scholarly journals Targeting epigenetic modifiers to reprogram macrophages in nonresolving inflammation-driven atherosclerosis

2021 ◽  
Author(s):  
Fengyan Jin ◽  
Jian Li ◽  
Jianfeng Guo ◽  
Thorsten R Doeppner ◽  
Dirk M Hermann ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Chronic Inflammatory Disease ◽  
Transcriptional Reprogramming ◽  
Epigenetic Modifiers ◽  
Promising Target ◽  
Epigenetic Machinery ◽  
Epigenetic Remodeling ◽  
Anti Inflammatory ◽  
Inflammatory Phenotypes

Abstract Epigenomic and epigenetic research has been providing a number of new insights into a variety of diseases caused by nonresolving inflammation, including cardiovascular diseases. Atherosclerosis (AS) has long been recognized as a chronic inflammatory disease of the arterials walls, characterized by local persistent and stepwise accelerating inflammation without resolution, also known as uncontrolled inflammation. The pathogenesis of AS is driven primarily by highly-plastic macrophages via their polarization to pro- or anti-inflammatory phenotypes as well as other novel subtypes recently identified by single-cell sequencing. Although emgerging evidence has indicated the key role of the epigenetic machinery in the regulation of macrophage plasticity, the investigation of epigenetic alterations and modifiers in AS and related inflammation is still in its infancy. An increasing number of the epigenetic modifiers (e.g., TET2, DNMT3A, HDAC3, HDAC9, JMJD3, KDM4A) have been identified in epigenetic remodeling of macrophages through DNA methylation or histone modifications (e.g., methylation, acetylation, and recently lactylation) in inflammation. These or many unexplored modifiers function to determine or switch the direction of macrophage polarization via transcriptional reprogramming of gene expression and intracellular metabolic rewiring upon microenvironmental cues, thereby representing a promising target for anti-inflammatory therapy in AS. Here, we review up-to-date findings involving the epigenetic regulation of macrophages to shed light on the mechanism of uncontrolled inflammation during AS onset and progression. We also discuss current challenges for developing an effective and safe anti-AS therapy that targets the epigenetic modifiers, and propose a potential anti-inflammatory strategy that repolarizes macrophages from pro- to anti-inflammatory phenotypes.

scholarly journals The Regulatory Role of α-Ketoglutarate Metabolism in Macrophages

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Shaojuan Liu ◽  
Jie Yang ◽  
Zhenfang Wu
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Macrophage Polarization ◽  
Animal Health ◽  
Tca Cycle ◽  
The Tca Cycle ◽  
Promising Target ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory

Macrophages are multifunctional immune cells whose functions depend on polarizable phenotypes and the microenvironment. Macrophages have two phenotypes, including the M1 proinflammatory phenotype and the M2 anti-inflammatory phenotype, which play important roles in many inflammatory responses and diseases. α-Ketoglutarate is a key metabolite of the TCA cycle and can regulate the phenotype of macrophage polarization to exert anti-inflammatory effects in many inflammation-related diseases. In this review, we primarily elucidate the metabolism, regulatory mechanism, and perspectives of α-ketoglutarate on macrophages. The regulation of macrophage polarization by α-ketoglutarate may provide a promising target for the prevention and therapy of inflammatory diseases and is beneficial to animal health.

Abstract 553: Siglec-1 (CD169) on Monocytes/Macrophages: A New Receptor For Extracellular Self-RNA in Triggering Inflammatory Responses via the Sheddase TACE/ADAM17

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Hector A Cabrera-Fuentes ◽  
Klaus T Preissner ◽  
William A Boisvert
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Transmembrane Protein ◽  
Macrophage Polarization ◽  
Extracellular Rna ◽  
Tnf Α ◽  
M1 Phenotype ◽  
Phenotype Markers ◽  
Anti Inflammatory

