Suppressor of Cytokine Signaling 1 is Involved in Gene Regulation Which Controls the Survival of Ly6Clow Monocytes in Mice

Schuett, Jutta; Kreutz, Julian; Grote, Karsten; Vlacil, Ann-Kathrin; Schuett, Harald; Oberoi, Raghav; Schmid, Andreas; Witten, Anika; Stoll, Monika; Schieffer, Bernhard; Rühle, Frank

doi:10.33594/000000024

Cited by 5 publications

(3 citation statements)

References 47 publications

(52 reference statements)

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“…In experimental models, SOCS1/3 knockdown aggravated graft arteriosclerosis and atherogenesis (Grothusen et al, 2012;Ortiz-Munoz et al, 2009;L. Qin et al, 2014;Schuett et al, 2019), while SOCS1 forced expression protected against vascular inflammation (Lopez-Sanz et al, 2018;L. Qin et al, 2014;Recio et al, 2015).…”

Section: Discussionmentioning

confidence: 98%

Protective effect of suppressor of cytokine signalling 1‐based therapy in experimental abdominal aortic aneurysm

Bernal

López-Sanz

Prieto

et al. 2020

British J Pharmacology

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Background and Purpose: Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by chronic inflammation, oxidative stress and proteolytic activity in the aortic wall. Targeting JAK/signal transducer and activator of transcription (JAK/STAT) pathway is a promising strategy for chronic inflammatory diseases. We investigated the vasculo-protective role of suppressor of cytokine signalling-1 (SOCS1), the negative JAK/STAT regulator, in experimental AAA. Experimental Approach: A synthetic, cell permeable peptide (S1) mimic of SOCS1 kinase inhibitory domain to suppress STAT activation was evaluated in the wellestablished mouse model of elastase-induced AAA by monitoring changes in aortic diameter, cellular composition and gene expression in abdominal aorta. S1 function was further evaluated in cultured vascular smooth muscle cells (VSMC) and macrophages exposed to elastase or elastin-derived peptides. Key Results: S1 peptide prevented AAA development, evidenced by reduced incidence of AAA, aortic dilation and elastin degradation, partial restoration of medial VSMC and decreased inflammatory cells and oxidative stress in AAA tissue. Mechanistically, S1 suppressed STAT1/3 activation in aorta, down-regulated cytokines, metalloproteinases and altered the expression of cell differentiation markers by favouring anti-inflammatory M2 macrophage and contractile VSMC phenotypes. In vitro, S1 suppressed the expression of inflammatory and oxidative genes, reduced cell migration and reversed the phenotypic switch of macrophages and VSMC. By contrast, SOCS1 silencing promoted inflammatory response. Conclusion and Implications:This preclinical study demonstrates the therapeutic potential of SOCS1-derived peptide to halt AAA progression by suppressing JAK/STAT-mediated inflammation and aortic dilation. S1 peptide may therefore be a valuable option for the treatment of AAA.

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Section: Discussionmentioning

confidence: 98%

Protective effect of suppressor of cytokine signalling 1‐based therapy in experimental abdominal aortic aneurysm

Bernal

López-Sanz

Prieto

et al. 2020

British J Pharmacology

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“…Its deficiency leads to inflammation ( Ihle et al, 1995 ; Ilangumaran et al, 2004 ), whereas its haploinsufficiency induces autoimmune diseases ( Hadjadj et al, 2020 ). The ROS-dependent apoptosis of immune cells induces SOCS1 expression, and conversely, SOCS1 overexpression represses apoptosis caused by oxidants ( Jung et al, 2016 ; Schuett et al, 2019 ). In atherosclerotic models, the inhibition of JAK2, STAT1, and STAT3 prevented lesion formation ( Torella et al, 2007 ; Miklossy et al, 2013 ), and many efforts based on the therapeutic role of SOCS1,3 effectively deregulate pathological JAK-STAT hyperactivation in cardiovascular disease studies ( Recio et al, 2015 ; Lopez-Sanz et al, 2018 ).…”

Section: Molecular Basis Of Jak-stat Regulation: Natural Inhibitionmentioning

confidence: 99%

Proteomimetics of Natural Regulators of JAK–STAT Pathway: Novel Therapeutic Perspectives

Manna

Benedictis

Marasco

2022

Front. Mol. Biosci.

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The JAK-STAT pathway is a crucial cellular signaling cascade, including an intricate network of Protein–protein interactions (PPIs) responsible for its regulation. It mediates the activities of several cytokines, interferons, and growth factors and transduces extracellular signals into transcriptional programs to regulate cell growth and differentiation. It is essential for the development and function of both innate and adaptive immunities, and its aberrant deregulation was highlighted in neuroinflammatory diseases and in crucial mechanisms for tumor cell recognition and tumor-induced immune escape. For its involvement in a multitude of biological processes, it can be considered a valuable target for the development of drugs even if a specific focus on possible side effects associated with its inhibition is required. Herein, we review the possibilities to target JAK–STAT by focusing on its natural inhibitors as the suppressor of cytokine signaling (SOCS) proteins. This protein family is a crucial checkpoint inhibitor in immune homeostasis and a valuable target in immunotherapeutic approaches to cancer and immune deficiency disorders.

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“…On the other hand, SOCS1 protein shows both pro-apoptotic and anti-apoptotic functions. Indeed, during the ROS-mediated apoptosis of immune cells, SOCS1 expression is induced by ROS, but conversely, SOCS1 overexpression leads to the inhibition of oxidant-induced apoptosis [21,22]. In experimental models, both gene deficiency and pharmacological inhibition of JAK2, STAT1 and STAT3 avoided atherosclerotic lesion formation [23,24].…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Effects of PS5, a Peptidomimetic of Suppressor of Cytokine Signaling 1, in Experimental Atherosclerosis

et al. 2020

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The chronic activation of the Janus kinase/signal transducer and activator of the transcription (JAK/STAT) pathway is linked to oxidative stress, inflammation and cell proliferation. Suppressors of cytokine signaling (SOCS) proteins negatively regulate the JAK/STAT, and SOCS1 possesses a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Several studies showed that KIR-SOCS1 mimetics can be considered valuable therapeutics in several disorders (e.g., diabetes, neurological disorders and atherosclerosis). Herein, we investigated the antioxidant and atheroprotective effects of PS5, a peptidomimetic of KIR-SOCS1, both in vitro (vascular smooth muscle cells and macrophages) and in vivo (atherosclerosis mouse model) by analyzing gene expression, intracellular O2•− production and atheroma plaque progression and composition. PS5 was revealed to be able to attenuate NADPH oxidase (NOX1 and NOX4) and pro-inflammatory gene expression, to upregulate antioxidant genes and to reduce atheroma plaque size, lipid content and monocyte/macrophage accumulation. These findings confirm that KIR-SOCS1-based drugs could be excellent antioxidant agents to contrast atherosclerosis.

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Suppressor of Cytokine Signaling 1 is Involved in Gene Regulation Which Controls the Survival of Ly6Clow Monocytes in Mice

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 5 publications

References 47 publications

Protective effect of suppressor of cytokine signalling 1‐based therapy in experimental abdominal aortic aneurysm

Protective effect of suppressor of cytokine signalling 1‐based therapy in experimental abdominal aortic aneurysm

Proteomimetics of Natural Regulators of JAK–STAT Pathway: Novel Therapeutic Perspectives

Antioxidant Effects of PS5, a Peptidomimetic of Suppressor of Cytokine Signaling 1, in Experimental Atherosclerosis

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