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Inflammation Explained - Research for Therapies / Review - Inflammation, metaflammation and immunometabolic disorders
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"ultimate goal is the development of successful translational approaches to treat patients or prevent disease.Biologics targeting classical inflammatory molecules including IL-1, IL-6 and TNF are already currently in clinical use for the treatment of rheumatoid arthritis, Crohn's disease and other chronic inflammatory diseases, and assessment of these patients provides some insight into whether these approaches might have metabolic benefit in these populations......In addition to these well-established immunomodulatory strategies, which perhaps represent the 'low-hanging fruit'......It has also been well-established that inflammation is essential for repair, remodelling, and even renewal of tissues, including those with critical metabolic function. These responses also need to be temporally and spatially regulated to maintain homeostasis, including metabolic homeostasis, otherwise they will be uniformly damaging when sustained. Hence, broad, potent or permanent interferences targeting immune resolution or activation may have unintended and adverse consequences for tissue health, and if these tissues and related functions are critical for metabolic homeostasis, for the metabolic health of the organism as well.
There is also tremendous redundancy in the pathways that support inflammation as well as its resolution, and this certainly is also the case in immunometabolic regulation (Supplementary Fig. 1, extended version available at http://www.metaflammation.org). This poses an important and unresolved question regarding how we design and interpret immunometabolic changes in genetic models, especially in inbred mouse strains. Just as a clinical study with a single subject may be informative but cannot be definitive or generalizable, genetic interventions in inbred strains have limitations in determining the efficacy or translatability of putative targets. Finally, in humans there is also tremendous inter-individual variability in the magnitude of the immune response, even exhibiting strong seasonal fluctuations132, 133, 134. Given these difficulties, and the need for therapeutic approaches that do not permanently interfere with entire branches of the immune system and are free of undesirable outcomes, translating our experimental insights into successful clinical interventions will require nuanced thinking, combinatorial approaches, and new experimental paradigms. "
Inflammation, metaflammation and immunometabolic disorders
Nature08 February 2017
Proper regulation and management of energy, substrate diversity and quantity, as well as macromolecular synthesis and breakdown processes, are fundamental to cellular and organismal survival and are paramount to health. Cellular and multicellular organization are defended by the immune response, a robust and critical system through which self is distinguished from non-self, pathogenic signals are recognized and eliminated, and tissue homeostasis is safeguarded. Many layers of evolutionarily conserved interactions occur between immune response and metabolism. Proper maintenance of this delicate balance is crucial for health and has important implications for many pathological states such as obesity, diabetes, and other chronic non-communicable diseases.
Metabolic inflammation was first described in adipose tissue, it presents the highest complexity at this site, and has been examined in detail with thousands of studies.
However, it is critical to emphasize that adipose tissue is neither the sole site of metaflammation nor could it be assumed to be the only player in metabolic homeostasis or related pathologies. Obesity-related influx of immune cells occurs in many other tissues such as the hypothalamus, liver, muscle, pancreatic islets and the gut (Fig. 1). The immunometabolic program within each organ also includes stromal components and metabolic cells, such as adipocytes, hepatocytes and β cells. These cells not only control the energy and substrate fluxes into the immune effectors but also themselves produce many cytokines, chemotactic molecules and lipid mediators. Hence, the systemic impact of metabolic inflammation as well as the bidirectional interactions between immune and stromal components are critical considerations in determining physiological and pathological outcomes. Some examples are provided in other sections of this text.
Emerging data from human trials
As we progress in our understanding of the molecular mechanisms that underlie the connections between obesity and metabolic disease, the ultimate goal is the development of successful translational approaches to treat patients or prevent disease. Biologics targeting classical inflammatory molecules including IL-1, IL-6 and TNF are already currently in clinical use for the treatment of rheumatoid arthritis, Crohn's disease and other chronic inflammatory diseases, and assessment of these patients provides some insight into whether these approaches might have metabolic benefit in these populations. However, the results of these studies have been variable; for example in the case of TNF, while some have concluded that anti-TNF therapy reduces risk of diabetes or improves insulin sensitivity, others have not replicated these findings. The same is also true in small proof-of-principle studies in obese patients. However, large retrospective and meta-analysis studies have concluded that anti-TNF therapy improved insulin sensitivity or hyperglycaemia and importantly, reduced lifetime risk of diabetes113, 114. Multiple studies have provided highly promising evidence that antagonizing IL-1 signalling improves insulin secretion and, in some patients, enhances insulin sensitivity26. A detailed analysis of the pros and cons of these trials was recently reported115. The limited success of these approaches targeting individual cytokines so far should not be considered endorsements or indictments of the proposed immune mechanisms; indeed successful immunological interventions have been extremely challenging even in diseases such as type 1 diabetes, where the immune mechanisms driving the pathology are well-established, and in others (such as Crohn's and rheumatoid arthritis), anti-cytokine treatments only benefit a small fraction of the patients116. Overall, it is clear that TNF or IL-1 blockade have benefits, but better patient selection and precision is needed to realize the full translational potential of these approaches.
