scholarly journals A Selective Neutraligand for CXCL12/SDF-1α With Beneficial Regulatory Functions in MRL/Lpr Lupus Prone Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Nicolas Schall ◽  
François Daubeuf ◽  
Claire Marsol ◽  
Patrick Gizzi ◽  
Nelly Frossard ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Inflammatory Diseases ◽  
Pathophysiological Mechanism ◽  
T Lymphocyte Subsets ◽  
Activation Markers ◽  
Immune Alterations ◽  
Novel Strategy ◽  
Regulatory Functions ◽  
Excessive Number

Dysregulation of CXCL12/SDF-1-CXCR4/CD184 signaling is associated with inflammatory diseases and notably with systemic lupus erythematosus. Issued from the lead molecule chalcone-4, the first neutraligand of the CXCL12 chemokine, LIT-927 was recently described as a potent analogue with improved solubility and stability. We aimed to investigate the capacity of LIT-927 to correct immune alterations in lupus-prone MRL/lpr mice and to explore the mechanism of action implemented by this small molecule in this model. We found that in contrast to AMD3100, an antagonist of CXCR4 and agonist of CXCR7, LIT-927 reduces the excessive number of several B/T lymphocyte subsets occurring in the blood of sick MRL/lpr mice (including CD3+/CD4-/CD8-/B220+ double negative T cells). In vitro, LIT-927 downregulated the overexpression of several activation markers on splenic MRL/lpr lymphocytes. It exerted effects on the CXCR4 pathway in MRL/lpr CD4+ T spleen cells. The results underline the importance of the CXCL12/CXCR4 axis in lupus pathophysiology. They indicate that neutralizing CXCL12 by the neutraligand LIT-927 can attenuate hyperactive lymphocytes in lupus. This mode of intervention might represent a novel strategy to control a common pathophysiological mechanism occurring in inflammatory diseases.

scholarly journals A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis

2017 ◽  
Vol 214 (11) ◽  
pp. 3449-3466 ◽  
Author(s):  
Alma-Martina Cepika ◽  
Romain Banchereau ◽  
Elodie Segura ◽  
Marina Ohouo ◽  
Brandi Cantarel ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Inflammatory Diseases ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Unknown Etiology ◽  
Integrated Analysis ◽  
Cell Phenotype ◽  
Protein Levels ◽  
Aryl Hydrocarbon ◽  
Immune Alterations

The etiology of sporadic human chronic inflammatory diseases remains mostly unknown. To fill this gap, we developed a strategy that simultaneously integrates blood leukocyte responses to innate stimuli at the transcriptional, cellular, and secreted protein levels. When applied to systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory disease of unknown etiology, this approach identified gene sets associated with specific cytokine environments and activated leukocyte subsets. During disease remission and off treatment, sJIA patients displayed dysregulated responses to TLR4, TLR8, and TLR7 stimulation. Isolated sJIA monocytes underexpressed the IL-1 inhibitor aryl hydrocarbon receptor (AHR) at baseline and accumulated higher levels of intracellular IL-1β after stimulation. Supporting the demonstration that AHR down-regulation skews monocytes toward macrophage differentiation, sJIA monocytes differentiated in vitro toward macrophages, away from the dendritic cell phenotype. This might contribute to the increased incidence of macrophage activation syndrome in these patients. Integrated analysis of high-dimensional data can thus unravel immune alterations predisposing to complex inflammatory diseases.

scholarly journals Mannose Treatment: A Promising Novel Strategy to Suppress Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Zhang ◽  
Hao Cheng ◽  
Yuanyuan Gui ◽  
Qipeng Zhan ◽  
Si Li ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
High Glucose ◽  
Inflammatory Diseases ◽  
Effector T Cells ◽  
Discovery Process ◽  
Fructose Intake ◽  
Novel Strategy ◽  
Inflammatory Macrophages ◽  
Regulatory Functions

High glucose and fructose intake have been proven to display pro-inflammatory roles during the progression of inflammatory diseases. However, mannose has been shown to be a special type of hexose that has immune regulatory functions. In this review, we trace the discovery process of the regulatory functions of mannose and summarize some past and recent studies showing the therapeutic functions of mannose in inflammatory diseases. We conclude that treatment with mannose can suppress inflammation by inducing regulatory T cells, suppressing effector T cells and inflammatory macrophages, and increasing anti-inflammatory gut microbiome. By summarizing all the important findings, we highlight that mannose treatment is a safe and promising novel strategy to suppress inflammatory diseases, including autoimmune disease and allergic disease.

