Inflammatory Dysregulation, Asthma, and Obesity in Children: What is the Relationship?

Pediatric obesity is one of the foremost global chronic medical conditions. It affects almost every organ system via mechanisms that tend to be organ-specific. Obesity-related asthma is one such pediatric comorbidity that is rising in incidence such that obesity is now considered the foremost modifiable risk factor for asthma. Immune dysregulation of both innate and adaptive responses is one of the best understood pathobiologic mechanisms underlying obesity-related asthma. From the perspective of innate immune dysregulation, there are higher proportions of pro-inflammatory M1 macrophages in systemic circulation and in the airway in pediatric studies; the underlying mechanisms are only studied among adults wherein airway M1 macrophages impaired efferocytosis and induced neutrophil recruitment in the airway. From the perspective of adaptive immune responses, there are higher proportion of T helper 1 cells that are associated with lower lung function supporting the non-allergic phenotype of pediatric obesity-related asthma. There is also substantial new literature from bulk and single cell transcriptomic T cell analyses that have identified novel pathways and distinct differentiation of Th cells in obese children as compared to healthy-weight children with asthma. CDC42 pathway is one such pathway that is upregulated in Th cells from obese children with asthma and is associated with Th cell chemotaxis and adhesion to airway smooth muscle (ASM), activating pathways that promote ASM contractility and proliferation. There is also increased recognition of the role of neutrophils, as compared to eosinophils, in pediatric obesity-related asthma but the mechanistic pathways that are functional relevance in disease phenotype have not yet been investigated. Finally, obesity-mediated metabolic abnormalities, including insulin resistance and dyslipidemia, have been epidemiologically linked with pediatric asthma but their underlying mechanisms are not known. In summary, there have been several strides in understanding the immune pathobiology of pediatric obesity-related asthma which have firmly established it as a distinct asthma phenotype, which have highlighted the need for further scientific investigation of mechanisms that underlie the contribution of immunometabolism.