ADAM15 expression is increased in lung CD8+ T cells, macrophages, and bronchial epithelial cells in patients with COPD and is inversely related to airflow obstruction

Abstract

Background A d isintegrin a nd m etalloproteinase domain-15 (ADAM15) is expressed by activated leukocytes, and fibroblasts in vitro. Whether ADAM15 expression is increased in the lungs of COPD patients is not known. Methods ADAM15 gene expression and/or protein levels were measured in whole lung and bronchoalveolar lavage (BAL) macrophage samples obtained from COPD patients, smokers, and non-smokers. Soluble ADAM15 protein levels were measured in BAL fluid (BALF) and plasma samples from COPD patients and controls. Cells expressing ADAM15 in the lungs were identified using immunostaining. Staining for ADAM15 in different cells in the lungs was related to forced expiratory volume in 1 s (FEV 1 ), ratio of FEV 1 to forced vital capacity (FEV 1 /FVC), and pack-years of smoking history. Results ADAM15 gene expression and/or protein levels were increased in alveolar macrophages and whole lung samples from COPD patients versus smokers and non-smokers. Soluble ADAM15 protein levels were similar in BALF and plasma samples from COPD patients and controls. ADAM15 immunostaining was increased in macrophages, CD8 + T cells, epithelial cells, and airway α-smooth muscle (α-SMA)-positive cells in the lungs of COPD patients. ADAM15 immunostaining in macrophages, CD8 + T cells and bronchial (but not alveolar) epithelial cells was related inversely to FEV 1 and FEV 1 /FVC, but not to pack-years of smoking history. ADAM15 staining levels in airway α-SMA-positive cells was directly related to FEV 1 /FVC. Over-expressing ADAM15 in THP-1 cells reduced their release of matrix metalloproteinases and CCL2. Conclusions These results link increased ADAM15 expression especially in lung leukocytes and bronchial epithelial cells to the pathogenesis of COPD.

Plasticity towards Rigidity: A Macrophage Conundrum in Pulmonary Fibrosis

“…Further, pharmacological inhibition of ADAM10 prevents lung fibrosis in mice [ 162 ]. Likewise, smoke increased ADAM15 expression in alveolar macrophages and in airway α-SMA-positive cells, while both ADAM10 and ADAM15 shed E-cadherin and changed the cell membrane structure [ 163 , 164 , 165 ]. Overall, the current studies show that macrophage-derived EVs are an important factor in establishing cell-to-cell communication and reorganizing the extracellular matrix via collagen degradation, cleavage of membrane proteins, stimulation of fibrotic signaling pathways, and activation of macrophages.…”

CiliOPD: a ciliopathy-associated COPD endotype

“…Focusing on the 10 commonly dysregulated genes, we confirmed the localization of the proteins and the expression of the transcripts in AEC (Additional file 1 : Figure S2 and Table 1 ). Among those 10 genes, 3 have been identified as associated with COPD in previous studies (ADAM15, DCDC2, WDR34) [ 6 , 21 – 24 ]. PROM2 was significantly upregulated in the 3 datasets in COPD patients (Fig.…”

“…The impacted biological processes corresponded to the aforementioned ones, suggesting that these genes may represent key actors to understand cilia dysfunction in COPD. Interestingly, 7 genes have been previously highlighted in experimental investigations in the context of COPD [ 6 , 17 – 24 ]. Although they were often fortuitously exposed, their associations with COPD were found sufficiently significate to be mentioned.…”

“…Transcriptomic studies unveiled an upregulation of NEK6 in COPD patients, a downregulation of BBS9 in large airway epithelial cells (LAEC) of smokers compared to non-smokers but not in SAEC, and a downregulation of WDR34 in SAEC of smokers compared to non-smokers but not in LAEC [ 6 , 19 ]. In vitro and in vivo approaches unveiled differential protein expression and localization for ADAM15 and GLI2 according to cell populations (epithelial cells vs non-epithelial cells or differentiated epithelial cells vs non-differentiated epithelial cells) and sub-cellular localization (cytoplasm vs nuclear) [ 17 , 18 , 21 , 24 ]. These findings were generally concordant to the relative gene expression levels we reported across multiple genesets.…”

Targeting M2 Macrophages Alleviates Airway Inflammation and Remodeling in Asthmatic Mice via miR-378a-3p/GRB2 Pathway

“…Bronchial tissues were cut into small pieces approximately 1 × 1 × 1 mm in size and incubated in RPMI 1640 containing 1 mg/ml collagenase I at 37°C for 4 h. Thereafter, the adherent cells within 30 min which were mainly airway fibroblasts were discarded and the suspended α-SMA-positive cells were pipetted into another culture flask. Successful isolation of α-SMA-positive cells was determined by immunofluorescence staining of α-SMA ( Wang et al, 2020 ). α-SMA-positive cells were cultured in RPMI 1640 containing 10% FBS and passaged every 6–8 days, and cells from 4 to 9 passages were used for further experiments.…”