scholarly journals GM-CSF Impairs Erythropoiesis by Disrupting Erythroblastic Island Formation via Macrophages

2021 ◽  
Author(s):  
Weijie Cao ◽  
Wenjuan Fan ◽  
Fang Wang ◽  
Yinyin Zhang ◽  
Guanghua Wu ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Inflammatory Diseases ◽  
Mouse Bone Marrow ◽  
Adhesion Molecule Expression ◽  
Supporting Function ◽  
Gm Csf ◽  
Erythroblastic Island ◽  
Novel Strategy

Abstract Anemia is a significant complication of chronic inflammation and may be related to dysregulated activities among erythroblastic island (EBI) macrophages. GM-CSF was reported to be upregulated and attracted as a therapeutic target in many inflammatory diseases. Among EBIs, we found that the GM-CSF receptor is preferentially and highly expressed among EBI macrophages but not among erythroblasts. GM-CSF treatment significantly decreases human EBI formation in vitro by decreasing the adhesion molecule expression of CD163. RNA-sequence analysis suggests that GM-CSF treatment impairs the supporting function of human EBI macrophages during erythropoiesis. GM-CSF treatment also polarizes human EBI macrophages from M2-like type to M1-like type. In addition, GM-CSF decreases mouse bone marrow (BM) erythroblasts as well as EBI macrophages, leading to a reduction in EBI numbers. In defining the molecular mechanism at work, we found that GM-CSF treatment significantly decreases the adhesion molecule expression of CD163 and Vcam1 in vivo. Importantly, GM-CSF treatment also decreases the phagocytosis rate of EBI macrophages in mouse BM as well as decreases the expression of the engulfment-related molecules Mertk, Axl, and Timd4. In addition, GM-CSF treatment polarizes mouse BM EBI macrophages from M2-like type to M1-like type. Thus, we document that GM-CSF impairs EBI formation in mice and humans. Our findings support that targeting GM-CSF or reprogramming EBI macrophages might be a novel strategy to treat anemia resulting from inflammatory diseases.

scholarly journals Ocular penetration of fluorometholone-loaded PEG-PLGA nanoparticles functionalized with cell-penetrating peptides

Nanomedicine ◽  
2019 ◽  
Vol 14 (23) ◽  
pp. 3089-3104 ◽  
Author(s):  
Roberto Gonzalez-Pizarro ◽  
Graziella Parrotta ◽  
Rodrigo Vera ◽  
Elena Sánchez-López ◽  
Ruth Galindo ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Physicochemical Characteristics ◽  
Plga Nanoparticles ◽  
Cell Penetrating Peptides ◽  
In Vivo Models ◽  
Corneal Epithelial ◽  
Cell Penetrating ◽  
Novel Strategy

Aim: Development of fluorometholone-loaded PEG-PLGA nanoparticles (NPs) functionalized with cell-penetrating peptides (CPPs) for the treatment of ocular inflammatory disorders. Materials & methods: Synthesized polymers and peptides were used for elaboration of functionalized NPs, which were characterized physicochemically. Cytotoxicity and ability to modulate the expression of proinflammatory cytokines were evaluated in vitro using human corneal epithelial cells (HCE-2). NPs uptake was assayed in both in vitro and in vivo models. Results: NPs showed physicochemical characteristics suitable for ocular administration without evidence of cytotoxicity. TAT-NPs and G2-NPs were internalized and displayed anti-inflammatory activity in both HCE-2 cells and mouse eye. Conclusion: TAT-NPs and G2-NPs could be considered a novel strategy for the treatment of ocular inflammatory diseases of the anterior and posterior segment.

scholarly journals Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19+CD24hiCD27+ Breg Cells

2020 ◽  
Vol 11 ◽  
Author(s):  
Jinyang Li ◽  
Ji Gao ◽  
Haoming Zhou ◽  
Jinren Zhou ◽  
Zhenghua Deng ◽  
...  
Keyword(s):  
B Cells ◽  
Glycogen Synthase ◽  
Inflammatory Diseases ◽  
Adaptive Immune System ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Activated T Cells ◽  
Novel Strategy ◽  
Gsk 3Β

