Monocytes, non-alcoholic liver disease crosstalk | ||
| Minia Journal of Medical Research | ||
| Volume 33, Issue 2, April 2022, Pages 45-48 PDF (124.78 K) | ||
| Document Type: Review Article | ||
| DOI: 10.21608/mjmr.2022.241606 | ||
| Authors | ||
| Mohammed A. Shaarawe1; Ghada M. El-Sagheer2; Ahmed Abdel Fadee3; Fawzeya M. Abdel Bari2 | ||
| 1Department of Internal Medicine, Faculty of Medicine, Minia University, Minya, Egypt. | ||
| 2Department of Internal Medicine, Faculty of Medicine, Minia University, Minya, Egypt | ||
| 3Department of Clinical Pathology, Faculty of Medicine, Minia University, Minya, Egypt. | ||
| Abstract | ||
| With the increasing prevalence of the obesity epidemic, non-alcoholic fatty liver disease (NAFLD) represent the most common liver disease worldwide and one of the important causes of hepatocellular carcinoma development. Also, it is strongly associated with type 2 diabetes mellitus. Metabolic inflammation has been suggested to play a central role in NAFLD progression. Monocytes represent a key player in meta-inflammation. Circulating monocytes, adipose tissue macrophages (ATM), and liver resident macrophages have roles in NAFLD development and progression. Adipose tissue macrophages accumulate as a result of adipose tissue hypoxia, they produce huge amount of cytokines inducing insulin resistance and excess fat accumulation in the liver. In this review, we highlight the burden of NAFLD, its association to metabolic parameters and obesity, with illustration of obesity induced inflammation and pathogenic pathways involved in insulin resistance development. We pointed to the plasticity of circulating monocytes, phenotypic and functional alteration of their subsets in NAFLD, and the therapeutic approaches targeting macrophages and their effects on improvement of insulin resistance and NAFLD progression. | ||
Highlights | ||
Acknowledgments This work was supported by Minia university medical staff. Financial Disclosure None to declare. Conflict of interest None to declare. | ||
| Keywords | ||
| NAFLD; Monocytes; Metabolic inflammation | ||
| Full Text | ||
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Introduction Non-alcoholic fatty liver disease (NAFLD) represents a major burden worldwide in a parallel manner with the upgrowing prevalence of obesity [1,2]. 30 -100% of type 2 diabetes mellitus -according to different studies- are estimated to have NAFLD [3,4]. The overall related mortality rate is closely related to the progression of fibrosis [5,6]. Nowadays, NAFLD is considered a component of metabolic syndrome, this is owed to the close association between hepatic fat accumulation and insulin resistance [7]. Many studied pathways seem to be drivers of the development and progression of NAFLD. Of these; chronic metabolic inflammation is considered a major player [8]. Metabolic inflammation or meta-inflammation is characterized by a status of sterile, low grade chronic inflammation, with monocytes are important regulators of this status. Monocytes produce plethora of cytokines regulating insulin signaling [9]. Moreover, they are source of cytokines that favor progression of non-alcoholic steatohepatitis (NASH) [10]. Monocytes are classified into 3 subsets, according their surface expression of CD14 and CD16; classical subset, CD 14++CD16-, intermediate, CD14++CD16+, and non-classic, CD14+CD16++. The latter two subsets are called proinflammatory, they are characterized by a pronounced cytokine production [11,12]. Beyond the previously mentioned simple classification; monocytes can respond to different metabolic stimuli by reprogramming that determine their polarization [13,14]. In this review, we will discuss the changes of percentages and polarization of circulating monocytes as well as adipose tissue macrophages, and their contribution to the development and progression of NAFLD.
Obesity induced inflammation and development of insulin resistance The positive energy balance from over nutrition induce excess fat accumulation within the adipose tissue, this evokes immune response in attempt to restore homeostasis. However, this response becomes later on maladaptive and promotes insulin resistance [15]. The obesity induced inflammation was firstly described based on the observation of increased tumor necrosis factor α (TNF α) in obese individuals. TNF α was discovered to be driven from adipose tissue macrophages (ATMs) [16]. Adipose tissue hypoxia-due to adipose tissue expansion exceeding oxygen supply from angiogenesis- is the main cause of ATMs attraction and activation [17]. Being activated, ATMs produce a plethora of cytokines which activate inflammatory pathways as C-jun N-terminal kinase (JNK) and IκB kinase β (IKK-β). These pathways lead to phosphorylation of insulin receptors and their substrate, hence affecting insulin signaling [18,19]. Many therapeutic approaches target inhibition of ATMs infiltration to adipose tissue as deletion of macrophage chemoattractant protein (MCP-1) or (CCL2), and inhibition of its receptor (CCR2) [20]. These approaches showed promising results in improving insulin resistance. Moreover, it was observed that these approaches ameliorate hepatic inflammation, confirming the central role of adipose tissue inflammation, specifically macrophages, in progression of NAFLD [15].