As an important component of atherosclerosis, monocytes/macrophages respond to external stimuli with rapid changes in their expression of many inflammation-related genes to undergo polarization towards the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotype. Although sialoadhesin (Sn), also known as SIGLEC-1 or CD169, is a transmembrane protein receptor expressed on monocytes and macrophages whether it has a role in macrophage polarization and ultimately, macrophage-driven atherogenesis, has not been investigated. We have previously shown that, independently of Toll-like receptor signaling, extracellular RNA (eRNA) could exert pro-thrombotic and pro-inflammatory properties in the cardiovascular system by inducing cytokine mobilization. In the current study, recombinant mouse macrophage CSF[[Unable to Display Character: –]]driven bone marrow-derived macrophage (BMDM) differentiation was found to be skewed towards the M1 phenotype by exposure of cells to eRNA. This resulted in up-regulation of inflammatory markers, whereas anti-inflammatory genes were significantly down-regulated by eRNA. Interestingly, eRNA was released from BMDM under hypoxia and induced TNF-α liberation by activating TNF-α converting enzyme (TACE) to provoke inflammation. Conversely, TNF-α promoted eRNA release, especially under hypoxia, feeding a vicious cycle of cell damage. Administration of RNase1 or TAPI (a TACE-inhibitor) prevented the production of inflammatory mediators. Murine BMDM isolated from mice deficient in sialoadhesin had the opposite reaction to eRNA treatment with a prominent down-regulation of pro-inflammatory cytokines/M1 phenotype markers, while anti-inflammatory cytokines/M2 phenotype markers were significantly raised. In keeping with the proposed role of eRNA as a pro-inflammatory “alarm signal”, these data further shed light on the role of eRNA in macrophage function in the context of chronic inflammatory diseases such as atherosclerosis. The identification of sialoadhesin as putative eRNA recognition site on macrophages may allow further investigation of the underlying mechanisms of eRNA-macrophage interaction and related signal transduction pathways. Siglec-1 thereby may provides a new target to treat eRNA-mediated vascular diseases.

scholarly journals Protective Role of C3aR (C3a Anaphylatoxin Receptor) Against Atherosclerosis in Atherosclerosis-Prone Mice

2020 ◽  
Vol 40 (9) ◽  
pp. 2070-2083
Author(s):  
Lin-Lin Wei ◽  
Ning Ma ◽  
Kun-Yi Wu ◽  
Jia-Xing Wang ◽  
Teng-Yue Diao ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Protective Role ◽  
Plaque Burden ◽  
Aortic Tissue ◽  
M2 Macrophage ◽  
Proinflammatory Mediators ◽  
Anti Inflammatory

Objective: Emerging evidence suggests that C3aR (C3a anaphylatoxin receptor) signaling has protective roles in various inflammatory-related diseases. However, its role in atherosclerosis has been unknown. The purpose of the study was to investigate the possible protective role of C3aR in aortic atherosclerosis and explore molecular and cellular mechanisms involved in the protection. Approach and Results: C3ar −/− /Apoe −/− mice were generated by cross-breeding of atherosclerosis-prone Apoe −/− mice and C3ar −/− mice. C3ar −/− /Apoe −/− mice and Apoe −/− mice (as a control) underwent high-fat diet for 16 weeks were assessed for (1) atherosclerotic plaque burden, (2) aortic tissue inflammation, (3) recruitment of CD11b + leukocytes into atherosclerotic lesions, and (4) systemic inflammatory responses. Compared with Apoe −/− mice, C3ar −/− /Apoe −/− mice developed more severe atherosclerosis. In addition, C3ar −/− /Apoe −/− mice have increased local production of proinflammatory mediators (eg, CCL2 [chemokine (C-C motif) ligand 2], TNF [tumor necrosis factor]-α) and infiltration of monocyte/macrophage in aortic tissue, and their lesional macrophages displayed an M1-like phenotype. Local pathological changes were associated with enhanced systemic inflammatory responses (ie, elevated plasma levels of CCL2 and TNF-α, increased circulating inflammatory cells). In vitro analyses using peritoneal macrophages showed that C3a stimulation resulted in upregulation of M2-associated signaling and molecules, but suppression of M1-associated signaling and molecules, supporting the roles of C3a/C3aR axis in mediating anti-inflammatory response and promoting M2 macrophage polarization. Conclusions: Our findings demonstrate a protective role for C3aR in the development of atherosclerosis and suggest that C3aR confers the protection through C3a/C3aR axis–mediated negative regulation of proinflammatory responses and modulation of macrophage toward the anti-inflammatory phenotype.

scholarly journals microRNA-155 Is Decreased During Atherosclerosis Regression and Is Increased in Urinary Extracellular Vesicles During Atherosclerosis Progression

2020 ◽  
Vol 11 ◽  
Author(s):  
Stephen Fitzsimons ◽  
Silvia Oggero ◽  
Robyn Bruen ◽  
Cathal McCarthy ◽  
Moritz J. Strowitzki ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Ex Vivo ◽  
Macrophage Polarization ◽  
Chronic Inflammatory Disease ◽  
Cholesterol Diet ◽  
Human Coronary Artery ◽  
Inflammatory Signaling ◽  
Anti Inflammatory

