C-type lectin receptor Dectin3 deficiency balances the accumulation and function of FoxO1-mediated LOX-1+ M-MDSCs in relieving lupus-like symptoms

AbstractRecent studies indicate that Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) can function as the signal of pattern recognition receptors, which play a pivotal role in the pathogenesis of the autoimmune disease. Systemic lupus erythematosus (SLE) is a classic autoimmune disease. Previous reports mainly focused on the potential role of TLRs in regulating the development of SLE, but little is known about the role of CLRs in the progression of SLE. Our previous studies showed that the inflammation-mediated accumulation of myeloid-derived suppressor cells (MDSCs) including granulocytic (G-MDSCs) and monocytic (M-MDSCs) participated in the pathogenesis of lupus. Mice deficient in Card9 (the downstream molecule of CLRs) were more susceptible to colitis-associated cancer via promoting the expansion of MDSCs. Whether the abnormal activation of CLRs regulates the expansion of MDSCs to participate in the pathogenesis of lupus remains unknown. In the present study, the expressions of CLRs were examined in both SLE patients and mouse models, revealing the expression of Dectin3 was positively correlated with SLEDAI. Dectin3 deficiency retarded the lupus-like disease by regulating the expansion and function of MDSCs. The mechanistic analysis revealed that Dectin3 deficiency promoted FoxO1-mediated apoptosis of MDSCs. Syk-Akt1-mediated nuclear transfer of FoxO1 increased in Dectin3-deficient MDSCs. Notedly, the accumulation of M-MDSCs mainly decreased in Dectin3−/− lupus mice, and the nuclear transfer of FoxO1 negatively correlated with the expression of LOX-1 on M-MDSCs. The silencing of FoxO1 expression in Dectin3−/− mice promoted the expansion of LOX-1+ M-MDSCs in vivo, and LOX-1+ M-MDSCs increased the differentiation of Th17 cells. Both LOX-1 expression on M-MDSCs and Dectin3 expression on MDSCs increased in patients with SLE. These data indicated that increased LOX-1+ M-MDSCs were related to the exacerbation of SLE development and might be potential target cells for the treatment of SLE.

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Stat5a/b contribute to interleukin 7–induced B-cell precursor expansion, but abl- andbcr/abl-induced transformation are independent of Stat5

Blood ◽

10.1182/blood.v96.6.2277 ◽

2000 ◽

Vol 96 (6) ◽

pp. 2277-2283 ◽

Cited By ~ 154

Author(s):

Veronika Sexl ◽

Roland Piekorz ◽

Richard Moriggl ◽

Juerg Rohrer ◽

Michael P. Brown ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Interleukin 4 ◽

Target Cells ◽

Interleukin 7 ◽

And Function ◽

Deficient Mice

Abstract The cytokines interleukin 7 (IL-7) and interleukin 4 (IL-4) regulate lymphoid differentiation and function and activate the transcription factor Stat5. Using mice deficient for the 2 highly related transcription factors, Stat5a and Stat5b (Stat5a/b−/−), we investigated the role of Stat5 for B-cell differentiation, expansion, and function. Peripheral blood B cells of Stat5-deficient mice are significantly reduced, but no proliferation defects in response to various mitogenic stimuli are found. Also, IgM and IgG1 antibody production and immunoglobulin class switching are not affected. Pre- and pro-B cells of Stat5-deficient animals were found to have reduced responses to IL-7. Pro- and pre-B cells are the target cells of the abloncogene and numerous studies have suggested that Stat5a/b is essential for transformation by derivatives of the Abelson(abl) gene. To assess the role of Stat5a/b in transformation, we have evaluated the ability of variousabl derivatives to transform cells from Stat5a/b-deficient mice in vitro or in vivo. We demonstrate that the absence of Stat5a/b is not essential for the induction of lymphoid or myeloid tumors in vivo or on the ability to transform bone marrow cells in vitro.

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Study on the Role of Vitamin D in Systemic Lupus Erythematosus

Journal of Advances in Medicine Science ◽

10.30564/jams.v4i1.2728 ◽

2021 ◽

Vol 4 (1) ◽

pp. 23

Author(s):

Jiadian Wang ◽

Muzi Cui ◽

Siyi Wang ◽

Xiao Xue ◽

Kerong Ren ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Vitamin D ◽

Lupus Erythematosus ◽

Biological Effects ◽

Research Progress ◽

Target Cells ◽

Systemic Lupus ◽

Vitamin D Receptors

Vitamin D is a hormone precursor with multiple biological effects. It binds to vitamin D receptors on target cells. It is an important participant in the metabolism of calcium and phosphorus in vivo. It is closely related to cell cycle, cell proliferation, differentiation, apoptosis, signal transduction and immune regulation. Its role in the treatment of infection, tumor and even immune diseases has been gradually recognized and studied. Patients with systemic lupus erythematosus generally have decreased levels of active vitamin D, and low levels of vitamin D are associated with disease occurrence, disease activity and complications. In the past ten years, a large number of studies have been carried out on it globally to explore the role of vitamin D in the occurrence and development of systemic lupus erythematosus. This paper summarizes its recent research progress.

