Epigenetic and Metabolic Regulation of Macrophages during Gout: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Isidoro Cobo.

Metabolites are the substrate, intermediate, or final products of metabolic reactions that drive the function of a given cell in a particular time and context. Therefore, metabolites provide essential information about the connection between gene expression and the environment, and, as such, they are elegant disease biomarkers. Macrophages represent an elegant model for understanding histone dynamics, transcription factor recruitment, and changes in gene expression during signal transduction by environmental signals.

  • metabolite
  • lipids
  • epigenetic
  • histone
  • transcription factor

1. Introduction

Gout is the most common inflammatory arthritis worldwide, and its incidence is rising in developed and underdeveloped countries [11][1]. Gout is caused by the deposition of monosodium urate crystals in the joints in patients with persistent hyperuricaemia (HU) [12,13,14,15,16][2][3][4][5][6]. Besides the local clinical manifestations in the joints, gout is associated with many other systemic complications, from renal disease [17,18][7][8] to cardiovascular disease [19[9][10][11][12],20,21,22], diabetes [23][13], and metabolic syndrome [24,25][14][15]. Since the deregulation of urate metabolism is at the heart of gout, it is vital to understand genetic conditions [26,27][16][17] and environmental or behavioural exposures such as diet [28,29,30,31,32,33][18][19][20][21][22][23] that modify blood urate levels and underlying molecular mechanisms [28,29,31][18][19][21]. Together with the acute inflammatory reaction, gout attacks are accompanied by an altered local and systemic metabolomic profile [34,35,36][24][25][26]. Diverse significantly dysregulated pathways have been described in individuals with hyperuricaemia and patients with gout compared to normouricaemic controls, among which arginine metabolism [37][27] and other amino acids [38][28] appeared to play a critical role. Lipid and carbohydrate metabolism are other proposed dysregulated pathways [39,40][29][30]. Finally, a significant increase in leukotriene B4 (LTB4) in plasma associated to an increased transcriptional level of 5-lipoxygenase in whole blood cells was described in patients with acute gout flares [41][31].
The deposition of MSUc in the joints causes a self-limited, acute inflammatory reaction. The effect MSUc during gouty inflammation offers a suitable system to understand anti-inflammatory programs of gene expression in macrophages. The original view was that biological systems resolve inflammation by diluting proinflammatory mediators that eventually restore tissue function. This view has been surpassed, thanks to the work of Dr Charles N. Serhan and others, by a more active notion where macrophages and other cell types produce specialized pro-resolving mediators (SPMs) and other anti-inflammatory oxylipins to counterbalance the initial wave of proinflammatory signals to prevent surplus inflammation and subsequent tissue damage [114,115,116,117,118,119][32][33][34][35][36][37]. Even though SPMs are oxylipins widely studied in the context of inflammation and have been primarily studied in other inflammatory diseases, including lung disease [118,120][36][38] and cancer [121][39], the role of SPMs in the resolution of gout flares remains unknown. SPMs, resolvins, protectins, and maresins are derived mostly from alpha linolenic acid (α-LA), which is an omega-3 essential fatty acid (EFA) from green leafy vegetables, flax and chia seeds, and walnuts. Omega-6 EFA are generally generated by linoleic acid (LA) from vegetable oils, meats, and eggs. Some omega-6 lipids, such as lipoxins, PGJ2, and PGB2, are also considered anti-inflammatory molecules [122][40].
The central catalytic enzymes involved in the generation of STMs are phospholipases (PLA)2 and lipoxygenases (LOX). The time course of biosynthesis and bioavailability of SPMs dictates their molecular function to ensure a cell type and context-specific response. In macrophages, lipoxin A4 (LXA4), protectin D1 (PD1) and resolvin D1 (RvD1) are involved in the clearance of apoptotic neutrophils and other polymorphonuclear cells [123,124,125][41][42][43]. Regardless of the subtype, SPMs exert their biological activity upon binding with high affinity to specific cognate receptors. Over the last years, the receptors for some of the SPMs have been characterized. LXA4 binds and signals through the LXA4 receptor (ALX or formyl peptide receptor(FPR2)) [126][44], RvE1 through chemokine-like receptor 1 (CMKLR1) [127][45], RvD1 through G protein-coupled receptor GPR32, and RvD2 through GPR18 [128,129][46][47]. Therefore, changes in EFA, an altered expression of the enzymatic cascade that bio-converts EFA to SPMs and other anti-inflammatory oxylipins, or changes in the expression and availability of any of the receptors will impact the activity of SPMs during the resolution of inflammation. Interestingly, the treatment of mice with MSUc results in an increased production of prostaglandins and other oxylipins suggesting that oxylipin metabolism could be also involved in limiting the duration of gouty inflammation by MSUc [130,131][48][49]. Below wresearchers will review some of the mechanisms that could contribute to regulate SPM production in macrophages during gout flares.