BackgroundAtherosclerosis is a chronic inflammatory disease driven by macrophage accumulation in medium and large sized arteries. Macrophage polarization and inflammation are governed by microRNAs (miR) that regulate the expression of inflammatory proteins and cholesterol trafficking. Previous transcriptomic analysis led us to hypothesize that miR-155-5p (miR-155) is regulated by conjugated linoleic acid (CLA), a pro-resolving mediator which induces regression of atherosclerosis in vivo. In parallel, as extracellular vesicles (EVs) and their miR content have potential as biomarkers, we investigated alterations in urinary-derived EVs (uEVs) during the progression of human coronary artery disease (CAD).MethodsmiR-155 expression was quantified in aortae from ApoE−/− mice fed a 1% cholesterol diet supplemented with CLA blend (80:20, cis-9,trans-11:trans-10,cis-12 respectively) which had been previously been shown to induce atherosclerosis regression. In parallel, human polarized THP-1 macrophages were used to investigate the effects of CLA blend on miR-155 expression. A miR-155 mimic was used to investigate its inflammatory effects on macrophages and on ex vivo human carotid endarterectomy (CEA) plaque specimens (n = 5). Surface marker expression and miR content were analyzed in urinary extracellular vesicles (uEVs) obtained from patients diagnosed with unstable (n = 12) and stable (n = 12) CAD.ResultsHere, we report that the 1% cholesterol diet increased miR-155 expression while CLA blend supplementation decreased miR-155 expression in the aorta during atherosclerosis regression in vivo. CLA blend also decreased miR-155 expression in vitro in human THP-1 polarized macrophages. Furthermore, in THP-1 macrophages, miR-155 mimic decreased the anti-inflammatory signaling proteins, BCL-6 and phosphorylated-STAT-3. In addition, miR-155 mimic downregulated BCL-6 in CEA plaque specimens. uEVs from patients with unstable CAD had increased expression of miR-155 in comparison to patients with stable CAD. While the overall concentration of uEVs was decreased in patients with unstable CAD, levels of CD45+ uEVs were increased. Additionally, patients with unstable CAD had increased CD11b+ uEVs and decreased CD16+ uEVs.ConclusionmiR-155 suppresses anti-inflammatory signaling in macrophages, is decreased during regression of atherosclerosis in vivo and is increased in uEVs from patients with unstable CAD suggesting miR-155 has potential as a prognostic indicator and a therapeutic target.

scholarly journals Genetic Blockade of NAAA Cell-specifically Regulates Fatty Acid Ethanolamides (FAEs) Metabolism and Inflammatory Responses

2022 ◽  
Vol 12 ◽  
Author(s):  
Xiaohua Xie ◽  
Yitian Li ◽  
Sennan Xu ◽  
Pan Zhou ◽  
Longhe Yang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Inflammatory Responses ◽  
Analgesic Effects ◽  
Fatty Acid Ethanolamides ◽  
A Cell ◽  
Anti Inflammatory ◽  
Inflammatory Phenotypes ◽  
Hydrolysis Of ◽  
Anti Inflammation

N-Acylethanolamine acid amidase (NAAA) is a lysosomal enzyme responsible for the hydrolysis of fatty acid ethanolamides (FAEs). However, the role of NAAA in FAEs metabolism and regulation of pain and inflammation remains mostly unknown. Here, we generated NAAA-deficient (NAAA-/-) mice using CRISPR-Cas9 technique, and found that deletion of NAAA increased PEA and AEA levels in bone marrow (BM) and macrophages, and elevated AEA levels in lungs. Unexpectedly, genetic blockade of NAAA caused moderately effective anti-inflammatory effects in lipopolysaccharides (LPS)-induced acute lung injury (ALI), and poor analgesic effects in carrageenan-induced hyperalgesia and sciatic nerve injury (SNI)-induced mechanical allodynia. These data contrasted with acute (single dose) or chronic NAAA inhibition by F96, which produced marked anti-inflammation and analgesia in these models. BM chimera experiments indicated that these phenotypes were associated with the absence of NAAA in non-BM cells, whereas deletion of NAAA in BM or BM-derived cells in rodent models resulted in potent analgesic and anti-inflammatory phenotypes. When combined, current study suggested that genetic blockade of NAAA regulated FAEs metabolism and inflammatory responses in a cell-specifical manner.

