Support for MET and MMP10 roles in eosinophilic asthma
medwireNews: MET and MMP10 gene expression are likely to play important roles in the cellular inflammation and airway remodeling associated with submucosal eosinophilia in patients with asthma, researchers report.
Stringent false discovery rate analysis of transcriptomic data from bronchial biopsies of 81 patients with moderate-to-severe asthma from the U-BIOPRED cohort showed that MET and MMP10 were the most differentially expressed genes between 33 patients with high numbers of mucosal eosinophils (9.8 counts/mm2), compared with 48 patients with low numbers (1.1 counts/mm2), being significantly over expressed in the former group.
Indeed, submucosal eosinophil counts were significantly correlated with MET and MMP10 expression, with MET explaining 55% of the variation in eosinophil counts and MMP10 explaining 47%. And when used together, expression of the two proteins classified high bronchial eosinophil inflammation with 85% accuracy.
Under less stringent conditions, Kian Fan Chung (Imperial College London, UK) and co-researchers identified 73 differentially expressed genes that were characteristic of the group with high eosinophil counts, and 33 of these were enriched in key pathways associated with eosinophilic airway inflammation and airway remodeling.
Specifically, from these 33 genes, six functionally relevant annotations were defined, including extracellular matrix (ECM) organization, with MMP10 as its most highly expressed gene, mast cell activation, C–C chemokine receptor binding, circulating immunoglobulin complex, serine proteinase inhibition, and microtubule bundle formation.
“These pathways were associated with eosinophilic airway inflammation, increased blood and tissue macrophages, low systemic C-reactive protein levels, and increased basement membrane thickness”, the team notes in Allergy.
Of the six pathways identified, ECM was a key driver and showed strong associations with both mast cell activation and C–C chemokine receptor binding.
The investigators therefore carried out a transcription factor binding site analysis to explore regulation of the MMP10 and MET genes within the ECM signature. They found that MMP10 and MET gene expression positively correlated with other ECM transcription factors, namely the ETS1 and SOX family proteins, respectively.
Further support for a role of MET and MMP10 in airway remodeling came from immunohistochemical analysis showing significantly higher expression of both proteins in bronchial epithelial cells and in subepithelial inflammatory cells from asthma patients, compared with healthy individuals.
“These findings indicate the potential involvement of these factors underlying the submucosal eosinophilic inflammation and subepithelial fibrosis observed in asthma that warrant further investigation”, the researchers conclude.
By Lucy Piper
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