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Fibroblast and Immune Cell Cross Talk in Cardiac Repair
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Stelios Psarras, Georgina Xanthou
Therapeutic infusion of IL-10 in MI induced an M2 alternative type of macrophage activation (73) and directly stimulated fibroblast proliferation and migration. Moreover, fibroblasts from IL-10-administered mice exhibited increased proliferation and a reduced collagen I/III ratio, associated with reduced fibrosis a week following MI (73) (Figure 5.2). Alternative macrophage activation regimes exhibit beneficial effects on fibroblasts and repair mechanisms in other settings as well. Indeed, tribbles pseudokinase-deficient (Trib1) mice show reduced numbers of alternatively activated macrophage populations following MI, and this is accompanied by impaired collagen deposition, leading to catastrophic rupture (69). Whereas IL-4 administration induced alternatively activated macrophages in wt mice, protecting from post-MI rupture, it failed to do so in Trib1−/− mice. However, the protective effects of IL-4 were indirect, involving increased OPN and IL-1α secretion by alternatively activated macrophages that induced myofibroblast formation, reinforcing repair (69) (Figure 5.2).
Dietary Carbohydrate Restriction in the Management of NAFLD and Metabolic Syndrome
Published in Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss, Nutrition and Cardiometabolic Health, 2017
Grace Marie Jones, Kathleen Mulligan, Jean-Marc Schwarz, Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss
Genome-wide association studies have identified loss-of-function gene variants that are involved in hepatic lipid metabolism and play a major role in the pathogenesis of NAFLD (Dongiovanni, Romeo et al. 2015). The I148M variant of the patatin-like phospholipase domain-containing 3 gene, PNPLA3 or adiponutrin, a lipase involved in the hydrolysis of triglycerides (Pingitore, Pirazzi et al. 2014), was strongly associated with increased fat levels and inflammation in the liver. Interestingly, Hispanics as a group are more susceptible to NAFLD and are more likely to have the I148M variant than African- or European-Americans (Romeo, Kozlitina et al. 2008). A second variant, E167K of the transmembrane 6 superfamily member 2 gene, was found in two separate studies (Holmen, Zhang et al. 2014, Kozlitina, Smagris et al. 2014) and has been shown to regulate hepatic lipid metabolism via VLDL secretion (Mahdessian, Taxiarchis et al. 2014). Additionally, the glucokinase regulator P446L polymorphism has a significant association with NAFLD and has been shown to increase DNL, liver fibrosis, and triglyceride levels (Speliotes, Yerges-Armstrong et al. 2011, Wu, Lemaitre et al. 2013, Petta, Miele et al. 2014, Aguilar-Olivos, Almeda-Valdes et al. 2015, Santoro, Caprio et al. 2015). Other genes involved in hepatic lipid metabolism, including FATP5, LYPLAL1, NCAN, PPAR, PPP1R3B, LPIN1, TRIB1, and UCP2,* have been implicated in the pathogenesis of NAFLD. However, further research is needed to clarify their suspected roles (Speliotes, Yerges-Armstrong et al. 2011, Kitamoto, Kitamoto et al. 2014).
Genetic background of coronary artery disease: clinical implications and perspectives
Published in Expert Review of Precision Medicine and Drug Development, 2020
Massimiliano Camilli, Giulia Iannaccone, Marco G. Del Buono, Filippo Crea, Nadia Aspromonte
TRIB1 resulted to play a role in CAD onset and to be implied in lipid metabolism, with a relevant impact on triglycerides, total cholesterol, HDL and LDL plasmatic levels [32,33,38,39]. TRIB1 acts on macrophages by conditioning their polarization, a phenomenon related to plaque progression [40,41]. The gene TRIB1 is contained in the 8q24 locus which hosts different other genes involved in metabolic syndrome in humans [42]. Probably all the transcripts obtained from this locus could contribute to CAD, either directly or indirectly.
Adipose Tissue Macrophage-Mediated Inflammation in Obesity: A Link to Posttranslational Modification
Published in Immunological Investigations, 2023
Dongqin Wei, Xin Tian, Xiangyun Zhai, Chao Sun
Similarly, an increasing number of studies also demonstrate the importance of ubiquitination modification in regulating ATM phenotypes. Among the numerous E3 ubiquitin ligases, TRAF6 (TNF receptor-associated factor 6), Pellino1, and Pellino2 mediate ubiquitination to promote M1 activation, but Pellino3 has a negative regulatory effect on the phenotype mediated by TRAF6 (Strickson et al. 2017; Yang et al. 2014). Tribbles pseudokinase 1 (Trib1), major vault protein (MVP) and DAB adaptor protein 2 (DAB2) are also inhibitors of M1 activation and are often expressed in the M2 phenotype (Adamson et al. 2016; Ben et al. 2019; Satoh et al. 2013). Earlier studies reported that Trib1 controls the differentiation of tissue-resident M2-like macrophages and is essential for inhibiting adipose tissue metabolism disorders (Satoh et al. 2013). Further analysis of the structure of Trib1 revealed that Trib1 interacts with E3 ubiquitin ligase constitutively photomorphogenic 1 to degrade proteins, such as CCAAT enhancer-binding protein alpha (Kung and Jura 2019). Recent studies have shown that mouse myeloid-specific deletion of MVP aggravates M1 macrophage infiltration and adipose tissue inflammation (Ben et al. 2019). Mechanistically, MVP inhibits the ubiquitination of TRAF6 and promotes M2 polarization (Ben et al. 2019). Likewise, the deletion of DAB2 in humans and mice leads to M1 polarization (Adamson et al. 2016). Another E3 ubiquitin ligase that has been widely studied to inhibit M1 polarization is cbl proto-oncogene B (Cbl-b), which degrades TLR4 through ubiquitination and inhibits the migration of macrophages induced by FFA (Abe et al. 2013). E3 ubiquitin ligase ring finger protein (RNF)213 plays a role in TNFα-mediated inflammation of ATMs (Sarkar and Thirumurugan 2021), but its specific mechanism has not been revealed. In addition to E3 ubiquitin ligases, a series of deubiquitinating enzymes regulating the phenotype of ATMs cannot be ignored. It has been reported that ubiquitin-specific peptidase (USP)2 reduces IR in HFD-induced obese mice, which is mainly related to the smaller M1 population of USP2-overexpressing mice (Saito et al. 2017). However, there is currently a lack of studies on the regulation of ATM phenotypes by deubiquitination. Given the importance of ubiquitination, further exploration of deubiquitinating enzymes will be necessary in the future.