFs promote changes in M0-macrophages that harmonize with both M1-and M2-phenotypes. Additionally, CAFs inhibit pro-inflammatory features of M1-macrophages by reducing nitric oxide production, pro-inflammatory cytokines, migration, and M1-surface markers expression. Radiation delivered as single-high dose or in fractioned regimens did not modify the immunoregulatory features exerted by CAFs over macrophages in vitro. Protein expression analyses of CAF supernatants showed that irradiated and non-irradiated CAFs produce approximately the same protein levels of immunoregulators. Thus, CAF-derived soluble factors mediate measurable changes on uncommitted macrophages and down-regulate pro-inflammatory features of M1-polarized macrophages. Notably, ionizing radiation does not curtail the CAF-mediated immunosuppressive effects.

scholarly journals Aspartate Metabolism Facilitates IL-1β Production in Inflammatory Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Hao Wang ◽  
Xueyue Zheng ◽  
Bingnan Liu ◽  
Yaoyao Xia ◽  
Zhongquan Xin ◽  
...  
Keyword(s):  
Immune Cells ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Hypoxia Inducible Factor ◽  
M1 Macrophages ◽  
M1 Macrophage ◽  
Ifn Γ ◽  
Inflammatory Macrophages

Increasing evidence support that cellular amino acid metabolism shapes the fate of immune cells; however, whether aspartate metabolism dictates macrophage function is still enigmatic. Here, we found that the metabolites in aspartate metabolism are depleted in lipopolysaccharide (LPS) plus interferon gamma (IFN-γ)-stimulated macrophages. Aspartate promotes interleukin-1β (IL-1β) secretion in M1 macrophages. Mechanistically, aspartate boosts the activation of hypoxia-inducible factor-1α (HIF-1α) and inflammasome and increases the levels of metabolites in aspartate metabolism, such as asparagine. Interestingly, asparagine also accelerates the activation of cellular signaling pathways and promotes the production of inflammatory cytokines from macrophages. Moreover, aspartate supplementation augments the macrophage-mediated inflammatory responses in mice and piglets. These results uncover a previously uncharacterized role for aspartate metabolism in directing M1 macrophage polarization.

scholarly journals CDC-derived extracellular vesicles reprogram inflammatory macrophages to an arginase 1-dependent proangiogenic phenotype

2020 ◽  
Vol 318 (6) ◽  
pp. H1447-H1460 ◽  
Author(s):  
Kyle I. Mentkowski ◽  
Asma Mursleen ◽  
Jonathan D. Snitzer ◽  
Lindsey M. Euscher ◽  
Jennifer K. Lang
Keyword(s):  
Myocardial Infarction ◽  
Extracellular Vesicles ◽  
Macrophage Polarization ◽  
Extracellular Vesicle ◽  
Primary Target ◽  
Relevant Model ◽  
M1 Macrophages ◽  
Arginase 1 ◽  
Inflammatory Macrophages ◽  
Insight Into

We hypothesized that in the window of therapeutic extracellular vesicle (EV) administration, inflammatory M1 macrophages are likely the primary target of cardiosphere-derived cell (CDC)-derived EVs. The effect of CDC-EVs on this population, however, is currently unknown. In this study, we demonstrate that CDC-derived EVs polarize M1 macrophages to a proangiogenic phenotype dependent on arginase 1 upregulation. These results provide insight into an immunomodulatory mechanism of CDC-EVs in a more physiologically relevant model of post-myocardial infarction (post-MI) macrophage polarization.

scholarly journals Correction to: Proteoglycan-4 is an essential regulator of synovial macrophage polarization and inflammatory macrophage joint infiltration

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Marwa Qadri ◽  
Gregory D. Jay ◽  
Ling X. Zhang ◽  
Tannin A. Schmidt ◽  
Jennifer Totonchy ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Synovial Macrophage ◽  
Proteoglycan 4 ◽  
Inflammatory Macrophage

An amendment to this paper has been published and can be accessed via the original article.

scholarly journals STING and cGAS gene expressions were downregulated among HIV-1-infected persons after antiretroviral therapy

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lorena Leticia Peixoto de Lima ◽  
Allysson Quintino Tenório de Oliveira ◽  
Tuane Carolina Ferreira Moura ◽  
Ednelza da Silva Graça Amoras ◽  
Sandra Souza Lima ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Load ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cell Count ◽  
Enzyme Linked Immunosorbent Assay ◽  
Type I ◽  
Α Level ◽  
The Impact ◽  
Hiv 1

