Platelet regulation of myeloid suppressor of cytokine signaling 3 accelerates atherosclerosis

Platelets are best known as mediators of hemostasis and thrombosis; however, their inflammatory effector properties are increasingly recognized. Atherosclerosis, a chronic vascular inflammatory disease, represents the interplay between lipid deposition in the artery wall and unresolved inflammation. Here, we reveal that platelets induce monocyte migration and recruitment into atherosclerotic plaques, resulting in plaque platelet-macrophage aggregates. In Ldlr−/− mice fed a Western diet, platelet depletion decreased plaque size and necrotic area and attenuated macrophage accumulation. Platelets drive atherogenesis by skewing plaque macrophages to an inflammatory phenotype, increasing myeloid suppressor of cytokine signaling 3 (SOCS3) expression and reducing the Socs1:Socs3 ratio. Platelet-induced Socs3 expression regulates plaque macrophage reprogramming by promoting inflammatory cytokine production (Il6, Il1b, and Tnfa) and impairing phagocytic capacity, dysfunctions that contribute to unresolved inflammation and sustained plaque growth. Translating our data to humans with cardiovascular disease, we found that women with, versus without, myocardial infarction have up-regulation of SOCS3, lower SOCS1:SOCS3, and increased monocyte-platelet aggregate. A second cohort of patients with lower extremity atherosclerosis demonstrated that SOCS3 and the SOCS1:SOCS3 ratio correlated with platelet activity and inflammation. Collectively, these data provide a causative link between platelet-mediated myeloid inflammation and dysfunction, SOCS3, and cardiovascular disease. Our findings define an atherogenic role of platelets and highlight how, in the absence of thrombosis, platelets contribute to inflammation.

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The role of CXC-chemokine receptor CXCR2 and suppressor of cytokine signaling-3 (SOCS-3) in renal cell carcinoma

BMC Cancer ◽

10.1186/1471-2407-14-149 ◽

2014 ◽

Vol 14 (1) ◽

Cited By ~ 15

Author(s):

Anastasios Stofas ◽

Georgia Levidou ◽

Christina Piperi ◽

Christos Adamopoulos ◽

Georgia Dalagiorgou ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Chemokine Receptor ◽

Renal Cell ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Cxc Chemokine ◽

Chemokine Receptor Cxcr2

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Role of Suppressor of Cytokine Signaling 2 during the development and resolution of an experimental arthritis

Cellular Immunology ◽

10.1016/j.cellimm.2021.104476 ◽

2022 ◽

pp. 104476

Author(s):

Allysson Cramer ◽

Izabela Galvão ◽

Nathália Venturini de Sá ◽

Paulo Gaio ◽

Natália Fernanda de Melo Oliveira ◽

...

Keyword(s):

Experimental Arthritis ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling

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Abstract 3691: Deletion of Suppressor Of Cytokine Signaling-1 in a Murine Model of Atherosclerosis Results in a Lethal Systemic Inflammation

Circulation ◽

10.1161/circ.118.suppl_18.s_467-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Christina Grothusen ◽

Harald Schuett ◽

Stefan Lumpe ◽

Andre Bleich ◽

Silke Glage ◽

...

Keyword(s):

Foam Cell ◽

Low Density Lipoprotein ◽

Cell Formation ◽

Density Lipoprotein ◽

Foam Cell Formation ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

The Impact

Introduction: Atherosclerosis is a chronic inflammatory disease of the cardiovascular system which may result in myocardial infarction and sudden cardiac death. While the role of pro-inflammatory signaling pathways in atherogenesis has been well characterized, the impact of their negative regulators, e.g. suppressor of cytokine signaling (SOCS)-1 remains to be elucidated. Deficiency of SOCS-1 leads to death 3 weeks post-partum due to an overwhelming inflammation caused by an uncontrolled signalling of interferon-gamma (IFNγ). This phenotype can be rescued by generating recombination activating gene (rag)-2, SOCS-1 double knock out (KO) mice lacking mature lymphocytes, the major source of IFNγ. Since the role of SOCS-1 during atherogenesis is unknown, we investigated the impact of a systemic SOCS-1 deficiency in the low-density lipoprotein receptor (ldlr) KO model of atherosclerosis. Material and Methods: socs-1 −/− /rag-2 −/− deficient mice were crossed with ldlr-KO animals. Mice were kept under sterile conditions on a normal chow diet. For in-vitro analyses, murine socs-1 −/− macrophages were stimulated with native low density lipoprotein (nLDL) or oxidized (ox)LDL. SOCS-1 expression was determined by quantitative PCR and western blot. Foam cell formation was determined by Oil red O staining. Results: socs-1 −/− /rag-2 −/− /ldlr −/− mice were born according to mendelian law. Tripel-KO mice showed a reduced weight and size, were more sensitive to bacterial infections and died within 120 days (N=17). Histological analyses revealed a systemic, necrotic, inflammation in Tripel-KO mice. All other genotypes developed no phenotype. In-vitro observations revealed that SOCS-1 mRNA and protein is upregulated in response to stimulation with oxLDL but not with nLDL. Foam cell formation of socs-1 −/− macrophages was increased compared to controls. Conclusion: SOCS-1 seemingly controls critical steps of atherogenesis by modulating foam cell formation in response to stimulation with oxLDL. SOCS-1 deficiency in the ldlr-KO mouse leads to a lethal inflammation. These observations suggest a critical role for SOCS-1 in the regulation of early inflammatory responses in atherogenesis.