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Stat5a/b contribute to interleukin 7–induced B-cell precursor expansion, but abl- andbcr/abl-induced transformation are independent of Stat5

Blood ◽

10.1182/blood.v96.6.2277.h8002277_2277_2283 ◽

2000 ◽

Vol 96 (6) ◽

pp. 2277-2283 ◽

Cited By ~ 10

Author(s):

Veronika Sexl ◽

Roland Piekorz ◽

Richard Moriggl ◽

Juerg Rohrer ◽

Michael P. Brown ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Interleukin 4 ◽

Target Cells ◽

Interleukin 7 ◽

And Function ◽

Deficient Mice

The cytokines interleukin 7 (IL-7) and interleukin 4 (IL-4) regulate lymphoid differentiation and function and activate the transcription factor Stat5. Using mice deficient for the 2 highly related transcription factors, Stat5a and Stat5b (Stat5a/b−/−), we investigated the role of Stat5 for B-cell differentiation, expansion, and function. Peripheral blood B cells of Stat5-deficient mice are significantly reduced, but no proliferation defects in response to various mitogenic stimuli are found. Also, IgM and IgG1 antibody production and immunoglobulin class switching are not affected. Pre- and pro-B cells of Stat5-deficient animals were found to have reduced responses to IL-7. Pro- and pre-B cells are the target cells of the abloncogene and numerous studies have suggested that Stat5a/b is essential for transformation by derivatives of the Abelson(abl) gene. To assess the role of Stat5a/b in transformation, we have evaluated the ability of variousabl derivatives to transform cells from Stat5a/b-deficient mice in vitro or in vivo. We demonstrate that the absence of Stat5a/b is not essential for the induction of lymphoid or myeloid tumors in vivo or on the ability to transform bone marrow cells in vitro.

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Action of taxol on mitosis: modification of microtubule arrangements and function of the mitotic spindle in Haemanthus endosperm.

The Journal of Cell Biology ◽

10.1083/jcb.96.2.527 ◽

1983 ◽

Vol 96 (2) ◽

pp. 527-540 ◽

Cited By ~ 57

Author(s):

J Molè-Bajer ◽

A S Bajer

Keyword(s):

Equatorial Region ◽

Polar Regions ◽

Higher Plant ◽

Chromosome Fragments ◽

Immunocytochemical Method ◽

And Function ◽

Spindle Function ◽

Direction Opposite

We have studied the effect of taxol on mitosis in Haemanthus endosperm. Immuno-Gold Stain (IGS), a new immunocytochemical method (17), was used to visualize microtubules (MTs) in the light microscope. Observations on MT arrangements were correlated with studies in vivo. Chromosome movements are affected in all stages of mitosis which progresses over at least 10(4) range of taxol concentrations. The three most characteristic effects on MTs are: (a) enhancement of the lateral associations between MTs, seen especially during the reorganization of the polar region of the spindle, (b) promotion of MT assembly, leading to the formation of additional MTs in the spindle and MT arrays in the cytoplasm, and (c) an increase in MT stability, demonstrated in their increased cold resistance. In this report, the emphasis is on the primary, immediate effects, occurring in the first 30 min of taxol action. Effects are detected after a few mins, are reversible, and are concentration/time dependent. The spindle and phragmoplast are remarkably modified due to the enhancement of lateral associations of MTs and the formation of abundant nonkinetochore and polar, asterlike MTs. The equatorial region of the interzone in anaphase may be entirely depleted of MTs, and the spindle may break perpendicular to the spindle axis. Mitosis is completed in these conditions, providing evidence for the motile autonomy of each half-spindle. Trailing chromosome arms in anaphase are often stretched and broken. Chromosome fragments are transported away from the polar regions, i.e., in the direction opposite to that expected (5, 6). This supplies the first direct evidence of pushing by elongating MTs in an anastral higher plant spindle. These observations draw attention to the relation between the lateral association of MT ends to assembly/disassembly and to the role of such an interaction in spindle function and organization.

