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Inflammation versus Resolution: New Insights and Therapeutic Challenges in Atherosclerosis
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Inflammation versus Resolution: New Insights and Therapeutic Challenges in Atherosclerosis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 4452

Special Issue Editors

Prof. Dr. Elena Monica Borroni

E-Mail Website
Guest Editor
1. Department of Medical Biotechnologies and Translational Medicine, University of Milan, 20133 Milan, Italy
2. Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
Interests: immunology; immundeficiencies; tumors; chemokine receptors; signaling
Special Issues, Collections and Topics in MDPI journals
Dr. Benedetta Savino

E-Mail Website
Guest Editor
1. Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
2. Humanitas Clinical and Research Center – IRCCS, Rozzano, Italy
Interests: immunology; tumors; macrophages
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Atherosclerosis is a leading cause of morbidity and mortality in the Western world. It is a lipid-driven inflammatory disease of the arterial intima in which the balance between pro-inflammatory and inflammation-resolving mechanisms dictates the final clinical outcome. In its pathogenesis, endothelial cell damage causes the accumulation of oxidized low-density lipoproteins and exposes proteoglycans, thus inducing the synthesis of chemotactic and adhesion molecules that promote the recruitment of inflammatory cells in the intima. Activated leukocytes stimulate a cascade of reactions that is normally counterbalanced by body defense mechanisms, resolving or stabilizing the lesion with the help of endogenous mediators—so-called SPMs (specialized pro-resolving mediators). Nevertheless, if the inflammatory response is not well tackled, an imbalance in the ratio between SPM and pro-inflammatory lipids leads to plaque progression and vulnerability to rupture and thrombosis.

This Special Issue is aimed to collect original research and review articles on genetic, molecular, and cellular mechanisms that are recognized as key players in inflammation and resolution, and which might represent valid targets of new therapeutic challenges for the treatment of atherosclerosis.

Prof. Dr. Elena Monica Borroni
Dr. Benedetta Savino
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (2 papers)

