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Inflammation, Metaflammation and Immunometabolic Disorders Gökhan S REVIEW doi:10.1038/nature21363 Inflammation, metaflammation and immunometabolic disorders Gökhan S. Hotamisligil1 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. he overwhelming frequency of metabolic diseases such as pressures, they have now become a prominent liability expressed in the obesity and diabetes may be related to organismal design and the form of obesity and related metabolic diseases such as diabetes (Fig. 1). T evolutionary constraints within which natural selection has acted So how do the interface of metabolism and immunity relate to this throughout history. Some of the initial thoughts and considerations of transformation? The evolutionary advantages of a strong defence system this relationship have been described previously1. However, it is worth are obvious in protecting against pathogens, and as a strong immune stressing that, in general, selective pressures in evolution do not favour the response is dependent on energy sources, one can also argue that the development of countermeasures against excess nutrients and energy, but integration of these systems and their cooperation in responding to rather select for phenotypes that ensure survival in the face of deficiencies. fluctuations in the energy and nutrient environment would be highly For example, while there seems to be no need to defend against obesity, a advantageous. From this perspective, an intriguing way to think about strong rationale can be envisioned to defend against starvation. The same this paradigm would be to envision immune mediators, such as cytokines, argument could be made regarding sugar concentrations in body fluids; as metabolic hormones. In fact, this aspect of immunometabolism is while hyperglycaemia is not an immediate threat to survival, hypogly- extremely well-conserved among organisms and will be the main topic caemia is. Hence, organisms harbour strong and redundant pathways of discussion in this work. Infection-related metabolic alterations, as well to seek food, favour energy efficiency and storage, produce glucose and as the metabolic and energetic programming of the immune response, prevent hypoglycaemia. While these features provide selective advantage are also critical components of immunometabolism that were recently in the context of supply limitations, with the removal of these selective reviewed elsewhere2 and will not be covered here. Immunometabolic disease clusters (obesity, diabetes, CVD, cancer, neurodegeneration, asthma) Liver Adipose tissue Pancreas Brain Nutrient-energy stress Hepatocytes Blood vessel β cells Meta ammation Sinusoids Immune cells Adipocyte α cells Neurons Immunometabolic dysfunction Ageing and premature death Figure 1 | Immunometabolic impact on health. Chronic metabolic nutrient availability, and in turn influence the intrinsic metabolic inflammation, metaflammation, in multiple organs is implicated in action within neighbouring cells critical for metabolic homeostasis, metabolic disease. In metabolic organs including the liver, brain, pancreas for example by altering lipid metabolism or inhibiting glucose uptake. and adipose tissue, inflammatory cell action and interactions within These tissues and mediators produced from them also cause systemic the stromal components is an important determinant of maintenance inflammatory responses and disrupt metabolic homeostasis. As a result, of tissue homeostasis as well as metabolic disease pathogenesis. Owing immunometabolic diseases often emerge as clusters and promote ageing, to their proximity, immune cells may sense and react to changes in disability and premature death. 1Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Broad Institute of Harvard and MIT, Boston, Massachusetts 02115, USA. 9 FEBRUARY 2017 | VOL 542 | NATURE | 177 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. RESEARCH REVIEW a Drosophila Mammals Figure 2 | Evolutionary conservation of Adipose immune and metabolic pathway crosstalk. Fat body tissue a, The Drosophila fat body serves to both sense and store nutrients and defend against pathogens; over the course of evolution a similar structure Liver in an ancient mammalian ancestor has given rise to the distinct metabolic and immune organs observed in modern mammals, including adipose Immune tissue and liver. b, Crosstalk between immune and blood and metabolic pathways is remarkably conserved cells from invertebrates to mammals. The principle framework of this relationship is defined by three integrated systems; Eiger (TNF) and its receptor b dlLP Insulin Spatzle Eiger LPS/FA TNF Wengen, dILP (insulin) and its receptors, and the TLR signalling pathways. TNF and TLR signalling block insulin signalling or production through JNK activation and MyD88, from flies to humans, dllnR Insulin receptor TNF and blocking these pathways rescues metabolic Toll Wengen TLR receptor defects, whereas activation results in abnormal IRS IRS metabolic homeostasis. This scheme implies dTRAF TRAF dMyD88 MyD88 JNK that cytokines can act as metabolic hormones nLAR to provide adaptations to nutrient fluctuations; IKK in more complex organisms they become a Dif - Cactus AKT1 AKT JNK JNK IKK liability in the face of chronic nutrient and energy /Basket exposure, such as the case in obesity. A full list of mediators and signaling networks can be found in GSK3 dFoxo GSK3 Foxo Supplemental Figure 1. Glucose Adipogenesis, Glucose Adipogenesis, metabolism lipogenesis dlLP metabolism lipogenesis Insulin I would also like to emphasize here the duration and scale of responses more recent maladaptive state of chronic nutrient and energy surplus as key determinants of outcomes. In the setting of infection, a successful exemplified by obesity (the same is also applicable to TLRs). Using this immune response is strong but often short-lived, resulting in elimination simple and highly preserved framework, it is possible to incorporate many of the pathogen followed by termination of the response, and the organism layers of complexity with numerous mediators, hormones, and signalling lives. If the result is a failure, the organism dies. In this evolutionary frame- systems to explore immunometabolism (Fig. 2). work, there is no host survival advantage to chronic inflammation or to a low-grade response incapable of pathogen elimination. These constraints Immunometabolic integration in invertebrates that govern the outcomes of immune responses are described in a recent The strong link between nutrient sensing and immune signalling is rooted review by R. Medzhitov3. It has also been well-established that inflam- in their common evolutionary origin. In Drosophila, for example, the fat mation is essential for repair, remodelling, and even renewal of tissues, body carries out liver, adipose, and immune functions1,4. The fat body is including those with critical metabolic function. These responses also capable of sensing both infectious and metabolic disturbances, and studies need to be temporally and spatially regulated to maintain homeostasis, of Drosophila have helped to illuminate highly conserved immuno- including metabolic homeostasis, otherwise they will be uniformly metabolic pathways discovered in mammals. Indeed, the fat body is the damaging when sustained. Hence, broad, potent or permanent major producer of Eiger, the Drosophila orthologue of TNF5. Activation interferences targeting immune resolution or activation may have of Wengen (a TNF receptor) or TLR signalling results in inhibition of unintended and adverse consequences for tissue health, and if these insulin action through JNK and MyD88 pathways converging on GSK3 tissues and related functions are critical for metabolic homeostasis, for and Foxo as targets6,7. Studies in humans and mammalian models have the metabolic health of the organism as well. Finally, it is discernible that demonstrated that JNK kinase activity has an important upstream role in such an ancient and critical response will present layers of specificity as integrating inflammatory and metabolic function, and this is conserved in well as redundancy, hence its experimental or therapeutic management Drosophila, where JNK signalling regulates the expression of the lipocalin requires thorough consideration beyond the targeting of individual Nlaz, an orthologue of RBP4, antagonizing expression of Drosophila components. insulin-like peptide (Dilp) and insulin/IGF signalling6,8. As in mammals, These considerations aside, the immunological aspect of metabolic exposure to dietary stress (overfeeding or a high-sugar diet) results in regulation in a multicellular organism could be framed in its most resistance to Dilp action in the fat body downstream of JNK activity9,10. fundamental form by examining a highly conserved relationship between A very recent
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