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In Vivo Role of Focal Adhesion Kinase in Regulating Pancreatic -Cell Mass and Function Through Insulin Signaling, Actin Dynamics, and Granule Trafficking

Diabetes ◽

10.2337/db11-1344 ◽

2012 ◽

Vol 61 (7) ◽

pp. 1708-1718 ◽

Cited By ~ 42

Author(s):

E. P. Cai ◽

M. Casimir ◽

S. A. Schroer ◽

C. T. Luk ◽

S. Y. Shi ◽

...

Keyword(s):

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Insulin Signaling ◽

Cell Mass ◽

Actin Dynamics ◽

Pancreatic Cell ◽

And Function

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Netrin-1 in Atherosclerosis: Relationship between Human Macrophage Intracellular Levels and In Vivo Plaque Morphology

Biomedicines ◽

10.3390/biomedicines9020168 ◽

2021 ◽

Vol 9 (2) ◽

pp. 168

Author(s):

Susanna Fiorelli ◽

Nicola Cosentino ◽

Benedetta Porro ◽

Franco Fabbiocchi ◽

Giampaolo Niccoli ◽

...

Keyword(s):

Progressive Increase ◽

Human Macrophage ◽

Plaque Morphology ◽

Artery Disease ◽

Atherosclerotic Process ◽

And Function ◽

And Control ◽

Macrophage Accumulation

Netrin-1 is a laminin-like protein that plays a pivotal role in cell migration and, according to the site of its release, exerts both pro and anti-atherosclerotic functions. Macrophages, key cells in atherosclerosis, are heterogeneous in morphology and function and different subpopulations may support plaque progression, stabilization, and/or regression. Netrin-1 was evaluated in plasma and, together with its receptor UNC5b, in both spindle and round monocyte-derived macrophages (MDMs) morphotypes from coronary artery disease (CAD) patients and control subjects. In CAD patients, plaque features were detected in vivo by optical coherence tomography. CAD patients had lower plasma Netrin-1 levels and a higher MDMs expression of both protein and its receptor compared to controls. Specifically, a progressive increase in Netrin-1 and UNC5b was evidenced going from controls to stable angina (SA) and acute myocardial infarction (AMI) patients. Of note, spindle MDMs of AMI showed a marked increase of both Netrin-1 and its receptor compared to spindle MDMs of controls. UNC5b expression is always higher in spindle compared to round MDMs, regardless of the subgroup. Finally, CAD patients with higher intracellular Netrin-1 levels showed greater intraplaque macrophage accumulation in vivo. Our findings support the role of Netrin-1 and UNC5b in the atherosclerotic process.

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The role of metalloproteinases and their inhibitors in regulating mammary epithelial morphology and function in vivo

Perspectives in Drug Discovery and Design ◽

10.1007/bf02172033 ◽

1995 ◽

Vol 2 (3) ◽

pp. 401-411 ◽

Cited By ~ 8

Author(s):

Carolyn J. Sympson ◽

Rabih S. Talhouk ◽

Mina J. Bissell ◽

Zena Werb

Keyword(s):

Mammary Epithelial ◽

Epithelial Morphology ◽

And Function

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The critical immunosuppressive effect of MDSC-derived exosomes in the tumor microenvironment

10.1101/2020.03.05.979195 ◽

2020 ◽

Cited By ~ 3

Author(s):

Mohammad H. Rashid ◽

Thaiz F. Borin ◽

Roxan Ara ◽

Raziye Piranlioglu ◽

Bhagelu R. Achyut ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Tumor Growth ◽

Cd8 T Cells ◽

Suppressor Cells ◽

Cell Types ◽

Biological Macromolecules

AbstractMyeloid-derived suppressor cells (MDSCs) are an indispensable component of the tumor microenvironment (TME), and our perception regarding the role of MDSCs in tumor promotion is attaining extra layer of intricacy in every study. In conjunction with MDSC’s immunosuppressive and anti-tumor immunity, they candidly facilitate tumor growth, differentiation, and metastasis in several ways that yet to be explored. Alike any other cell types, MDSCs also release a tremendous amount of exosomes or nanovesicles of endosomal origin and partake in intercellular communications by dispatching biological macromolecules. There has not been any experimental study done to characterize the role of MDSCs derived exosomes (MDSC exo) in the modulation of TME. In this study, we isolated MDSC exo and demonstrated that they carry a significant amount of proteins that play an indispensable role in tumor growth, invasion, angiogenesis, and immunomodulation. We observed higher yield and more substantial immunosuppressive potential of exosomes isolated from MDSCs in the primary tumor area than those are in the spleen or bone marrow. Our in vitro data suggest that MDSC exo are capable of hyper activating or exhausting CD8 T-cells and induce reactive oxygen species production that elicits activation-induced cell death. We confirmed the depletion of CD8 T-cells in vivo by treating the mice with MDSC exo. We also observed a reduction in pro-inflammatory M1-macrophages in the spleen of those animals. Our results indicate that immunosuppressive and tumor-promoting functions of MDSC are also implemented by MDSC-derived exosomes which would open up a new avenue of MDSC research and MDSC-targeted therapy.

