Obesity is a chronic metabolic disorder which affects around 600 million adults and 42 million children worldwide. Most of the world’s population live in countries where being overweight or obese is linked to higher levels of complications and deaths than being underweight. Obesity is defined as abnormal or excessive fat (adipose) accumulation that may impair health and increase risk of conditions such as cardiovascular disease, diabetes, some cancers, and musculoskeletal disorders. The underlying mechanisms of obesity are complex, involving genetic, lifestyle, socioeconomic, psychological, and environmental factors.
A growing body of evidence suggests that obesity also increases the risk of developing asthma and having severe asthma attacks. Furthermore, previous research has suggested that patients with obesity and asthma have higher healthcare costs compared to non-obese patients. There are several mechanisms that may explain obesity-induced or obesity-exacerbated asthma, such as excess weight around the chest and abdomen, changes in respiratory function, or chronic airway inflammation.
A high-fat diet can be a major contributor to obesity in humans, and previous animal studies have shown that a high-fat diet can modify immune responses in the lung and contribute to airway inflammation resulting from inhaled aeroallergens. A high-fat diet can promote chronic, low-grade inflammation through various mechanisms, including the gut microbiome and circulating inflammatory markers. Previous studies have pointed to an important function of adipose tissue and associated adipocytes cells for storing excess energy in the form of fat as well as locally producing pro-inflammatory mediators.
Dr Amarjit Mishra, Assistant Professor at Auburn University, USA, aims to understand more about the regulatory pathways involved in airway inflammation. The Laboratory of Lung Inflammation, led by Dr Mishra, is also interested in metabolic cues that co-ordinate immune cell activation and differentiation. In particular, their research focuses on how allergen-mediated signals and co-opt metabolic signalling pathways coordinate immune cell responses. Learning more about the link between obesity, inflammation, and asthma is important for developing novel therapeutic treatments to prevent and treat asthma in people with obesity.
Exploring the effects of a high-fat diet
Whereas most previous studies have focused on adipose tissue, fewer studies have explored obesity-associated dysregulation in the lungs and other extrapulmonary tissue sites. In the lung, one immune cell of interest is the dendritic cell. Dendritic cells are part of a group of cells known as antigen presenting cells. They present a small part of a dangerous object, such as inhaled allergens, to other immune cells which will then mount the correct immune response against the potential threat. Airway, or lung, dendritic cells appear to have a short lifespan, suggesting that they are continuously replaced by haemopoietic stem cells – cells which reside in the bone marrow and are essential for the formation of new blood cells. Previous studies have shown that obesity is associated with changes to the haemopoietic cell population, but less is known about the impact of obesity on dendritic cell progenitors and their ability to promote airway inflammation.
Dr Mishra provided mice with either a high-fat diet, where 60% of the calories were derived from fat, or a low-fat diet, with 10% of calories from fat. The mice were also given an extract containing house dust mite, a common aeroallergen which often triggers asthma symptoms and episodes. This was injected during the sensitisation phase but given as an inhaled dose during the challenge phase. At the end of the experimental phase, cells were obtained from the mice and analysed to investigate the types and quantities of cells present in the lung.
The study utilised several different assays to characterise the cell populations, including flow cytometry, which measures physical and chemical characteristics of cells, and gene analysis.
Immune cells and inflammation
Dr Mishra was able to show that more immune cells were recruited to the lungs of mice fed a high-fat diet compared to those on a low-fat diet.
The researchers also identified changes in the cells that go on to differentiate into dendritic cells. These changes included increased proliferation and differentiation of these progenitor cells in response to inhaled allergens (house dust mite). The changes in the proliferation capacity of dendritic cell progenitors were reflected in changes in the cell proliferation cycle, where there was a decrease in the quiescent phase compared to the active phase.
Markers of stress, such as p38 MAPK (mitogen-activated protein kinase), were also assessed. The results showed a significantly increased level of reactive oxygen species (highly reactive chemicals formed by unstable oxygen molecules) in progenitors of dendritic cells from mice fed a high-fat diet. As these reactive oxygen species can activate pathways involving p38 MAPK, this suggests that tight control of p38 MAPK is important during times of stress, such as obesity.
Next, the researchers wanted to explore the functional consequences of changes in dendritic cells and their progenitors. They found that there was an increase in the number of inflammatory cells in the lungs in mice fed a high-fat diet, compared to those fed a low-fat diet. Dr Mishra and colleagues suggest that obesity exacerbates house dust mite-induced allergic responses and triggers immune responses in the lungs.
They also found increased expression of an enzyme called A Disintegrin And Metalloproteinase enzyme (ADAM17). ADAM17 is able to facilitate changes in molecules shown to be involved in a range of cancer and inflammatory conditions. The enzyme is a key regulator of p38 MAPK and is required for the proliferation of dendritic progenitor cells in obesity. Therefore, inhibiting the action of ADAM17 may help to reduce the inflammatory responses in asthma associated with obesity.
