Trends in Molecular Medicine
ReviewChronic adipose tissue inflammation: all immune cells on the stage
Section snippets
Metabolism and inflammation
Chronic, low-grade inflammation in metabolic syndromes is known as metainflammation (Box 1) and it is different from acute inflammation both in kinetics of recruitment and residence time of immune cells [1]. In normal physiology, rapid changes in metabolic pathways are vital for acute inflammatory response. The best example for this is observed in sepsis patients who have a strong systemic inflammatory response leading to tissue necrosis, cardiac dysfunction, and death. These patients have very
Adipose tissue resident immune cells
Adipose tissue is an endocrine organ exemplified by the fact that many adipokines, cytokines, and chemokines are released in the circulation from adipose tissue. There are different types of fat tissues in the body including subcutaneous (under the skin) and visceral (around the internal organs) adipose tissues that differ in terms of structure, function, and cellular composition [10]. Although subcutaneous fat might be beneficial for insulin sensitivity [11], accumulation of fat in visceral
Macrophages
Macrophages are tissue resident phagocytes and along with their sentinel role in innate immunity they fulfill many important homeostatic functions, such as clearing cellular debris, regulating angiogenesis, and remodeling extracellular matrix (ECM) in several tissues [13]. During cold stress, for example, they regulate gene expression in brown and white adipose tissue through secretion of catecholamines to regulate overall body temperature [14].
Macrophages are the most abundant immune cell type
Dendritic cells
Dendritic cells (DCs) are professional antigen presenting cells, they recognize foreign antigens, take up and process them, and present the antigenic peptides on major histocompatibility complex (MHC) molecules on their surface to initiate its recognition by T cells [34]. Because T cells are an essential part of adipose immunity, and expansion of specific T cell subtypes is observed in adipose tissue, the relative abundance and function of DCs are important to determine in adipose tissue. There
Mast cells
Mast cells are the first line responders against invading pathogens because of their close proximity to the external environment, particularly in skin and mucosa, and because they possess rapid degranulation ability. Mast cells of different numbers, phenotypes, and activation status are present in virtually all tissues [36]. Mast cell specific tryptase staining has documented their presence in human and mouse white adipose tissue (WAT) [37]. Although not as abundant as macrophages, their
Neutrophils
Neutrophils are the most abundant white blood cells in the immune system, which are short-lived, dormant cells in the blood [39]. Owing to their rapid recruitment to peripheral tissues upon infection, they are the primary effector cells in acute inflammation. The role of neutrophils in adipose tissue inflammation, however, has only recently been examined. Plasma levels of myeloperoxidase and calprotectin (mainly secreted by neutrophils) were found to be increased in obese human patients
Eosinophils
Eosinophils are a type of granulocytes that combat parasitic infections and mediate allergic response, but their precise roles in many other physiological contexts are poorly defined [43]. Recently, their role in obesity-induced adipose tissue inflammation has been investigated. They were found to be present in different adipose tissues, especially in metabolically active perigonadal and mesenteric depots [16]. Interestingly, total numbers of eosinophils are decreased in DIO and genetically
B cells
B cells are actively involved in both innate and adaptive immunity. They are unique immune cells in that they can express certain TLRs for pathogen-associated pattern recognition and act as antigen presenting cells via MHC-1 and MHC-2 molecules, as well as secreting antigen specific antibodies important for humoral immunity [44]. Importantly, total numbers of B cells in VAT are elevated during diet-induced obesity [45]. Interestingly, the ratio of class-switched IgG+ B cells in VAT and the
T cells
T cells are thymus-derived lymphocytes and are major players in adaptive immunity. They shift from naïve states to several effectors during an immune response [46]. The two main subsets of T cells, CD4+ and CD8+ cells, express pro- and anti-inflammatory cytokines including IFN-γ (Th1 subtype), IL-4, IL-5, and IL-13 (Th2 subtype), IL-17, IL-21, and IL-22 (Th17 subtype), IL-10, and transforming growth factor-β (TGF-β) (Treg subtype).
