S100 A alarmins and Thymic stromal lymphopoietin (TSLP) regulation in severe asthma following bronchial thermoplasty

Abstract

Abstract Rationale: Severe asthma affects a small proportion of asthmatics but represents a significant healthcare challenge. Bronchial thermoplasty (BT) is an interventional treatment approach preconized for uncontrolled severe asthma after considering biologics therapy. Success of the recently approved anti-TSLP and BT in improving asthma control regardless of asthma inflammatory endotype reemphasize the role of bronchial epithelium and its secreted mediators in severe asthma pathophysiology. Objectives: Identifying new potential pathophysiological pathways relevant to severe asthma and modulated by bronchial thermoplasty. Methods: In this study we evaluated the transcriptome of cultured bronchial epithelial cells (BECs) of severe asthmatics obtained pre- and post-BT treatment using microarrays. We further validated gene and protein expressions in BECs and in bronchial biopsies with immunohistochemistry pre- and post-BT treatment. Measurements and main results: Transcriptomics analysis revealed that a large portion of differentially expressed genes (DEG) was involved in anti-viral response, anti-microbial response and pathogen induced cytokine storm signaling pathway. S100A gene family stood out as five members of this family where consistently downregulated post-BT. Further validation revealed that S100A7, S100A8, S100A9 and their receptor (RAGE, TLR4, CD36) expressions were highly enriched in severe asthmatic BECs. Further, these S100A family members were downregulated at the gene and protein levels in BECs and in bronchial biopsies of severe asthmatics post-BT. TLR4 and CD36 protein expression were also reduced in BECs post-BT. Thymic stromal lymphopoietin (TSLP) and human b-defensin 2 (hBD2) were significantly decreased while no significant change was observed in IL-25 and IL-33. Conclusions: These data suggest that BT might improve asthma control by downregulating epithelial derived S100A family expression and related downstream signaling pathways.