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Immunometabolism in Type 2 Diabetes Mellitus: Tissue-Specific Interactions

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Immunometabolism in Type 2 Diabetes Mellitus: Tissue-Specific Interactions State of the art paper Immunometabolism in type 2 diabetes mellitus: tissue-specific interactions Erika Pinheiro-Machado1, Ewa Gurgul-Convey2, Michal T. Marzec3 1University Medical Center Groningen, Department of Pathology and Medical Biology, Corresponding author: Netherlands Assoc. Prof. Michal T. Marzec 2Institute of Clinical Biochemistry, Hannover Medical School, Germany University of Copenhagen 3Department of Biomedical Sciences, University of Copenhagen, Denmark Department of Biomedical Sciences Submitted: 14 August 2019 Panum Institute, room 12.6.10 Accepted: 23 October 2019 Blegdamsvej 3 DK-2200 Copenhagen N Arch Med Sci Denmark DOI: https://doi.org/10.5114/aoms.2020.92674 E-mail: [email protected] Copyright © 2020 Termedia & Banach Abstract The immune system is frequently described in the context of its protective function against infections and its role in the development of autoimmuni- ty. For more than a decade, the interactions between the immune system and metabolic processes have been reported, in effect creating a new re- search field, termed immunometabolism. Accumulating evidence supports the hypo thesis that the development of metabolic diseases may be linked to inflammation, and reflects, in some cases, the activation of immune responses. As such, immunometabolism is defined by 1) inflammation as a driver of disease development and/or 2) metabolic processes stimulating cellular differentiation of the immune components. In this review, the main factors capable of altering the immuno-metabolic communication leading to the development and establishment of obesity and diabetes are compre- hensively presented. Tissue-specific immune responses suggested to impair metabolic processes are described, with an emphasis on the adipose tissue, gut, muscle, liver, and pancreas. Key words: immunity, metabolism, tissue-specific, diabetes. Introduction Obesity prevalence has doubled in more than 70 countries and con- tinuously increases globally since 1980 [1]. Studies have associated high body mass index (BMI) and physical inactivity with a set of chronic diseas- es such as type 2 diabetes (T2DM), and an array of other disorders [2–4]. The main link between these metabolic disorders is the ability to induce insulin resistance and, as a consequence, affect the whole organism’s function. However, some organs and tissues exacerbate the pathological conditions including: 1) adipose tissue (AT) – the site of fat accumulation, 2) the gut – the site for the microbiota and metabolites that have been associated with metabolic disorders [5], 3) muscles – the primary site of insulin resistance [6], 4) the liver – obesity is a major risk factor for liver damage, and finally, 5) the pancreas – once impaired it leads to compromised insulin production and secretion. All metabolic processes that these organs are involved in are also influenced by immunological responses that stimulate and maintain them. The interface between the immune system and metabolism has been investigated over the last 15 years and has been branded with the term Michal T. Marzec, Erika Pinheiro-Machado, Ewa Gurgul-Convey immunometabolism. This interdisciplinary ap- tors were shown to improve insulin sensitivity and proach made the field essential for understand- reduce AT inflammation via inhibition of TNF-α, ing the pathology and progression of metabolic IL-1β, IL-6 and IL-8 secretion [26]. diseases as immunometa bolism places the low- The analysis of AT from obese patients showed grade chronic inflammation as the central cause that macrophages were able to infiltrate this tis- and consequence of metabolic disorders [7]. In- sue [27] and that FFAs promoted the polarization flammation is described as a prompt and a short- of these cells towards a proinflammatory pheno- term response to deal with injuries and infec- type (M1 macrophages) [28]. It is important to tions, providing repair to injured tissues, and it mention that macrophage polarization has been is composed of a series of signals and pathways clustered into two major macrophage polarization that are rapidly resolved upon healing. In con- programs, classically activated macrophages or M1 trast, low-grade chronic systemic inflammation and alternatively activated macrophages or M2, or metaflammation is primarily caused by per- each related to specific immune responses, among sistent activation of the innate immune system which both progression and resolution of in- that promotes increased production and secretion flammation constitute critical determinants [29]. of proinflammatory cytokines and other media- However, this clear distinction has been challenged tors [8, 9]. It is generally believed