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Adaptive Immunity and Metabolic Health: Harmony Becomes Dissonant in Obesity and Aging

Leena P. Bharath, Blanche C. Ip, Barbara S. Nikolajczyk

10.1002/cphy.c160042

Source: Volume 7, Issue 4, October 2017

Published online: September 2017

Full Article on Wiley Online Library



ABSTRACT

Adipose tissue (AT) is the primary energy reservoir organ, and thereby plays a critical role in energy homeostasis and regulation of metabolism. AT expands in response to chronic overnutrition or aging and becomes a major source of inflammation that has marked influence on systemic metabolism. The chronic, sterile inflammation that occurs in the AT during the development of obesity or in aging contributes to onset of devastating diseases such as insulin resistance, diabetes, and cardiovascular pathologies. Numerous studies have shown that inflammation in the visceral AT of humans and animals is a critical trigger for the development of metabolic syndrome. This work underscores the well‐supported conclusion that the inflammatory immune response and metabolic pathways in the AT are tightly interwoven by multiple layers of relatively conserved mechanisms. During the development of diet‐induced obesity or age‐associated adiposity, cells of the innate and the adaptive immune systems infiltrate and proliferate in the AT. Macrophages, which dominate AT‐associated immune cells in mouse models of obesity, but are less dominant in obese people, have been studied extensively. However, cells of the adaptive immune system, including T cells and B cells, contribute significantly to AT inflammation, perhaps more in humans than in mice. Lymphocytes regulate recruitment of innate immune cells into AT, and produce cytokines that influence the helpful‐to‐harmful inflammatory balance that, in turn, regulates organismal metabolism. This review describes inflammation, or more precisely, metabolic inflammation (metaflammation) with an eye toward the AT and the roles lymphocytes play in regulation of systemic metabolism during obesity and aging. © 2017 American Physiological Society. Compr Physiol 7:1307‐1337, 2017.

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Figure 1. Figure 1. Obese AT is a major source of inflammation and metabolic dysregulation. Chronic over nutrition causes the AT to undergo remodeling and expansion to store excess lipids and to protect against obesity‐associated metabolic dysregulation. When AT is overwhelmed due to pathological and excessive accumulation of lipids, it results in chronic inflammation and metabolic pathology. Pathologically obese AT is characterized by: (A) chronic inflammation, as evidenced by an increased number and frequency of immune cells from both the innate and the adaptive systems that results in an elevation of proinflammatory cytokines and an imbalance between a pro‐ and anti‐inflammatory responses, favoring a more proinflammatory environment; (B) Insulin resistance, resulting in decreased glucose intake and insulin sensitivity, and increased peripheral insulin resistance that sets the stage for development of T2D; (C) Adipocyte dysfunction, resulting in an increase in oxidative stress, promoting free radicle‐mediated damage of cellular proteins and organelles, causing ER stress/mitochondrial dysfunction, eventually leading to adipocyte necrosis and fibrosis; (D) Metabolic syndrome, characterized by hypertension, hypercholesterolemia with low HDL and high LDL and triglycerides. Apart from the immune cells that are shown in the image, several other immune cell types, such as neutrophils, NK cells, iNKT cells infiltrate the obese and inflamed AT.
Figure 2. Figure 2. Effect of physiological hyperglycemia on cytokine production by T cells stimulated in the context of PBMCs. PBMCs from 11 subjects (6 healthy, 2 pre‐T2D, 3 T2D) were stimulated with αCD3/αCD28 for 68 h in low glucose (100 mg/dL) or high glucose (200 mg/dL). High glucose modestly but significantly increased IL‐17A (***P< 0.0001) and IFNγ (13 %, P = 0.02) secretion by stimulated PBMCs as compared to low glucose. Average among samples is indicated by bold line in each panel. Power was insufficient for group‐by‐group analysis although response within groups was especially heterogeneous for TNFα and IL‐6.
Figure 3. Figure 3. Immune cell infiltrates promote AT inflammation. The quantity and types of immune cells in AT are influenced by obesity and the associated metabolic dysregulation. Obese AT is characterized by increased numbers and (especially in mice) proportions of macrophages. Macrophages also shift to a proinflammatory phenotype, resulting in the production of cytokines such as IL‐1β, IL‐6, TNFα, and chemokines such as MCP1. Adipocytes, macrophages and other cells of the innate immune system, along with the B cells that infiltrate the obese AT, can act as antigen presenting cells to activate CD4+ and CD8+ T cells. Obese AT has increased Th17 cells, mostly notably in humans, which secrete proinflammatory cytokines such as IL‐17A/F and IL‐21. This is in contrast to lean AT that has relatively high frequencies of regulatory T cells (Tregs) that suppress immune response to maintain homeostasis. Adipocyte cytokines, or adipokines such as leptin, increase in obesity, can promote an imbalance in Th17/Treg and also Th1/Th2 responses. Obese AT has a decline in B regulatory and B1‐a B cells, which results in a decline in anti‐inflammatory cytokine such as IL‐10. An increase in the frequency of MAITs results in increased production of IL‐17A. Similarly, an increase in NK cell proliferation in obese AT promotes IFNγ production and promotes the differentiation and accumulation of inflammatory macrophages.
Figure 4. Figure 4. Aging promotes adipocyte dysfunction. Aging AT is under a state of chronic sterile inflammation, which falls broadly under the term inflammaging. Environment, genetics, and the process of aging itself regulate the development of inflammation in the adipose. Inflammaging results in infiltration of proinflammatory cells such as the cytotoxic T cells (CD8+) and macrophages, along with a decline in T regulatory cells and Th2 responses. Accumulation of toxic metabolites of free fatty acids and the accompanying oxidative stress causes a redox imbalance, resulting in the activation of inflammatory pathways such as the MAPK and IKK leading to the activation of the master inflammatory regulator NF‐κB. The diverse proinflammatory environment, along with the higher proinflammatory cytokines and chemokines promote a stress response, resulting in cell cycle arrest and eventually apoptosis of the adipocyte.