CD19+CD24hiCD27+ memory Breg cells exhibit decreased abundance in patients with chronic graft-versus-host disease (cGVHD) after liver transplantation and produce less IL-10 than those from patients without cGVHD and healthy donors. Due to the lack of Breg cells and the difficulty in expanding them in vitro, in mouse models and early human clinical trials, the adoptive transfer of Breg cells to autoimmune diseases is greatly restricted. Glycogen synthase kinase 3β (GSK-3β) is a multifunctional serine/threonine (ser/thr) protein kinase that can participate in B cell growth, metabolic activity, and proliferation. Phosphoprotein array analysis showed that p-GSK-3β-s9 was highly expressed in mBreg cells. Furthermore, here, we demonstrated that GSK-3β expression in mBreg cells is lower than that observed in B cells by flow cytometry. We found that the treatment of B cells with the specific GSK-3β inhibitor SB216763 can significantly increase the proportion and immunosuppressive function of mBreg cells in vitro. Nuclear factor of activated T cells (NFAT) is one of a pivotal regulator of gene expression in adaptive immune system. Here, we observed that inhibition of GSK-3β by SB216763 results in enhanced expression of NFATc1 in B cells, which is essential in regulating the ability of B cells to secrete IL-10. By constructing a xGVHD mouse model, we observed that SB216763-treated mBreg cells effectively prevent xenogeneic GVHD. Here we propose a novel strategy using SB216763 to inhibit GSK-3β and then enhance the proportion and immunosuppressive function of mBreg cells by increasing the expression of NFATc1. This approach may be used as a therapy to ameliorate GVHD and inflammatory diseases.

scholarly journals The Effects of Vitamin D on Immune System and Inflammatory Diseases

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1624
Author(s):  
Tomoka Ao ◽  
Junichi Kikuta ◽  
Masaru Ishii
Keyword(s):  
Vitamin D ◽  
Infectious Diseases ◽  
Lupus Erythematosus ◽  
Inflammatory Diseases ◽  
Active Form ◽  
Dihydroxyvitamin D ◽  
Treatment And Prevention ◽  
The Impact ◽  
The Relationship

Immune cells, including dendritic cells, macrophages, and T and B cells, express the vitamin D receptor and 1α-hydroxylase. In vitro studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, has an anti-inflammatory effect. Recent epidemiological evidence has indicated a significant association between vitamin D deficiency and an increased incidence, or aggravation, of infectious diseases and inflammatory autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. However, the impact of vitamin D on treatment and prevention, particularly in infectious diseases such as the 2019 coronavirus disease (COVID-19), remains controversial. Here, we review recent evidence associated with the relationship between vitamin D and inflammatory diseases and describe the underlying immunomodulatory effect of vitamin D.

scholarly journals Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus–prone B6.Sle1.Yaa animals

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4534-4540 ◽  
Author(s):  
Kenichiro Maeda ◽  
Alex Malykhin ◽  
Brittany N. Teague-Weber ◽  
Xiao-Hong Sun ◽  
A. Darise Farris ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Interleukin 6 ◽  
Inflammatory Diseases ◽  
Myeloid Cell ◽  
Systemic Lupus ◽  
Inflammatory Conditions ◽  
B Lymphoid

Abstract We previously reported the inhibitory action of interleukin-6 (IL-6) on B lymphopoiesis with SHIP−/− mice and showed that IL-6 biases lineage commitment toward myeloid cell fates in vitro and in vivo. Because elevated IL-6 is a feature of chronic inflammatory diseases, we applied an animal model of systemic lupus erythematosus (SLE) to determine whether IL-6 has similar effects on hematopoiesis. We found that IL-6 levels were elevated in the B6.Sle1.Yaa mice, and the increase was accompanied by losses of CD19+ B cells and more primitive B-lymphoid progenitors in bone marrow. Both the CD19+ B-cell population and their progenitors recovered in an IL-6−/− background. The uncommitted progenitors, containing precursors for both lymphoid and myeloid fates, expressed IL-6 receptor-α chain and responded to IL-6 by phosphorylation of STAT3. IL-6 stimulation caused uncommitted progenitors to express the Id1 transcription factor, which is known to inhibit lymphopoiesis and elevate myelopoiesis, and its expression was MAPK dependent. We conclude that chronic inflammatory conditions accompanied by increased IL-6 production bias uncommitted progenitors to a myeloid fate by inducing Id1 expression.

scholarly journals GM-CSF impairs erythropoiesis by disrupting erythroblastic island formation via macrophages