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New targeted therapies for treatment of thrombosis in antiphospholipid syndrome

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399407000506 ◽

2007 ◽

Vol 9 (30) ◽

pp. 1-15 ◽

Cited By ~ 23

Author(s):

Silvia S. Pierangeli ◽

Mariano E. Vega-Ostertag ◽

Emilio B. González

Keyword(s):

Antiphospholipid Syndrome ◽

Targeted Therapies ◽

Lupus Erythematosus ◽

Pregnancy Loss ◽

Cell Activation ◽

Clinical Manifestations ◽

Target Cells ◽

Endothelial Cell Activation ◽

In Vivo Models

Antiphospholipid (aPL) antibodies (Abs) are associated with thrombosis and pregnancy loss in antiphospholipid syndrome (APS), a disorder initially characterised in patients with systemic lupus erythematosus (SLE) but now known to occur in the absence of other autoimmune disease. There is strong evidence that aPL Abs are pathogenic in vivo, from studies of animal models of thrombosis, endothelial cell activation and pregnancy loss. In recent years, progress has been made in characterising the molecular basis of this pathogenicity, which includes direct effects on platelets, endothelial cells and monocytes as well as activation of complement. This review summarises the clinical manifestations of APS and current modalities of treatment, and explains recent advances in understanding the molecular events triggered by aPL Abs on target cells in coagulation pathways as well as effects of aPL Abs on complement activation. Based on this information and on additional scientific evidence using in vitro and in vivo models, new potential targeted therapies for treatment and/or prevention of thrombosis in APS are proposed and discussed.

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Immunoproteasomes as a novel antiviral mechanism in rhinovirus-infected airways

Clinical Science ◽

10.1042/cs20180337 ◽

2018 ◽

Vol 132 (15) ◽

pp. 1711-1723 ◽

Cited By ~ 3

Author(s):

Kris Genelyn Dimasuay ◽

Amelia Sanchez ◽

Niccolette Schaefer ◽

Jorge Polanco ◽

Deborah A. Ferrington ◽

...

Keyword(s):

Viral Load ◽

Antigen Processing ◽

Lower Airway ◽

Chronic Obstructive ◽

Deficient Mouse ◽

Obstructive Pulmonary Disease ◽

Tracheal Epithelial Cells ◽

And Function

Rhinovirus (RV) infection is involved in acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). RV primarily infects upper and lower airway epithelium. Immunoproteasomes (IP) are proteolytic machineries with multiple functions including the regulation of MHC class I antigen processing during viral infection. However, the role of IP in RV infection has not been explored. We sought to investigate the expression and function of IP during airway RV infection. Primary human tracheobronchial epithelial (HTBE) cells were cultured at air–liquid interface (ALI) and treated with RV16, RV1B, or interferon (IFN)-λ in the absence or presence of an IP inhibitor (ONX-0914). IP gene (i.e. LMP2) deficient mouse tracheal epithelial cells (mTECs) were cultured for the mechanistic studies. LMP2-deficient mouse model was used to define the in vivo role of IP in RV infection. IP subunits LMP2 and LMP7, antiviral genes MX1 and OAS1 and viral load were measured. Both RV16 and RV1B significantly increased the expression of LMP2 and LMP7 mRNA and proteins, and IFN-λ mRNA in HTBE cells. ONX-0914 down-regulated MX1 and OAS1, and increased RV16 load in HTBE cells. LMP2-deficient mTECs showed a significant increase in RV1B load compared with the wild-type (WT) cells. LMP2-deficient (compared with WT) mice increased viral load and neutrophils in bronchoalveolar lavage (BAL) fluid after 24 h of RV1B infection. Mechanistically, IFN-λ induction by RV infection contributed to LMP2 and LMP7 up-regulation in HTBE cells. Our data suggest that IP are induced during airway RV infection, which in turn may serve as an antiviral and anti-inflammatory mechanism.

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