Abstract Background The HIV-1 epidemic is still considered a global public health problem, but great advances have been made in fighting it by antiretroviral therapy (ART). ART has a considerable impact on viral replication and host immunity. The production of type I interferon (IFN) is key to the innate immune response to viral infections. The STING and cGAS proteins have proven roles in the antiviral cascade. The present study aimed to evaluate the impact of ART on innate immunity, which was represented by STING and cGAS gene expression and plasma IFN-α level. Methods This cohort study evaluated a group of 33 individuals who were initially naïve to therapy and who were treated at a reference center and reassessed 12 months after starting ART. Gene expression levels and viral load were evaluated by real-time PCR, CD4+ and CD8+ T lymphocyte counts by flow cytometry, and IFN-α level by enzyme-linked immunosorbent assay. Results From before to after ART, the CD4+ T cell count and the CD4+/CD8+ ratio significantly increased (p < 0.0001), the CD8+ T cell count slightly decreased, and viral load decreased to undetectable levels in most of the group (84.85%). The expression of STING and cGAS significantly decreased (p = 0.0034 and p = 0.0001, respectively) after the use of ART, but IFN-α did not (p = 0.1558). Among the markers evaluated, the only markers that showed a correlation with each other were STING and CD4+ T at the time of the first collection. Conclusions ART provided immune recovery and viral suppression to the studied group and indirectly downregulated the STING and cGAS genes. In contrast, ART did not influence IFN-α. The expression of STING and cGAS was not correlated with the plasma level of IFN-α, which suggests that there is another pathway regulating this cytokine in addition to the STING–cGAS pathway.

scholarly journals The Dynamic Interaction between Extracellular Matrix Remodeling and Breast Tumor Progression

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1046
Author(s):  
Jorge Martinez ◽  
Patricio C. Smith
Keyword(s):  
Extracellular Matrix ◽  
Type I Collagen ◽  
Cell Metabolism ◽  
Breast Tumors ◽  
Extracellular Matrix Remodeling ◽  
Type I ◽  
Matrix Remodeling ◽  
Desmoplastic Reaction ◽  
The Impact

Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as “desmoplastic reaction”. This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors.

scholarly journals Treadmill Running Changes Endothelial Lipase Expression: Insights from Gene and Protein Analysis in Various Striated Muscle Tissues and Serum

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 906
Author(s):  
Agnieszka Mikłosz ◽  
Bartłomiej Łukaszuk ◽  
Adrian Chabowski ◽  
Jan Górski
Keyword(s):  
Protein Expression ◽  
Density Lipoprotein ◽  
Treadmill Running ◽  
Endothelial Lipase ◽  
Type I ◽  
Fiber Types ◽  
Gene And Protein Expression ◽  
Single Bout ◽  
The Impact ◽  
White Gastrocnemius

Endothelial lipase (EL) is an enzyme capable of HDL phospholipids hydrolysis. Its action leads to a reduction in the serum high-density lipoprotein concentration, and thus, it exerts a pro-atherogenic effect. This study examines the impact of a single bout exercise on the gene and protein expression of the EL in skeletal muscles composed of different fiber types (the soleus—mainly type I, the red gastrocnemius—mostly IIA, and the white gastrocnemius—predominantly IIX fibers), as well as the diaphragm, and the heart. Wistar rats were subjected to a treadmill run: 1) t = 30 [min], V = 18 [m/min]; 2) t = 30 [min], V = 28 [m/min]; 3) t = 120 [min], V = 18 [m/min] (designated: M30, F30, and M120, respectively). We established EL expression in the total muscle homogenates in sedentary animals. Resting values could be ordered with the decreasing EL protein expression as follows: endothelium of left ventricle > diaphragm > red gastrocnemius > right ventricle > soleus > white gastrocnemius. Furthermore, we observed that even a single bout of exercise was capable of inducing changes in the mRNA and protein level of EL, with a clearer pattern observed for the former. After 30 min of running at either exercise intensity, the expression of EL transcript in all the cardiovascular components of muscles tested, except the soleus, was reduced in comparison to the respective sedentary control. The protein content of EL varied with the intensity and/or duration of the run in the studied whole tissue homogenates. The observed differences between EL expression in vascular beds of muscles may indicate the muscle-specific role of the lipase.