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Sox2 controls neural stem cell self-renewal through a Fos-centered gene regulatory network

10.1101/2020.03.17.995621 ◽

2020 ◽

Author(s):

Miriam Pagin ◽

Simone Giubbolini ◽

Cristiana Barone ◽

Gaia Sambruni ◽

Yanfen Zhu ◽

...

Keyword(s):

Molecular Mechanisms ◽

Cytokine Signaling ◽

Normal Brain ◽

Suppressor Of Cytokine Signaling ◽

Self Renewal ◽

Upstream Regulator ◽

Socs3 Expression ◽

Pharmacological Manipulations

AbstractThe Sox2 transcription factor is necessary for the long-term self-renewal of neural stem cells (NSC). Its mechanism of action is still poorly defined. To identify molecules regulated by Sox2, and acting in mouse NSC maintenance, we transduced, individually or in combination, into Sox2-deleted NSC, genes whose expression is strongly downregulated following Sox2 loss (Fos, Jun, Egr2). Fos alone rescued long-term proliferation, as shown by in vitro cell growth and clonal analysis. Further, Fos requirement for efficient long-term proliferation was demonstrated by the strong reduction of NSC clones capable of long-term expansion following CRISPR/Cas9-mediated Fos inactivation. Previous work showed that the Suppressor of cytokine signaling 3 (Socs3) gene is strongly downregulated following Sox2 deletion, and its reexpression by lentiviral transduction rescues long-term NSC proliferation. Fos appears to be an upstream regulator of Socs3, possibly together with Jun and Egr2; indeed, Sox2 reexpression in Sox2-deleted NSC progressively activates both Fos and Socs3 expression; in turn, Fos transduction activates Socs3 expression. Based on available SOX2 ChIPseq and ChIA-PET data, as well as results from the literature, we propose a model whereby Sox2 is a direct activator of both Socs3 and Fos, as well as possibly Jun and Egr2; in turn, Fos, Jun and Egr2 may activate Socs3. These results provide the basis for developing a model of a network of interactions, regulating critical effectors of NSC proliferation and long-term maintenance.Significance statementProliferation and maintenance of NSC are essential during normal brain development, and, postnatally, for the maintenance of hippocampal function and memory until advanced age. Little is known about the molecular mechanisms that maintain the critical aspects of NSC biology (quiescence and proliferation) in postnatal age. Our work provides a methodology, transduction of genes deregulated following Sox2 deletion, that allows to test many candidate genes for their ability to sustain NSC proliferation. In principle, this may have interesting implications for identifying targets for pharmacological manipulations.

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Effects of Ecklonia cava ethanolic extracts on airway hyperresponsiveness and inflammation in a murine asthma model: Role of suppressor of cytokine signaling

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2007.07.009 ◽

2008 ◽

Vol 62 (5) ◽

pp. 289-296 ◽

Cited By ~ 59

Author(s):

Se-Kwon Kim ◽

Da-Young Lee ◽

Won-Kyo Jung ◽

Ji-Hye Kim ◽

Inhak Choi ◽

...

Keyword(s):

Airway Hyperresponsiveness ◽

Ecklonia Cava ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Asthma Model ◽

Ethanolic Extracts ◽

Murine Asthma Model

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miR-221 and miR-155 regulate human dendritic cell development, apoptosis, and IL-12 production through targeting of p27kip1, KPC1, and SOCS-1

Blood ◽

10.1182/blood-2010-12-322503 ◽

2011 ◽

Vol 117 (16) ◽

pp. 4293-4303 ◽

Cited By ~ 182

Author(s):

Changming Lu ◽

Xin Huang ◽

Xiaoxiao Zhang ◽

Kristin Roensch ◽

Qing Cao ◽

...

Keyword(s):

Cytokine Signaling ◽

Wild Type ◽

Suppressor Of Cytokine Signaling ◽

Hematopoietic Progenitor ◽

Monocyte Differentiation ◽

P27kip1 Protein ◽

And Function ◽

Antigen Presenting ◽

Dc Maturation

Abstract Dendritic cells (DCs) are potent antigen-presenting cells derived from hematopoietic progenitor cells and circulating monocytes. To investigate the role of microRNAs (miRNAs) during DC differentiation, maturation, and function, we profiled miRNA expression in human monocytes, immature DCs (imDCs), and mature DCs (mDCs). Stage-specific, differential expression of 27 miRNAs was found during monocyte differentiation into imDCs and mDCs. Among them, decreased miR-221 and increased miR-155 expression correlated with p27kip1 accumulation in DCs. Silencing of miR-221 or overexpressing of miR-155 in DCs resulted in p27kip1 protein increase and DC apoptosis. Moreover, mDCs from miR-155−/− mice were less apoptotic than those from wild-type mice. Silencing of miR-155 expression had little effect on DC maturation but reduced IL-12p70 production, whereas miR-155 overexpression in mDCs enhanced IL-12p70 production. Kip1 ubiquitination-promoting complex 1, suppressor of cytokine signaling 1, and CD115 (M-CSFR) were functional targets of miR-155. Furthermore, we provide evidence that miR-155 indirectly regulated p27kip1 protein level by targeting Kip1 ubiquitination-promoting complex 1. Thus, our study uncovered miRNA signatures during monocyte differentiation into DCs and the new regulatory role of miR-221 and miR-155 in DC apoptosis and IL-12p70 production.

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