Metabolism of Epithelial Cells in Health and Allergic Disease: Collegium Internationale Allergologicum Update 2021

Abstract

Concomitant dramatic increase in prevalence of allergic and metabolic diseases is part of a modern epidemic afflicting technologically advanced societies. While clinical evidence points to clear associations between various metabolic factors and atopic disease, there is still a very limited understanding of the mechanisms that link the two. Dysregulation of central metabolism in metabolic syndrome, obesity, diabetes, and dyslipidemia has a systemic impact on multiple tissues and organs, including cells of the epithelial barrier. While much of epithelial research in allergy has focused on the immune-driven processes, a growing number of recent studies have begun to elucidate the role of metabolic components of disease. This review will revisit clinical evidence for the relationship between metabolic and allergic diseases, as well as discuss potential mechanisms driving metabolic dysfunction of the epithelial barrier. Among them, novel studies highlight links between dysregulation of the insulin pathway, glucose metabolism, and loss of epithelial differentiation in asthma. Studies of mitochondrial structure and bioenergetics in lean and obese asthmatic phenotypes recently came to light to provide a novel framework linking changes in tricarboxylic acid cycle and oxidative phosphorylation with arginine metabolism and nitric oxide bioavailability. New research established connections between arachidonate metabolism, autophagy, and airway disease, as well as systemic dyslipidemia in atopic dermatitis and ceramide changes in the epidermis. Taken together, studies of metabolism have a great potential to open doors to a new class of therapeutic strategies, better characterization of disease endotypes, as well as enable a systems biology approach to mechanisms of allergic disease.

Metabolic Reprogramming of Nasal Airway Epithelial Cells Following Infant Respiratory Syncytial Virus Infection

“…Earlylife exposures, such as viral infections and other environmental factors, may modify an individual's susceptibility and are likely to be more informative in our understanding of the underlying mechanisms of asthma development as well as provide targets for disease prevention. Host metabolism is sensitive to changes in diet, environment, or microbiome and represents one of the least understood early-life factors that may contribute to aberrant development of the epithelial barrier or immune skewing associated with the development of asthma [13,28]. During viral infections, infected cells need to produce high amounts of energy to support active virus replication.…”

“…The modification of host airway epithelial cellular metabolism by early-life exposures is one such overlooked factor despite the central importance of metabolism in regulating development and function of the epithelial barrier [12,13]. Several studies have documented that human RSV infection in vivo and bronchiolitis are accompanied by systemic changes in metabolism [14][15][16][17][18].…”

Cellular and systemic energy metabolic dysregulation in asthma development—a hypothesis-generating approach

“…11 At the cellular level, the following assertions remain to be tested in newborns developing wheeze: (1) dysregulated glucose metabolism is accompanied by changes in insulin signaling pathway; (2) there are defects in insulin-dependent glucose transport mechanisms into epithelial cells; and (3) levels of glucose uptake are sufficient, but the glucose is utilized in anabolic rather than catabolic reactions, which is a feature of the epithelium of adults with asthma. 3 Moreover, whether such metabolic defects persist later in life or are sensitive to hormonal changes around puberty remains to be determined.…”

“…21,22 We have previously shown that dysregulation of insulin signaling is specific to type 2 high inflammation. 3 Intriguingly, it is well documented that the type 2 cytokines IL-4 and IL-13 signal through insulin receptor substrates, IRS1 and IRS2, for activation of PI3K and other downstream pathways, which warrants investigation of the cross talk between insulin and allergic inflammation. 3,23 Our study has many strengths, including assessment of both intracellular and systemic energy metabolism and the effect of early-life metabolism on longitudinal respiratory outcomes.…”

“…2 This was overrepresented by the downregulation of the insulin target genes INSR and IRS2, decrease in expression of pyruvate metabolism markers, and changes in mitochondrial respiratory chain genes. 2,3 Consequently, perturbation of epithelial cell metabolism in infancy may have a lasting effect on the differentiation of AEC via alteration of fundamental developmental AEC differentiation programs and/or epigenetic reprogramming. 4 Such perturbation of lung development has the potential to result in lasting epithelial barrier dysfunction that may render the airway more susceptible to allergic sensitization.…”