Figure 1. Obese AT is a major source of inflammation and metabolic dysregulation. Chronic over nutrition causes the AT to undergo remodeling and expansion to store excess lipids and to protect against obesity‐associated metabolic dysregulation. When AT is overwhelmed due to pathological and excessive accumulation of lipids, it results in chronic inflammation and metabolic pathology. Pathologically obese AT is characterized by: (A) chronic inflammation, as evidenced by an increased number and frequency of immune cells from both the innate and the adaptive systems that results in an elevation of proinflammatory cytokines and an imbalance between a pro‐ and anti‐inflammatory responses, favoring a more proinflammatory environment; (B) Insulin resistance, resulting in decreased glucose intake and insulin sensitivity, and increased peripheral insulin resistance that sets the stage for development of T2D; (C) Adipocyte dysfunction, resulting in an increase in oxidative stress, promoting free radicle‐mediated damage of cellular proteins and organelles, causing ER stress/mitochondrial dysfunction, eventually leading to adipocyte necrosis and fibrosis; (D) Metabolic syndrome, characterized by hypertension, hypercholesterolemia with low HDL and high LDL and triglycerides. Apart from the immune cells that are shown in the image, several other immune cell types, such as neutrophils, NK cells, iNKT cells infiltrate the obese and inflamed AT.


Figure 2. Effect of physiological hyperglycemia on cytokine production by T cells stimulated in the context of PBMCs. PBMCs from 11 subjects (6 healthy, 2 pre‐T2D, 3 T2D) were stimulated with αCD3/αCD28 for 68 h in low glucose (100 mg/dL) or high glucose (200 mg/dL). High glucose modestly but significantly increased IL‐17A (***P< 0.0001) and IFNγ (13 %, P = 0.02) secretion by stimulated PBMCs as compared to low glucose. Average among samples is indicated by bold line in each panel. Power was insufficient for group‐by‐group analysis although response within groups was especially heterogeneous for TNFα and IL‐6.