Circulating monocytes and NAFLD Circulating monocytes are heterogenous and play important roles in host defense and tissue homeostasis. Experimental studies revealed that in setting of liver injury, peripheral monocytes are recruited within the liver driving inflammation and fibrogenesis [21].Also, many human studies had demonstrated elevated circulating total monocytes percentages in patients with NAFLD [22]. Three functionally and phenotypically different subsets of human monocytes are identified. Classical monocytes CD14++CD16-, express high level of CCR2 and have high phagocytic capacity. CD16+ monocytes, expressing CX3CR, are called proinflammatory, they include 2 subsets; intermediate CD14++CD16+ which suggested to have a prominent role in inflammation, and non-classical subset CD14+CD16+ which has angiogenic and surveillance function [23]. Many studies had investigated the alteration of different monocytes subsets in patients with NAFLD and revealed that the proinflammatory, CD16+, populations are increased in NAFLD patients [24].The increased proinflammatory monocytes had been also detected in other comorbid conditions that commonly accompany NAFLD as types 2 diabetes mellitus, dyslipidemia and obesity [25]. These findings augment the prominent role of increased circulating monocytes and alteration of their subsets in the development and progression of NAFLD, also provide another future therapeutic target in controlling NASH progression.
Conclusion NAFLD is considered nowadays a main component of metabolic syndrome. It is usually associated with many comorbid metabolic derangements as obesity and insulin resistance. Of the prominent pathophysiologic mechanisms of NAFLD development is metabolic inflammation or meta-inflammation, which is a chronic state of low-grade inflammation that accompanies obesity. Macrophages are considered key regulators of this metabolic inflammation, either circulating monocytes, adipose tissue macrophages or liver resident macrophages. They produce a plethora of cytokines that control the state of insulin resistance and influence NASH progression. Thus, further clinical trials of macrophages-targeting therapeutic approaches should be provided. As they will introduce a promising hope for breaking the complex pathophysiological circle of NAFLD, obesity, insulin resistance. | ||
| References | ||
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References [1] Yki-Jarvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2014;2:901– 910. [2] Younossi Z, AnsteeQM,MariettiM, Hardy T, Henry L, EslamM, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15:11–20. [3] Jinjuvadia R, Antaki F, Lohia P, Liangpunsakul S. The association between nonalcoholic fatty liver disease and metabolic abnormalities in the United States population. J Clin Gastroenterol 2017;51:160–166. [4] Kwok R, Choi KC,Wong GL, Zhang Y, Chan HL, Luk AO, et al. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut 2016;65:1359–1368. [5] Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of PatientsWith Nonalcoholic Fatty Liver Disease. Gastroenterology 2015;149:389–397 e10. [6] Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015;61:1547– 1554 [7] Lonardo A, Nascimbeni F, Mantovani A, Targher G. Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence? J Hepatol 2018;68:335– 352. [8] Devisscher L, Verhelst X, Colle I, Van Vlierberghe H, Geerts A. The role of macrophages in obesity-driven chronic liver disease. J Leukoc Biol 2016;99:693–698. [9] Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature 2017;542:177–185. [10] Baffy G. Kupffer cells in non-alcoholic fatty liver disease: the emerging view. J Hepatol. 2011;51:212–23. [11] Anbazhagan K, Duroux-RichardI, Jorgensen C, Apparailly F. Transcriptomic network support distinct roles of classical and non-classical monocytes in human. Int Rev Immunol. 2014;33:470–89. [12] Seidler S, Zimmermann HW, Weiskirchen R, Trautwein C, Tacke F. Elevated circulating soluble interleukin-2 receptor in patients with chronic liver diseases is associated with non-classical monocytes. BMC Gastroenterol. 2012;12:38. [13] Xue J, Schmidt SV, Sander J, Draffehn A, KrebsW, Quester I, et al. Transcriptome- based network analysis reveals a spectrum model of human macrophage activation. Immunity 2014;40:274–288. [14] Krenkel O, Tacke F. Macrophages in Nonalcoholic Fatty Liver Disease: A Role Model of Pathogenic Immunometabolism. Semin Liver Dis 2017;37:189–197. [15] Lefere, S., & Tacke, F. Macrophages in obesity and non-alcoholic fatty liver disease: Crosstalk with metabolism. JHEP reports, 2019;1:30-43. [16] Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 1995;95:2409–2415. [17] Lefere S, Van Steenkiste C, Verhelst X, Van Vlierberghe H, Devisscher L, Geerts A. Hypoxia-regulated mechanisms in the pathogenesis of obesity and non-alcoholic fatty liver disease. CellMol Life Sci 2016;73:3419–3431. [18] Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 2002;277:48115–48121. [19] Ozes ON, Akca H, Mayo LD, Gustin JA, Maehama T, Dixon JE, et al. A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proc Natl Acad Sci U S A 2001;98:4640–4645. [20] Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006;116:1494–1505. [21] Melino M, Gadd VL, Alexander KA, Beattie L, Lineburg KE, Martinez M, et al. Spatiotemporal Characterization of the Cellular and Molecular Contributors to Liver Fibrosis in a Murine Hepatotoxic-Injury Model. Am J Pathol. 2016. [22] Gadd VL, Melino M, Roy S, Horsfall L, O'Rourke P, Williams MR, et al. Portal, but not lobular, macrophages express matrix metalloproteinase-9: association with the ductular reaction and fibrosis in chronic hepatitis C. Liver Int. 2013; 33: 569–79. [23] Stansfield BK, Ingram DA. Clinical significance of monocyte heterogeneity. Clin Transl Med. 2015; 4: 5. [24] Gadd VL, Patel PJ, Jose S, Horsfall L, Powell EE, Irvine KM (2016) Altered Peripheral Blood Monocyte Phenotype and Function in Chronic Liver Disease: Implications for Hepatic Recruitment and Systemic Inflammation. PLoS ONE 11(6): e0157771. [25] Cannon JG, Sharma G, Sloan G, Dimitropoulou C, Baker RR, Mazzoli A, et al. Leptin regulates CD16 expression on human monocytes in a sex-specific manner. Physiological reports. 2014; 2. | ||
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