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Asthma and obesity are non-communicable diseases with high and increasing prevalences. Both are characterized by the presence of local and systemic inflammatory processes, whereby their mutual pathomechanistic relationship within obesity-associated asthma are not fully elucidated. This research work hypothesized that inflammatory mechanisms in obese adipose tissue modify the inflammatory phenotype of an induced allergic airway inflammation (AAI) and that altered activation processes in CD4+ T cells are crucially involved. To test this hypothesis, BALB/c and C57BL/6 mice were fed for several weeks with a high-fat diet (HFD) in order to induce obesity-like metabolic changes and a mixed inflammatory phenotype of AAI was induced in the animals by exposure to house dust mite (HDM) extracts. In both strains, HFD resulted in comparable metabolic changes, such as higher plasma levels of a variety of metabolic parameters and features of type 2 diabetes. However, strain-dependent differences were observed with regard to excessive weight gain, which occurred only in C57BL/6 mice, but not in BALB/c mice. Weight gain in HFD-fed C57BL/6 mice was associated with pronounced adipocyte hypertrophy and increased inflammatory processes in the obese adipose tissue. As intended, HDM-exposure of control diet (ND)-fed mice resulted in a mixed inflammatory phenotype characterized by an influx of eosinophils and neutrophils in the bronchoalveolar lavage (BAL) and in lung tissue in both mouse strains. While per se no differences in the induced AAI between the HFD/HDM group and the ND/HDM group were detected in BALB/c mice, a more eosinophilic inflammation was observed in HFD-fed HDM-exposed C57BL/6 mice in comparison to their lean counterparts. Further investigations revealed increased levels of inflammatory cytokines in the BAL and higher numbers of inflammatory immune cells in the lung tissue of HFD/HDM C57BL/6 mice. This suggested that weight gain and associated inflammatory processes in obese adipose tissue are crucial for modifying characteristic features of the induced AAI. Single cell analysis of CD45+ lung cells was conducted to further analyze the cellular and molecular changes of the induced inflammatory phenotype in the airways of C57BL/6 mice. Interestingly, a CD4+ T cell subcluster was identified to be exclusively present in the lungs of lean, but not in obese HDM-exposed mice. In this subcluster, expression of markers associated with typical characteristics of Th2, Th1, and Treg cells and in addition, co-inhibitory receptors such as PD-1, CTLA-4, and LAG-3 was detected. Subsequent flow cytometric analyses confirmed the presence of Th2 and Treg cells expressing the coinhibitory receptors identified in lungs of HDM-exposed mice. To further investigate whether hypertrophic activated adipocytes release factors that might be involved in the regulation of co-inhibitory receptor expression of CD4+ T cells, supernatants from in vitro cultured adipocytes of HFD-fed mice were applied to differentiated Th2 and Treg cells. In line with the previous results, during the activation process lower numbers of Th2 cells were observed expressing CTLA-4 or LAG-3, while in Treg cells a reduction of CTLA-4+ cells was seen in response to the adipocyte supernatant. Overall, HFD changes the inflammatory phenotype of a HDM-induced AAI only in association with weight gain and related inflammatory processes in the obese adipose tissue. Further, the expression of co-inhibitory receptors PD-1, CTLA-4, and LAG-3 on CD4+ T cells, which may represent a putative disease-limiting mechanism, was observed in response to the induction of AAI only in lean mice. However, the absence of CD4+ T cells expressing such receptors might in turn underlie altered and potentially aggravated and/or prolonged inflammatory processes in obese HDM-exposed mice. By demonstrating obesity-mediated alterations of the AAI phenotype and the identification of putative immune mechanisms behind this observation, these findings provide significant deeper insights into the specific pathophysiology of obesity-associated asthma with implications for the development of stratified therapy concepts for this disease condition.

Asthma is a chronic inflammatory disease of the respiratory tract characterized by recurrent breathing problems resulting from airway obstruction and hyperresponsiveness. Human airway epithelium plays an important role in the initiation and control of the immune responses to different types of environmental factors contributing to asthma pathogenesis. Using pattern recognition receptors airway epithelium senses external stimuli, such as allergens, microbes, or pollutants, and subsequently secretes endogenous danger signaling molecules alarming and activating dendritic cells. Hence, airway epithelial cells not only mediate innate immune responses but also bridge them with adaptive immune responses involving T and B cells that play a crucial role in the pathogenesis of asthma. The effects of environmental factors on the development of asthma are mediated, at least in part, by epigenetic mechanisms. Those comprise classical epigenetics including DNA methylation and histone modifications affecting transcription, as well as microRNAs influencing translation. The common feature of such mechanisms is that they regulate gene expression without affecting the nucleotide sequence of the genomic DNA. Epigenetic mechanisms play a pivotal role in the regulation of different cell populations involved in asthma pathogenesis, with the remarkable example of T cells. Recently, however, there is increasing evidence that epigenetic mechanisms are also crucial for the regulation of airway epithelial cells, especially in the context of epigenetic transfer of environmental effects contributing to asthma pathogenesis. In this review, we summarize the accumulating evidence for this very important aspect of airway epithelial cell pathobiology.