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Research

15 pages, 2902 KiB  
Article
Trichostatin D as a Novel KLF2 Activator Attenuates TNFα-Induced Endothelial Inflammation
by Lijuan Lei, Minghua Chen, Chenyin Wang, Xinhai Jiang, Yinghong Li, Weizhi Wang, Shunwang Li, Liping Zhao, Ren Sheng, Jiangxue Han, Yuyan Zhang, Yuchuan Chen, Biying Yan, Yexiang Wu, Liyan Yu, Shuyi Si and Yanni Xu
Int. J. Mol. Sci. 2022, 23(21), 13477; https://doi.org/10.3390/ijms232113477 - 03 Nov 2022
Cited by 1 | Viewed by 1740
Abstract
Krüppel-like factor 2 (KLF2) is an atherosclerotic protective transcription factor that maintains endothelial cell homeostasis through its anti-inflammatory, anti-oxidant, and antithrombotic properties. The aim of this study was to discover KLF2 activators from microbial secondary metabolites and explore their potential molecular mechanisms. By [...] Read more.
Krüppel-like factor 2 (KLF2) is an atherosclerotic protective transcription factor that maintains endothelial cell homeostasis through its anti-inflammatory, anti-oxidant, and antithrombotic properties. The aim of this study was to discover KLF2 activators from microbial secondary metabolites and explore their potential molecular mechanisms. By using a high-throughput screening model based on a KLF2 promoter luciferase reporter assay, column chromatography, electrospray ionization mass spectrometry (ESI-MS), and nuclear magnetic resonance (NMR) spectra, trichostatin D (TSD) was isolated from the rice fermentation of Streptomyces sp. CPCC203909 and identified as a novel KLF2 activator. Real-time-quantitative polymerase chain reaction (RT-qPCR) results showed that TSD upregulated the mRNA level of KLF2 in endothelial cells. Functional assays showed that TSD attenuated monocyte adhesion to endothelial cells, decreased vascular cell adhesion protein 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression, and exhibited an anti-inflammatory effect in tumor necrosis factor alpha (TNFα)-induced endothelial cells. We further demonstrated through siRNA and western blot assays that the effects of TSD on monocyte adhesion and inflammation in endothelial cells were partly dependent on upregulating KLF2 expression and then inhibiting the NOD-like receptor protein 3 (NLRP3)/Caspase-1/interleukin-1beta (IL-1β) signaling pathway. Furthermore, histone deacetylase (HDAC) overexpression and molecular docking analysis results showed that TSD upregulated KLF2 expression by inhibiting HDAC 4, 5, and 7 activities. Taken together, TSD was isolated from the fermentation of Streptomyces sp. CPCC203909 and first reported as a potential activator of KLF2 in this study. Furthermore, TSD upregulated KLF2 expression by inhibiting HDAC 4, 5, and 7 and attenuated endothelial inflammation via regulation of the KLF2/NLRP3/Caspase-1/IL-1β signaling pathway. Full article
(This article belongs to the Special Issue Inflammation versus Resolution: New Insights and Therapeutic Challenges in Atherosclerosis)
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18 pages, 2644 KiB  
Article
Neuropeptide Y Promotes Human M2 Macrophage Polarization and Enhances p62/SQSTM1-Dependent Autophagy and NRF2 Activation
by Elisabetta Profumo, Elisa Maggi, Marzia Arese, Claudio Di Cristofano, Bruno Salvati, Luciano Saso, Rita Businaro and Brigitta Buttari
Int. J. Mol. Sci. 2022, 23(21), 13009; https://doi.org/10.3390/ijms232113009 - 27 Oct 2022
Cited by 8 | Viewed by 2090
Abstract
Neuropeptide Y (NPY) is an abundantly expressed peptide capable of modulating innate and adaptive immune responses and regulating chemotaxis and cytokine secretion by macrophages. Abnormal regulation of NPY is involved in the development of atherosclerosis. The inflammatory infiltrate within atherosclerotic plaque is characterized [...] Read more.
Neuropeptide Y (NPY) is an abundantly expressed peptide capable of modulating innate and adaptive immune responses and regulating chemotaxis and cytokine secretion by macrophages. Abnormal regulation of NPY is involved in the development of atherosclerosis. The inflammatory infiltrate within atherosclerotic plaque is characterized by accumulation of macrophages, which are subject to reprogram their phenotypes in response to environmental signals. Macrophage number and phenotype influence plaque fate. Here, we investigated the effect of NPY on the changes in phenotype and functions of human macrophages, from the pro-inflammatory phenotype M1 to the reparative M2, indicative of atherosclerosis regression or stabilization. Human monocytes were differentiated in vitro into macrophages with M-CSF (M0) and polarized towards an M1 phenotype with IFN-γ plus LPS M(IFN-γ/LPS) or M2 with IL-10 (M IL-10) and further challenged with NPY (10−7–10−9 M) for 8–36 h. Cell phenotype and functions were analyzed by immunofluorescence and immunochemical analyses. NPY affected macrophage surface markers and secretome profile expression, thus shifting macrophages toward an M2-like phenotype. NPY also prevented the impairment of endocytosis triggered by the oxysterol 7-keto-cholesterol (7KC) and prevented 7KC-induced foam cell formation by reducing the lipid droplet accumulation in M0 macrophages. NPY-treated M0 macrophages enhanced the autophagosome formation by upregulating the cell content of the autophagy markers LC3-II and p62-SQSTM1, increased activation of the anti-oxidative transcription factor NRF2 (NF-E2-related factor 2), and subsequently induced its target gene HMOX1 that encodes heme oxygenase-1. Our findings indicate that NPY has a cytoprotective effect with respect to the progression of the inflammatory pathway, both enhancing p62/SQSTM1-dependent autophagy and the NRF2–antioxidant signaling pathway in macrophages. NPY signaling may have a crucial role in tissue homeostasis in host inflammatory responses through the regulation of macrophage balance and functions within atherosclerosis. Full article
(This article belongs to the Special Issue Inflammation versus Resolution: New Insights and Therapeutic Challenges in Atherosclerosis)
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