Studies in obese humans show increased IFN-γ production by Th1
Hematopoietic stem and progenitor cells
Hematopoietic stem cells are self-renewing, multipotent cells that produce and replenish all blood cell types [76]. Bone marrow is the site where hematopoietic stem and progenitor cells (HSPCs) mainly reside in the body. Adipose tissue has many characteristic features resembling bone marrow, such as the presence of stromal cells with a capacity to differentiate to many different cell types, and a hypoxic environment that is important for hematopoietic stem cell niches. Although it was known
Insulin signaling and resistance through inflammatory cytokines
Insulin is produced by pancreatic β cells and bind to the insulin receptor on target cells. Downstream activation of several pathways (see Figure I in Box 2) leads to many outcomes such as increased glucose uptake, inhibition of gluconeogenesis, increased lipid synthesis, and decreased lipolysis. There are several mechanisms of inflammation-associated insulin resistance (Box 3). For example, activation of kinases IKK2 and JNK leads to (inhibitory) serine phosphorylation of IRS1 and IRS2 and
Anti-inflammatory therapies
Different forms of anti-inflammatory approaches have been tested to improve insulin sensitivity and novel anti-inflammatory drugs and antibodies are still being developed for clinical trials. Although some trials with anti-inflammatory agents showed efficacy for improved glucose levels, many of them lack the desired improvement in insulin sensitivity; therefore, there is still a need to develop effective, tolerable, and target specific approaches. Below some tested options have been listed.
Salicylates
Salicylates have been used for reducing pain and inflammation for many years. Aspirin is an acetyl derivative of salicylic acid and mainly blocks the enzymes cyclooxygenase 1 (COX1) and COX2 that produce prostaglandins and thromboxanes, and when used at higher doses it inhibits IKK2 86, 87. High dose administration of salicylates improves insulin sensitivity in obese mice [88]. Treatment with salsalate, the nonacetylated form of salicylate, was shown to lower glycated hemoglobin (HbA1c) (a
Blockade of IL-1β and TNF-α
Blockade of proinflammatory cytokines is a promising approach to treat several inflammatory diseases such as rheumatoid arthritis and psoriasis. The same approach is also being tested for insulin resistance. IL-1β is secreted from cells after caspase 1-dependent inflammasome activation and it is highly proinflammatory. Anakinra is a recombinant human IL-1Ra used to block IL-1. Anakinra treatment has resulted in reduced inflammation and improved insulin production from pancreatic β cells,
Exercise
Probably the cheapest anti-inflammatory therapy is regular exercise. It has been known for many years that exercise has beneficial effects for health and accumulating evidence suggests that it has anti-inflammatory actions through several mechanisms. It reduces visceral fat mass, inhibits macrophage infiltration to adipose tissue, downregulates TLR expression, and increases circulating Treg cell levels, among many other functions [93]. Changing lifestyles with more physical activity was shown
Bariatric surgery
Bariatric surgery provides robust and rapid improvements in insulin sensitivity and has anti-inflammatory effects, although the molecular mechanisms are elusive [95]. Particularly for morbid obesity cases, it seems to be the best therapy available [96].
Other approaches such as use of statins and glucocorticoids as anti-inflammatory therapies for insulin resistance are still not very effective in improving insulin sensitivity [97]. Resolvins, TLR inhibitors, histone deacetylase (HDAC)
Controversies, open questions, and future perspectives
One important point to make is the unknown interrelationship between different inflammatory pathways and their activation in different tissues and genetic backgrounds during obesity (Box 4). For example, both nuclear factor-κB (NF-κB) and NLRP3 inflammasome activation have been known to occur in obesity and insulin resistance. Although shutting down NF-κB activity through blocking IKK2 was suggested to treat insulin resistance, NF-κB was also shown to negatively regulate IL-1β secretion that is
Concluding remarks
It is conceivable that insulin resistance does not have one concrete mechanism to explain and there might be various instigators. Although difficult to define exactly, changing lifestyles with excess food intake, lipid-rich diets, and concomitant expansion of adipose tissue are considered to be the prime danger signals for the initiation of insulin resistance. By contrast, activation of inflammatory pathways has been observed in all insulin target tissues (adipose, liver, muscle, pancreas, and
Acknowledgments
We would like to thank Mark Febbraio for critical discussion.
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