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Weijie Cao ◽  
Wenjuan Fan ◽  
Fang Wang ◽  
Yinyin Zhang ◽  
Guanghua Wu ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Inflammatory Diseases ◽  
Mouse Bone Marrow ◽  
Adhesion Molecule Expression ◽  
Supporting Function ◽  
Gm Csf ◽  
Erythroblastic Island ◽  
Novel Strategy

AbstractAnemia is a significant complication of chronic inflammation and may be related to dysregulated activities among erythroblastic island (EBI) macrophages. GM-CSF was reported to be upregulated and attracted as a therapeutic target in many inflammatory diseases. Among EBIs, we found that the GM-CSF receptor is preferentially and highly expressed among EBI macrophages but not among erythroblasts. GM-CSF treatment significantly decreases human EBI formation in vitro by decreasing the adhesion molecule expression of CD163. RNA-sequence analysis suggests that GM-CSF treatment impairs the supporting function of human EBI macrophages during erythropoiesis. GM-CSF treatment also polarizes human EBI macrophages from M2-like type to M1-like type. In addition, GM-CSF decreases mouse bone marrow (BM) erythroblasts as well as EBI macrophages, leading to a reduction in EBI numbers. In defining the molecular mechanism at work, we found that GM-CSF treatment significantly decreases the adhesion molecule expression of CD163 and Vcam1 in vivo. Importantly, GM-CSF treatment also decreases the phagocytosis rate of EBI macrophages in mouse BM as well as decreases the expression of the engulfment-related molecules Mertk, Axl, and Timd4. In addition, GM-CSF treatment polarizes mouse BM EBI macrophages from M2-like type to M1-like type. Thus, we document that GM-CSF impairs EBI formation in mice and humans. Our findings support that targeting GM-CSF or reprogramming EBI macrophages might be a novel strategy to treat anemia resulting from inflammatory diseases.

Thrombin Generation Measured Ex Vivo Following Microvasculor Injury Is Increased in SLE Patients with Antiphospholipid-protein Antibodies

1997 ◽  
Vol 78 (04) ◽  
pp. 1173-1177 ◽  
Author(s):  
Jacek Musiał ◽  
Jakub Swadźba ◽  
Miłosz Jankowski ◽  
Marek Grzywacz ◽  
Stanisława Bazan-Socha ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Thrombin Generation ◽  
Ex Vivo ◽  
Skin Incision ◽  
Anticardiolipin Antibodies ◽  
Small Blood Vessel ◽  
Anionic Phospholipids ◽  
Increased Risk ◽  
High Concentrations

SummaryAntiphospholipid-protein antibodies (APA) include lupus-type anticoagulant (LA) and antibodies recognizing complexes of anionic phospholipids (e.g. cardiolipin) and proteins (e.g. prothrombin and (β2-glycoprotein I). The presence of APA is associated with an increased risk of both arterial and venous thrombosis. However, the pathogenic mechanism leading to thrombosis in patients with APA remains unclear. We studied 32 patients with systemic lupus erythematosus (SLE) who were divided into two groups depending on the presence (n = 19) or absence (n = 13) of APA. Healthy volunteers (n = 12) matched by age and sex served as controls. In all subjects LA and IgG class anticardiolipin antibodies (ACA) were determined. Thrombin generation was monitored ex vivo measuring fibrinopeptide A (FPA) and prothrombin fragment F1 + 2 (F1 + 2) in blood emerging from a skin microvasculature injury, collected at 30 second intervals. In subjects with antiphospholipid antibodies mean FPA and F1 + 2 concentrations were signiF1cantly higher at most blood sampling times than in controls. In some SLE patients with APA the process of thrombin generation was clearly disturbed and very high concentrations of F1brinopeptide A were detected already in the F1rst samples collected. Two minutes after skin incision SLE patients without APA produced slightly more FPA, but not F1 + 2, as compared to healthy subjects. Mathematical model applied to analyze the thrombin generation kinetics revealed that APA patients generated signiF1cantly greater amounts of thrombin than healthy controls (p = 0.02 for either marker). In contrast, in the same patients generation of thrombin in recalciF1ed plasma in vitro was delayed pointing to the role of endothelium in the phenomenon studied. In summary, these data show for the F1rst time that in SLE patients with antiphospholipid-protein antibodies thrombin generation after small blood vessel injury is markedly increased. Enhanced thrombin generation might explain thrombotic tendency observed in these patients.

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