Figure 3. Immune cell infiltrates promote AT inflammation. The quantity and types of immune cells in AT are influenced by obesity and the associated metabolic dysregulation. Obese AT is characterized by increased numbers and (especially in mice) proportions of macrophages. Macrophages also shift to a proinflammatory phenotype, resulting in the production of cytokines such as IL‐1β, IL‐6, TNFα, and chemokines such as MCP1. Adipocytes, macrophages and other cells of the innate immune system, along with the B cells that infiltrate the obese AT, can act as antigen presenting cells to activate CD4+ and CD8+ T cells. Obese AT has increased Th17 cells, mostly notably in humans, which secrete proinflammatory cytokines such as IL‐17A/F and IL‐21. This is in contrast to lean AT that has relatively high frequencies of regulatory T cells (Tregs) that suppress immune response to maintain homeostasis. Adipocyte cytokines, or adipokines such as leptin, increase in obesity, can promote an imbalance in Th17/Treg and also Th1/Th2 responses. Obese AT has a decline in B regulatory and B1‐a B cells, which results in a decline in anti‐inflammatory cytokine such as IL‐10. An increase in the frequency of MAITs results in increased production of IL‐17A. Similarly, an increase in NK cell proliferation in obese AT promotes IFNγ production and promotes the differentiation and accumulation of inflammatory macrophages.


Figure 4. Aging promotes adipocyte dysfunction. Aging AT is under a state of chronic sterile inflammation, which falls broadly under the term inflammaging. Environment, genetics, and the process of aging itself regulate the development of inflammation in the adipose. Inflammaging results in infiltration of proinflammatory cells such as the cytotoxic T cells (CD8+) and macrophages, along with a decline in T regulatory cells and Th2 responses. Accumulation of toxic metabolites of free fatty acids and the accompanying oxidative stress causes a redox imbalance, resulting in the activation of inflammatory pathways such as the MAPK and IKK leading to the activation of the master inflammatory regulator NF‐κB. The diverse proinflammatory environment, along with the higher proinflammatory cytokines and chemokines promote a stress response, resulting in cell cycle arrest and eventually apoptosis of the adipocyte.
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Teaching Material

L. P. Bharath, B. C. Ip, B. S. Nikolajczyk. Adaptive Immunity and Metabolic Health: Harmony Becomes Dissonant in Obesity and Aging. Compr Physiol 7: 2017, 1307-1337.

Didactic Synopsis

The information in this article will help teach the following important points

  • Adipose tissue (AT) is both an immunological and metabolic organ, in addition to its well-known role as a storage organ.
  • Safe storage of lipids in AT is important to prevent free fatty acid-mediated immunological and metabolic dysregulation.
  • Lymphocytes (T and B cells among others) contribute significantly to the development of obesity- and aging-associated immune and metabolic dysregulation.
  • Obesity causes an imbalance in T cells and T cell responses in the AT causing increased Th1s and Th17s compared to Treg and Th2 responses.
  • Nutrients in general and fatty acids in particular (saturated vs. unsaturated fatty acids) can skew the AT immune responses, either to a pro- or anti-inflammatory phenotype.
  • “Inflammaging” and effects of menopause may in part account for age-associated metabolic declines and confound the associated shift in AT distribution in the elderly.
  • This review will provide an overview of the crosstalk between the adaptive immune system and metabolism in the context of obesity and aging.

Didactic Legends

The figures–in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. This figure illustrates the pathological changes that occur in the adipose tissue (AT) during the development of obesity

Teaching points:

  • The obese AT has increased presence of immune system cells that contrasts with lean AT.
  • The cells that infiltrate the AT and are shown in the figure include the T and B cells from the lymphoid lineage and the macrophages from the myeloid lineage.
  • Brief descriptions of the lineages of the immune cells, can be introduced here.
  • Apart from the cells mentioned in the image, there are other cells such as the neutrophils, NK cells, iNKT cells and dendritic cells that have altered frequencies and impact inflammation in obese AT.
  • Consequences of pro-inflammatory immune cell infiltration include elevated cytokines and a balance shift in Th1/Th2 responses and Th17/Treg ratio.
  • The subsets of T cells and the T cell responses can be introduced here.
  • Obese AT is also characterized by decreased glucose uptake and insulin sensitivity. Impaired insulin sensitivity eventually leads to the development of diabetes.
  • Pathological accumulation of lipids in the AT promotes oxidant stress, causing high intracellular levels of superoxide and hydrogen peroxide that can damage proteins by interfering with post-translational modifications. Increased oxidant stress can also affect organelles such as the endoplasmic reticulum and the mitochondria, causing a stress response, eventually leading to adipocyte necrosis and fibrosis of the AT.
  • AT dysfunction promotes hypercholesterolemia with high LDL and triglycerides and low levels of HDL, which will support the development of metabolic syndrome.