2. Phospholipases A2

Phospholipase A2 (PLA2) encompasses a superfamily of enzymes with more than 50 members, whose expression and activity dictate a cell-specific and temporal response [132,133,134,135][50][51][52][53]. PLA2 is the first enzymatic machinery in the metabolism of SPMs. Therefore, extensive work has been put into understanding PLA2 regulation during inflammatory processes in macrophages [136][54]. PLA2 enzymes can act as degradative, biosynthetic (when coupled to an acetyltransferase) or as a signalling enzyme. This versatility of action, the high degree of functional redundancy, and their dynamic expression have made the PLA2 family challenging to ascribe to specific regulatory signalling programs. It is widely accepted that many different mechanisms, including increased [Ca2+] [137][55], ceramide phosphate [138][56], phosphatidylinositol [139[57][58],140], bisphosphate [141][59], and phosphorylation [142][60] activate PLA2. In addition, the transcription of the endogenous secretory phospholipase A2 group IIA (sPLA2-IIA) gene is regulated by the direct binding of CCAAT/Enhancer Binding Protein (C/EBP), NFKB, and ETS proto-oncogene TF (ETS) transcription factors to the PLA2 regulatory region [143,144][61][62]. Interestingly, whereas Pla2g4a and Pla2g5 are upregulated, Pla2g15 is downregulated, suggesting a role of Pla2 transcriptional regulation in macrophages during gout.

3. COXyclooxygenases and ALOX5/ALOX5AP

The next step in the formation of oxylipins associated to the resolution of inflammation involves the conversion of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and some products derived from AA by cyclooxygenases (COX) and lipoxygenases. MSUc stimulates COX-2 expression in peripheral monocytes, which correlated with the synthesis of pro-inflammatory oxylipins such as prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) [145][63]. Leukotriene B4 (LTB4) was also relevant in the MSUc-induced maturation of IL-1b [146][64]. Of interest, PGD2 and 15d-PGJ2 had an anti-inflammatory role in animal models of MSUc-induced inflammation [147,148][65][66]. Of the genes coding for lipoxygenases, ALOX5/Alox5 and Alox5 activating protein ALOX5AP/Alox5ap are the two most expressed in unprimed MDM and BMDM. The significance of ALOX5/ALOX5AP during gout is supported by a study by Luo and colleagues where after performing metabolomics of PUFA of patients with acute gout plasma validated in two independent cohorts, they found a higher increase in leukotriene B4 (LTB4), accounting for altered activity of lipoxygenase 5 [41][31]. Notably, stimulation with MSUc leads to downregulation of ALOX5 in unprimed MDM and BMDM and downregulation of Alox5ap in unprimed BMDM [35][25], which is in accordance with a negative feedback mechanism of metabolic networks to regulate active metabolic pathways [149,150][67][68]. Importantly, ALOX5/ALOX5AP are JUN target genes, and treatment with JNK inhibitor SP600125 ameliorates the downregulation by MSUc, providing further evidence that ALOX5 and ALOX5AP repression by JUN could contribute to the formation of oxylipins during gouty inflammation. Interestingly, the expression of the main LXA4 receptor, FPR2, is downregulated in unprimed MDM stimulated with MSUc. Of interest, besides the participation of 5-LOX in inflammation by promoting the biosynthesis of leukotrienes, this enzyme possesses other non-canonical functions as transcriptional regulator in monocytic cells including the interaction with β-catenin, p53, and chromatin [151,152][69][70]. These results provide substantial evidence to suggest a role of signalling by LOX products and their downstream signalling during the resolution of gout flares.

4. Activation of Enzymatic Pathways by Damaged Subcellular Organelles

During the early stages of the acute phase of gout flares, ingested MSUc induces the rupture of lysosome in leukocytes and the release of the lysosomal content into the surrounding medium, which is a hallmark of damage induced by MSUc [153,154,155,156,157][71][72][73][74][75]. Aberrant lysosomal compartment leads to increased intracellular and extracellular [Ca2+] [158,159][76][77], which can activate PLA2 to release free fatty acids that fuel the synthesis of new pro- and anti-inflammatory oxylipins.

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