scholarly journals Polarized Macrophages in Periodontitis: Characteristics, Function, and Molecular Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoyu Sun ◽  
Jike Gao ◽  
Xiang Meng ◽  
Xiaoxuan Lu ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Research Progress ◽  
Periodontal Tissue ◽  
M2 Macrophages ◽  
Molecular Signaling ◽  
Local Inflammatory Response ◽  
Anti Inflammatory ◽  
M1 Type ◽  
M1 And M2 Macrophages

Periodontitis (PD) is a common chronic infectious disease. The local inflammatory response in the host may cause the destruction of supporting periodontal tissue. Macrophages play a variety of roles in PD, including regulatory and phagocytosis. Moreover, under the induction of different factors, macrophages polarize and form different functional phenotypes. Among them, M1-type macrophages with proinflammatory functions and M2-type macrophages with anti-inflammatory functions are the most representative, and both of them can regulate the tendency of the immune system to exert proinflammatory or anti-inflammatory functions. M1 and M2 macrophages are involved in the destructive and reparative stages of PD. Due to the complex microenvironment of PD, the dynamic development of PD, and various local mediators, increasing attention has been given to the study of macrophage polarization in PD. This review summarizes the role of macrophage polarization in the development of PD and its research progress.

scholarly journals IGF2R-initiated proton rechanneling dictates an anti-inflammatory property in macrophages

2020 ◽  
Vol 6 (48) ◽  
pp. eabb7389
Author(s):  
Xuefeng Wang ◽  
Liangyu Lin ◽  
Bin Lan ◽  
Yu Wang ◽  
Liming Du ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Growth Factor ◽  
Low Dose ◽  
High Dose ◽  
Intermembrane Space ◽  
Mitochondrial Intermembrane Space ◽  
Anti Inflammatory ◽  
Inflammatory Macrophages ◽  
Inflammatory Phenotypes

Metabolic traits of macrophages can be rewired by insulin-like growth factor 2 (IGF2); however, how IGF2 modulates macrophage cellular dynamics and functionality remains unclear. We demonstrate that IGF2 exhibits dual and opposing roles in controlling inflammatory phenotypes in macrophages by regulating glucose metabolism, relying on the dominant activation of the IGF2 receptor (IGF2R) by low-dose IGF2 (L-IGF2) and IGF1R by high-dose IGF2. IGF2R activation leads to proton rechanneling to the mitochondrial intermembrane space and enables sustained oxidative phosphorylation. Mechanistically, L-IGF2 induces nucleus translocation of IGF2R that promotes Dnmt3a-mediated DNA methylation by activating GSK3α/β and subsequently impairs expression of vacuolar-type H+-ATPase (v-ATPase). This sequestrated assembly of v-ATPase inhibits the channeling of protons to lysosomes and leads to their rechanneling to mitochondria. An IGF2R-specific IGF2 mutant induces only the anti-inflammatory response and inhibits colitis progression. Together, our findings highlight a previously unidentified role of IGF2R activation in dictating anti-inflammatory macrophages.

scholarly journals Divergent Effect of Cigarette Smoke on Innate Immunity in Inflammatory Bowel Disease: A Nicotine-Infection Interaction

2020 ◽  
Vol 21 (16) ◽  
pp. 5801 ◽  
Author(s):  
Dania AlQasrawi ◽  
Ahmad Qasem ◽  
Saleh A. Naser
Keyword(s):  
Inflammatory Bowel Disease ◽  
Cigarette Smoke ◽  
Bowel Disease ◽  
Mycobacterium Avium Subspecies Paratuberculosis ◽  
Microbial Infection ◽  
Inflammatory Bowel ◽  
Anti Inflammatory ◽  
Inflammatory Phenotypes

Cigarette smoke (CS) has adverse effects in patients with Crohn’s disease (CD), an inflammatory bowel disease (IBD) that has been associated with microbial infection, immuno-dysregulation, and mucosal dysfunction. However, CS seems to provide relief and protection to patients with another IBD known as ulcerative colitis (UC). These two subsets are featured as M1- and M2-mediated responses, respectively. Nicotine is the most active, addictive, and studied ingredient in CS. The mechanism of how nicotine and/or other CS ingredients induce pro-inflammatory or anti-inflammatory phenotypes in IBD patients remains under investigation. Our most recent in vitro nicotine study provided significant insights toward understanding the contradictory effects of nicotine on IBD patients, and it elucidated the mechanistic role of α7nAChR in modulation of macrophages in tobacco smokers. Shifting the beneficial effect of nicotine to a harmful outcome in CD patients was linked to a nicotine-microbe interaction that supports a microbial etiology in CD pathogenesis. Among the most debated pathogens in CD etiology is Mycobacterium avium subspecies paratuberculosis (MAP). Other studies associated nicotine with upregulation of miR-124 expression in macrophages, which led to anti-inflammatory response. This review discusses published work on the role of nicotine in modulation of the innate immune response and subsequent signaling in macrophages in IBD subsets.

scholarly journals Macrophage polarization in chronic kidney disease: a balancing act between renal recovery and decline?