In addition to these well-established immunomodulatory strategies, which perhaps represent the 'low-hanging fruit' to be used for additional indications, the use of other anti-inflammatory molecules such as resolvins, ω-3 fatty acids, palmitoleate, or fatty acid-hydroxyl fatty acids provide extremely promising prospects for translational opportunities through lipid mediators or metabolism with encouraging leads98. There is also an exciting prospect related to erythropoietin (EPO), which has potent anti-inflammatory and tissue-protective effects, acting as a direct and indirect antagonist of TNF117. These actions of EPO are independent of its haematopoietic effects, and are signalled through an atypical heteromeric low-affinity receptor. Recently, a selective peptide agonist of this form of the receptor called ARA290 has been shown to be effective against obesity-induced inflammation and insulin resistance in mice118, and proof-of-principle studies in humans showed promising improvements in glucose control and dyslipidemia119. There is now a larger clinical trial planned to test the EPO receptor antagonist ARA290 (NCT01933529). Finally, it is important to note that essentially all existing anti-diabetic remedies, including metformin, thiozolidinediones, DPP4 inhibitors, incretin agonists, and even lifestyle interventions including exercise and caloric restriction, all exhibit anti-inflammatory activity120, 121, 122. Notably, statins reportedly exert pro-inflammatory action, such as stimulation of inflammasome activity, which may underlie the perplexing increase in diabetes risk identified in some studies with statin use123, 124. While each one of these approaches presents pros and cons, especially in the complex multifactorial metabolic disease space, they all point to critical and causal involvement of abnormal immune response in metabolic pathologies. I am hopeful that there will be more refined and better stratified clinical studies116 and many additional approaches to clarify further the immune-metabolic basis of obesity and diabetes and its effective translation to human diseases (Box 1).
Nutrients and metabolites as fuel and signalling molecules
The concept that nutrients, particularly circulating lipids, have a role in determining insulin sensitivity dates from at least as early as the 1960s, when it was recognized that lipids and fatty acids reduced insulin-induced glucose uptake in isolated heart muscle79. This effect was subsequently shown systemically in animal models including rats and in humans80. Since then, it has become clear from studies in humans and animal models that lipid-induced insulin resistance and impaired glucose metabolism may also involve other mechanisms, including the activation of inflammatory pathways81, 82, 83, 84. For example, the innate immune component TLR4 has been identified as a receptor for saturated and polyunsaturated fatty acids19, 85, 86, and although this sensing may occur indirectly, mice with loss of function of TLR4 are protected from the effects of diets high in saturated fat87, 88. Deletion of the TLR adaptor molecule MyD88 in the central nervous system also protects mice from diet-induced insulin resistance89. Taken together, ample evidence supports the involvement of TLR signalling in metabolic control in multiple experimental models7, 88.
Notably, other critical mechanisms may contribute to the role of lipid-induced insulin resistance independent of TLR signalling. For example, mice fed a high-fat diet exhibit changes in their serum, muscle and adipose tissue lipid profiles indicative of mitochondrial dysfunction, and incubating macrophages with these lipids drives expression of proinflammatory cytokines90, 91. Furthermore, many cytokines also induce the production of ceramides, which themselves may have potent metabolic effects, as has been reviewed elsewhere92. Another line of evidence indicates that lipid-induced insulin resistance in skeletal muscle is associated with accumulation of fatty acyl-CoA and DAG, leading to activation of PKCϑ, which blocks insulin action through IRS-1 serine phosphorylation and other mechanisms84, 93. Similar results have also been observed in human studies94. However, the full extent of this pathway's ability to mediate diet-induced insulin resistance is unclear, in part because animal models used to investigate the role of PKCϑ in the development of insulin resistance have given rise to complex results95, 96. Fatty-acid-induced activation of PKC as well as JNK in macrophages has also been linked to the production of inflammatory cytokines and promotion of muscle insulin resistance97. The interactions between direct mechanistic targets of these pathways, and how they are linked to metabolic pathologies is being explored, however it is clear that the DAG-PKC and the ceramide pathways are extremely promising avenues for further research with important implications for human metabolic disease. More research is necessary to fully understand whether these pathways are indeed separate from or an integrated part of the immunometabolic systems described here. As many lines of evidence demonstrate activity of signalling molecules such as PKC or JNK in both metabolic and immune responses, a model integrating these systems (see ref. 37) is likely to be most accurate (Fig. 3, references available at http://www.metaflammation.org). While it is not possible to cover the topic in further depth, it is important to note that there are also many lipids that play anti-inflammatory roles and produce metabolic benefits that have been identified98.

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