scholarly journals Iron Released after Cryo-Thermal Therapy Induced M1 Macrophage Polarization, Promoting the Differentiation of CD4+ T Cells into CTLs

2021 ◽  
Vol 22 (13) ◽  
pp. 7010
Author(s):  
Shicheng Wang ◽  
Man Cheng ◽  
Peng Peng ◽  
Yue Lou ◽  
Aili Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Antitumor Immunity ◽  
Macrophage Polarization ◽  
Thermal Therapy ◽  
High Plasticity ◽  
Antitumor Effects ◽  
M1 Macrophages ◽  
Splenic Macrophages ◽  
M1 Macrophage

Macrophages play critical roles in both innate and adaptive immunity and are known for their high plasticity in response to various external signals. Macrophages are involved in regulating systematic iron homeostasis and they sequester iron by phagocytotic activity, which triggers M1 macrophage polarization and typically exerts antitumor effects. We previously developed a novel cryo-thermal therapy that can induce the mass release of tumor antigens and damage-associated molecular patterns (DAMPs), promoting M1 macrophage polarization. However, that study did not examine whether iron released after cryo-thermal therapy induced M1 macrophage polarization; this question still needed to be addressed. We hypothesized that cryo-thermal therapy would cause the release of a large quantity of iron to augment M1 macrophage polarization due to the disruption of tumor cells and blood vessels, which would further enhance antitumor immunity. In this study, we investigated iron released in primary tumors, the level of iron in splenic macrophages after cryo-thermal therapy and the effect of iron on macrophage polarization and CD4+ T cell differentiation in metastatic 4T1 murine mammary carcinoma. We found that a large amount of iron was released after cryo-thermal therapy and could be taken up by splenic macrophages, which further promoted M1 macrophage polarization by inhibiting ERK phosphorylation. Moreover, iron promoted DC maturation, which was possibly mediated by iron-induced M1 macrophages. In addition, iron-induced M1 macrophages and mature DCs promoted the differentiation of CD4+ T cells into the CD4 cytolytic T lymphocytes (CTL) subset and inhibited differentiation into Th2 and Th17 cells. This study explains the role of iron in cryo-thermal therapy-induced antitumor immunity from a new perspective.

scholarly journals The Influence of Concentration and Temperature on the Membrane Resistance of Ion Exchange Membranes and the Levelised Cost of Hydrogen from Reverse Electrodialysis with Ammonium Bicarbonate

Membranes ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 135
Author(s):  
Yash Dharmendra Raka ◽  
Robert Bock ◽  
Håvard Karoliussen ◽  
Øivind Wilhelmsen ◽  
Odne Stokke Burheim
Keyword(s):  
Ion Exchange ◽  
Waste Heat ◽  
Ammonium Bicarbonate ◽  
Operating Efficiency ◽  
Membrane Thickness ◽  
Ion Exchange Membranes ◽  
Reverse Electrodialysis ◽  
Ohmic Resistance ◽  
Production Of Hydrogen ◽  
The Impact

The ohmic resistances of the anion and cation ion-exchange membranes (IEMs) that constitute a reverse electrodialysis system (RED) are of crucial importance for its performance. In this work, we study the influence of concentration (0.1 M, 0.5 M, 1 M and 2 M) of ammonium bicarbonate solutions on the ohmic resistances of ten commercial IEMs. We also studied the ohmic resistance at elevated temperature 313 K. Measurements have been performed with a direct two-electrode electrochemical impedance spectroscopy (EIS) method. As the ohmic resistance of the IEMs depends linearly on the membrane thickness, we measured the impedance for three different layered thicknesses, and the results were normalised. To gauge the role of the membrane resistances in the use of RED for production of hydrogen by use of waste heat, we used a thermodynamic and an economic model to study the impact of the ohmic resistance of the IEMs on hydrogen production rate, waste heat required, thermochemical conversion efficiency and the levelised cost of hydrogen. The highest performance was achieved with a stack made of FAS30 and CSO Type IEMs, producing hydrogen at 8.48× 10−7 kg mmem−2s−1 with a waste heat requirement of 344 kWh kg−1 hydrogen. This yielded an operating efficiency of 9.7% and a levelised cost of 7.80 € kgH2−1.

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