2019 ◽  
Vol 317 (6) ◽  
pp. F1409-F1413 ◽  
Author(s):  
Jason E. Engel ◽  
Alejandro R. Chade
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Injury ◽  
Dynamic Balance ◽  
Macrophage Polarization ◽  
M1 Phenotype ◽  
Anti Inflammatory ◽  
And Function ◽  
Injury Potential

Macrophages are heterogenous cells of the innate immune system that can fluidly modulate their phenotype to respond to their local microenvironment. They are found throughout the renal compartments, where they contribute to homeostasis and function. However, renal injury activates molecular pathways that initially stimulate differentiation of macrophages into a proinflammatory M1 phenotype. Later in the course of healing, abundant apoptotic debris and anti-inflammatory cytokines induce the production of anti-inflammatory M2 macrophages, which contribute to tissue regeneration and repair. Thus, the dynamic balance of M1 and M2 populations may outline the burden of inflammation and process of tissue repair that define renal outcomes, which has been the impetus for therapeutic efforts targeting macrophages. This review will discuss the role of these phenotypes in the progression of chronic renal injury, potential pathogenic mechanisms, and the promise of macrophage-based therapeutic applications for chronic kidney disease.

scholarly journals A Novel Putative Role of TNK1 in Atherosclerotic Inflammation Implicating the Tyk2/STAT1 Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Mei-Hua Bao ◽  
Qiao-Li Lv ◽  
Hai-Gang Li ◽  
Yi-Wen Zhang ◽  
Bao-Feng Xu ◽  
...  
Keyword(s):  
Western Blot ◽  
Low Density Lipoprotein ◽  
Clinical Manifestations ◽  
Density Lipoprotein ◽  
Cholesterol Content ◽  
Chronic Inflammatory Disease ◽  
Inflammatory Factors ◽  
Anti Inflammatory ◽  
Oil Red O

Objective. Atherosclerosis is a chronic inflammatory disease which is responsible for many clinical manifestations. The present study was to investigate the anti-inflammatory functions and mechanisms of TNK1 in atherosclerosis. Methods. The ApoE(-/-) mice and human carotid endarterectomy (CEA) atherosclerotic plaques were used to investigate the differential expression of TNK1. The ApoE(-/-) mice were fed with high-fat diet (HFD) or normal-fat diet (NFD) for 8 weeks; the aorta was separated and stained with oil red O to evaluate the formation of atherosclerosis. TNK1 in mice aorta was measured by qPCR. The human CEA were obtained and identified as ruptured and stable plaques. The level of TNK1 was measured by qPCR and Western-blot staining. Further studies were conducted in THP-1 cells to explore the anti-inflammatory effects of TNK1. We induced the formation of macrophages by incubating THP-1 cells with PMA (phorbol 12-myristate 13-acetate). Afterwards, oxidized low-density lipoprotein (oxLDL) was used to stimulate the inflammation, and the secretion of inflammatory factors was measured by ELISA and qPCR. The levels of TNK1, total STAT1 and Tyk2, and the phosphorylation of STAT1 and Tyk2 were measured by western blot to uncover the mechanisms of TNK1. Results. The oil red O staining indicated obvious deposition of lipid on the aorta of ApoE(-/-) mice after 8-week HFD treatment. The TNK1 level was much higher in both the HFD-fed ApoE(-/-) mice aorta arch and the ruptured human CEA plaques. We found that TNK1 was highly expressed in THP-1 cells, compared to other atherosclerotic related cells (HUVEC, HBMEC, and HA-VSMC), indicating TNK1 might be involved in the inflammation. Suppressing the expression of TNK1 by shTNK1 inhibited the oxLDL-induced secretion of inflammatory factors, such as IL-12, IL-6, and TNF-α. ShTNK1 also inhibited the uptake of lipid and decreased the cellular cholesterol content in THP-1 cells. Furthermore, the shTNK1 suppressed the oxLDL-induced phosphorylation of Tyk2 and STAT1. Conclusion. TNK1 participated in the inflammation in atherosclerosis. shTNK1 suppressed the oxLDL-induced inflammation and lipid deposition in THP-1 cells. The mechanism might be related to the Tyk2/STAT signal pathway.

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