The use of integrative OMICs to decipher heterogeneous chronic complex disease mechanism: Severe Asthma as a model

We reanalyze publicly available transcriptome and proteome data to identify novel differentially expressed genes and pathways in asthma. We specifically take into account the confounding factors that might interfere with the analysis.  Our approach identifies genes differently expressed in asthmatic structural cells (bronchial epithelium and fibroblasts), circulating immune cells (PBMCs), plasma, and saliva. The genes are related to two interacting pathways (Wnt signaling and cell cycle/proliferation), which can mediate or counteract the effect of each other in healthy versus asthmatic tissue.  Our analysis shows that AREG, a member of the EGFR family, is a putative biomarker for the detection and control of asthma.  It is differentially expressed in structural cells, circulating immune cells, and saliva of asthma samples compared to healthy controls. Its protein levels in plasma and saliva show a promising diagnostic value for severe versus nonsevere asthma.   Mechanistically, we predict that AREG participates in the response of structural cells to microbial stimuli through TLR4, which needs AREG to maintain its expression. Asthmatic fibroblasts respond differently to LPS due to different AREG-TLR4 interactions, different downstream response genes of the AP-1 system, and the noncanonical Wnt pathways. Our results propose that AREG can potentially protect LPS-induced damage by inhibiting the inflammasome marker gene expression, such as IL1β,  in lung and spleen immune cells and particularly natural killer cells. AREG can mediate resistance to apoptosis,  pyroptosis, autophagy, and senescence induction to maintain cell survival and to mediate apoptosis resistance. Asthmatic fibroblasts respond differently to AREG compared to healthy fibroblasts. AREG is deleterious in the former when exposed to TNFα or LPS, indicating their intolerance towards inflammatory mediators of Th1 nature. We further find that Wnt5B upregulation in asthmatic fibroblasts in response to LPS reverses the otherwise beneficial effects of AREG in healthy fibroblasts to be suicidal to asthmatic ones. In summary, our reanalysis and experimental validation have uncovered novel pathways and players in asthmatic tissue, which has a high potential of clinical relevance in understanding how to control asthmatic fibrosis, which is the main culprit for tissue remodeling, severity, and resistance to steroids.