Indeed, mice without ADAM17 that are fed a high-fat diet appear to be protected from obesity-related complications, such as insulin resistance, diabetes, and non-alcoholic fatty liver disease. Other studies have also suggested a pivotal role of ADAM17 in energy homeostasis.
Dr Mishra concludes that these metabolic changes are associated with molecular events such as activation of p38 MAPK and ADAM17 in the dendritic cell-specific progenitor cells accelerating airway inflammation. These molecular events are tightly coupled with lung recruitment of immune cells and allergen-induced asthma in obesity.
Underlying mechanisms of asthma
Diet-induced obesity can modify immune responses in the lung and influence the severity of airway inflammation. While some underlying mechanisms have been explored, the involvement of dendritic cells remains poorly understood. Dr Mishra’s work has established that allergic airway inflammation in obesity leads to changes in haematopoiesis and generation of proinflammatory lung dendritic cells and has shown a mechanistic link between dendritic cell progenitors and exacerbation of allergic asthma in obesity involving the ADAM17-p38 MAPK pathway.
ADAM17 up-regulation in obesity affects DC-restricted progenitors. (A) Histogram and (B) representative FACS plots showing basal and PMA-stimulated levels of phosphorylated p38 and (C) mean percentages of EdU (5-ethynyl-2′-deoxyuridine) showing proliferation of CDPs treated with selective ADAM17 inhibitor. BM hematopoietic stem cells were isolated from HFD mice and cultured overnight in presence of ADAM17 inhibitor TMI 1 (50 μM). Phosphorylation and proliferation analyses showing on gated LSK+ CD115+ Flt3+ cells. (D) qRT-PCR analyses for S-G2/M-cyclins (B2, G1, and F) gene expression in cultured cells isolated from HFD mice. Data expressed as mean ± s.e.m. n = 4. Student’s t-test *P < 0.05. (E) Schematic representation of proposed ADAM17-p38 MAPK signaling in DC-restricted progenitors in obesity-associated airway inflammation.
Increased proliferation of haemopoietic stem cells and reactive oxygen species are hallmarks of obesity-related changes. High levels of oxidative stress in obesity can lead to changes in dendritic cell populations and Dr Mishra was able to show that oxidative stress and p38 MAPK activation in obesity correlates with proliferation of dendritic cell progenitors. A high-fat diet can affect the bone marrow microenvironment, and subsequently the dynamics of stem and progenitor cell populations. This may also be influenced by changes in adipose tissues, but further research is required to learn more about this relationship.
Despite a growing understanding of the chronic nature of obesity, there is still a lack of specific anti-inflammatory therapies. Dendritic cell metabolism is interlinked with immune pathways and metabolic signalling. Therefore, given the role that dendritic cells play in promoting inflammation and their rapid turnover in lung tissue, dendritic cells in the lung may provide a promising target for the prevention and management of obesity-related asthma and other airway diseases.
- Mishra, A. (2017). Metabolic Plasticity in Dendritic Cell Responses: Implications in Allergic Asthma. Journal of immunology research, 5134760. Available at: https://doi.org/10.1155/2017/5134760
- Jaiswal, A. K. et al. (2020). Dendritic Cell-Restricted Progenitors Contribute to Obesity-Associated Airway Inflammation via Adam17-p38 MAPK-Dependent Pathway. Frontiers in immunology, 11, 363. Available at: https://doi.org/10.3389/fimmu.2020.00363
- Jaiswal, A. K. et al. (2020). Pyruvate kinase M2 in lung APCs regulates Alternaria-induced airway inflammation. Immunobiology, 225 (4): 151956. Available at: https://doi.org/10.1016/j.imbio.2020.151956
- Mishra, A. et al. (2021). Mitochondrial Metabolite Itaconate is a Crucial Determinant of Dendritic Cells Immune-Priming Function(s) and Contribute to Resolute Allergen-Induced Airway Inflammation. American Journal of Respiratory and Critical Care Medicine, 203, A1400.
Dr Mishra’s research interest has focused on understanding metabolic reprogramming of immune cells and the effects of obesity and metabolism on lung disease to develop novel treatments specifically targeting this disease.
National Institutes of Health, National Heart, Lung, and Blood Institute
Dr Stewart J. Levine, Laboratory of Asthma and Lung inflammation, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
Dr Mishra is an Assistant Professor at the Pathobiology Department, College of Veterinary Medicine, Auburn University, USA. His research is focused on molecular regulatory modules associated with obesity-induced airway inflammation in asthma exacerbation. He translates observations into novel treatments, drugs, and therapeutics strategies.
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