Figure 2.This figure illustrates the production of cytokines by PBMCs in response to treatment with normal and physiologically high levels of glucose.

Teaching points:

  • Elevated levels of glucose may result in increased production of pro inflammatory cytokines.
  • Pro-inflammatory cytokines are those that promote inflammation. Some examples of pro-inflammatory cytokines are IL-17A, IFNγ and TNFa.
  • Anti-inflammatory cytokines are opposing in action to the pro-inflammatory cytokines and they can ameliorate or prevent inflammation. Some examples of anti-inflammatory cytokines are IL-4, IL-10 and IL-13.
  • Some cytokines are pleiotrophic meaning they can be either pro- or anti-inflammatory and can play different roles in different cell types or under different stimulus. An example of a pleiotrophic cytokine is IL-6
  • High blood glucose concentrations have been shown to increase T cell chemokine expression and also alter the ability of B cells to produce antibodies.
  • When PBMCs were treated with physiologically high levels of glucose and stimulated with T cell-targeted stimuli, an increase in production of T cell cytokines IL-17A and IFN γ was observed in comparison to low glucose conditions.
  • No increase in classical diabetogenic cytokines such TNFα and IL-6 was observed in T cell-stimulated PBMCs from T2D versus the ND subjects.
  • A stimulus from excess glucose alone in the circulation can promote inflammation.

Figure 3. This figure illustrates the immunological events that occur within an obese AT

Teaching points:

  • An obese AT is a ripe environment for infiltration of proinflammatory cells.
  • Multiple types of adaptive immune cells (T cells, B cells, iNKTs etc.) and cells of the innate immune system, such as macrophages, increase in the obese AT. Since this review is on adaptive immune system, the cells of the innate immune system are not addressed in detail.
  • The AT adipocytes, B cells and macrophages can present antigens to the T cells and activate both CD4+ and CD8+ T cells. The MHC II (HLA for human) houses antigenic peptides in a groove that physically interacts with T cell receptors on the CD4+ T cells and the MHC I/peptide combiantion interacts with the receptors on the CD8+ T cells. These interactions lead to activation of T cells.
  • The activated T cells and macrophages produce cytokines that are either pro-inflammatory, anti-inflammatory or plieotropic,depending on the stimulus. In obese AT, the stimulus is pro-inflammatory and hence cytokines, such as the IL-6, IL-1b, TNFα and chemokines such as MCP1 are produced. The B cells produce the antibodies in response to antigens, the identity of which is currently unknown.
  • Th17 pro-inflammatory response also occur in the obese AT in people (but significantly less so in mice), resulting in the production of cytokines such as IL-17A/F, IL-21 and IL-22.
  • The pro-inflammatory responses, including inflammation from Th17s, are checked by Tregs (also known as suppressor T cells).
  • In obese AT, a decline in Tregs occur, resulting in exaggerated inflammatory responses. The presence of adipokines such as leptin downregulates Tregs and supports pro-inflammatory Th1s, thereby contributing to development of inflammation.

Figure 4. This figure illustrates that the aging AT is under a chronic inflammatory stimulus, which would eventually result in the development of adipocyte dysfunction.

Teaching points:

  • Inflammaging occurs systemically and in the AT due to environmental factors such as nutrient excess, exposure to environmental pollutants, and genetics of the individual. Aging-associated changes also occur at the cellular and molecular levels.
  • The primary changes that occur in aging ATare activation of inflammation, accumulation of toxic lipid metabolites, activation of pro-inflammatory pathways along with the development of oxidant stress.
  • The organelles in the aging AT such as the endoplasmic reticulum and mitochondria undergo a stress response due to accumulation of oxidants such as superoxide and hydrogen peroxide.
  • The dysfunctional adipocyte undergoes cell cycle arrest and eventually necrosis.


Related Articles:

Diabetes and Obesity
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Article Title: Adaptive Immunity and Metabolic Health: Harmony Becomes Dissonant in Obesity and Aging
 

How to Cite

Leena P. Bharath, Blanche C. Ip, Barbara S. Nikolajczyk. Adaptive Immunity and Metabolic Health: Harmony Becomes Dissonant in Obesity and Aging. Compr Physiol 2017, 7: 1307-1337. doi: 10.1002/cphy.c160042