that persistent with data identifying a metabolically activated over-nutrition, physical inactivity and exposure to macrophage phenotype that is mechanistically dis- certain epigenetic factors contribute to the devel- tinct from M1 or M2 activation [30, 31]. opment of low-grade systemic inflammation asso- Nevertheless, the presence of classical M1 mac- ciated with metabolic diseases [10–12]. The con- rophages in AT of obese patients and high-fat fed stant activation of the innate immune system has animal models (HFD; HFD-fed M-JAK2–/– and HFD- been shown to induce the production of stimuli fed MIF–/– C57Bl\6J) was clearly associated with that may additionally activate the adaptive im- impaired insulin action [32, 33]. Beyond the innate mune system. In some tissues, such as visceral AT, immune system, it has also been demonstrated an alternative chain of events combining the im- that the adaptive immune response with T and B mune response and inflammation was described, lymphocytes may influence metabolic processes. in which the adaptive immune cells (CD4 and/or So far, the immuno-metabolic crosstalk has been CD8 T cells) were shown to trigger AT inflamma- described in various tissues, suggesting function- tion [13, 14]. Together, it is proposed that an inter- al links with consequences for translational stud- play between disturbed metabolic state and these ies [34, 35]. low-grade chronic inflammatory responses culmi- This review aims to present and discuss the up- nate in a vicious cycle leading to the development dated knowledge about important processes in of metabolic diseases, such as T2DM [15–17]. the intercommunication between the immune An inflammatory state playing a role in the de- system and metabolism (see Figure 1). Although velopment of metabolic diseases was shown for much of what is known about these interactions the first time in 1993 [18] when the adipose tissue during obesity and obesity-related diseases was (AT) was described to produce the proinflamma- first described in AT, other organs are also involved tory cytokine tumor necrosis factor α (TNF-α). In and they will be discussed in more detail in forth- accordance, it was proposed that obesity could coming sections. be associated with enhanced expression of proin- flammatory mediators and that this environment Tissue-specific immune responses leading to could modulate glucose metabolism and/or insu- metabolic diseases lin action [19]. Adipose tissue Increased serum free fatty acids (FFAs) lev- els have been associated with insulin resistance Initially treated as a deposit for triacylglycerol in obese individuals [20–23]. Especially satu- and thus as a sole energy-storage tissue, the AT rated FFAs have been correlated with induction is now considered a multifunctional endocrine of the inflammatory response and insulin resis- organ that is able to synthesize bioactive fac- tance in insulin target tissues, while polyunsatu- tors (adipokines) to regulate metabolism, energy rated FFAs have been described as generally an- intake, fat storage and immunity [36, 37]. Com- ti-inflammatory [24]. In contrast to omega-6 FFAs, posed mainly of adipocytes, the AT also contains omega-3 FFAs by stimulating the biosynthesis pre-adipocytes, endothelial cells, fibroblasts, and of specialized pro-resolving lipid mediators (SPMs; a diversity of immune cells such as macrophages, such as protectins, resolvins, lipoxins, maresins) in neutrophils, T lymphocytes, and others, with clear immune cells and other tissues are believed to differences observed between obese and lean adi- possess a strong protective anti-inflammatory po- pose tissue, as well as distinct functions of viscer- tential [25]. Specialized pro-resolving lipid media- al fat (VAT) and subcutaneous fat (SAT) [38, 39]. 2 Arch Med Sci Immunometabolism in type 2 diabetes mellitus: tissue-specific interactions ADIPOSE TISSUE GUT MUSCLE LIVER PANCERAS ↑ Macrophage Short chain fatty acid Infiltration of T cells Kupffer cells: Insulin-secreting recruitment: accumulation and macrophages M1 polarization cells: oxidative stress, M1 polarization in VAT TLR recognition ↑ Proinflammatory ↑ Macrophage ER stress induction ↓ M2 macrophage of PAMPS in other cytokines infiltration (JNK activation) and mitochondrial in SAT tissues JNK activation ↑ Neutrophils activity dysfunction ↑ Proinflammatory Disruption of T and Relatively expression (neutrophil elastase) Imbalance in cytokines production B cell function of innate immune ↑ Proinflammatory arachidonic acid ↑ Nuetrophils activity ↑ Proinflammatory receptors: TLR4, cytokines production metabolism ↑ CD3+, CD8+ and cytokines 5, 9 are the most PPAR-γ, NF-κB Intra-islet IAPP CD4+ T cell levels ↑ Inflammasomes abundant activation deposits formation/ and B cells Dysregulation Dysregulation of Tregs TLR4 and activation of myokines TYPE 2 DIABETES ↓ Tregs levels Imbalance
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