Asthma and Obesity: Two Diseases on the Rise and Bridged by Inflammation

Abstract

Asthma and obesity are two epidemics affecting the developed world. The relationship between obesity and both asthma and severe asthma appears to be weight-dependent, causal, partly genetic, and probably bidirectional. There are two distinct phenotypes: 1. Allergic asthma in children with obesity, which worsens a pre-existing asthma, and 2. An often non allergic, late-onset asthma developing as a consequence of obesity. In obesity, infiltration of adipose tissue by macrophages M1, together with an increased expression of multiple mediators that amplify and propagate inflammation, is considered as the culprit of obesity-related inflammation. Adipose tissue is an important source of adipokines, such as pro-inflammatory leptin, produced in excess in obesity, and adiponectin with anti-inflammatory effects with reduced synthesis. The inflammatory process also involves the synthesis of pro-inflammatory cytokines such as IL-1β, IL-6, TNFα, and TGFβ, which also contribute to asthma pathogenesis. In contrast, asthma pro-inflammatory cytokines such as IL-4, IL-5, IL-13, and IL-33 contribute to maintain the lean state. The resulting regulatory effects of the immunomodulatory pathways underlying both diseases have been hypothesized to be one of the mechanisms by which obesity increases asthma risk and severity. Reduction of weight by diet, exercise, or bariatric surgery reduces inflammatory activity and improves asthma and lung function.

Keywords: asthma; cytokines; inflammation; obesity; phenotype.

Figure 1

Interrelationship between the inflammatory processes that account for the asthma-obesity phenotype. Eosinophilic asthma is triggered by type 2 inflammation where Th2, ILC2, and type 2 cytokines are involved. This could be allergic (when immunoglobulin E (IgE) is present) or non-allergic. Non-eosinophilic asthma (neutrophils are present in the airway lumen) is mediated by type 1 inflammation and Th1, Th17, and ILC3 release type 1 cytokines. Inflammation in obesity is due to the imbalance of adipokines. Leptin stimulates adipocytes to release inflammatory mediators and activates M1 macrophages intracellular multiprotein complex, NLRP3. The activation of NLRP3 in M1 macrophages resident on adipose tissue and in the lungs, resulting in an amplification in IL-1β production, the subsequent ILC3 activation, and IL-17 secretion, which in turn facilitates airway hyperresponsiveness (AHR) in patients. In obesity, pro-inflammatory cytokines such IL-1β, IL-6, and TNFα contribute to asthma pathogenesis. In contrast, cytokines that are pro-inflammatory in asthma such as IL-4, IL-13, and IL-33 contribute to maintain the lean state through the activation of anti-inflammatory M2 macrophages.