T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction

Abstract

Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)-β. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS, and 16 with RAS. We demonstrated that C-C motif chemokine 2 secreted by T cells supports TGF-β-induced MMP-9 production by BECs after binding to C-C chemokine receptor type 2. Longitudinal investigation in LTRs revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (odds ratio [OR] = 6.19, p = 0.002) or RAS (OR = 3.9, p = 0.024) and predicted the occurrence of CLAD 12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD.

Needs for Systems Approaches to Better Treat Individuals With Severe Asthma: Predicting Phenotypes and Responses to Treatments

“…Conversely, the neutrophilic proteotype was associated with the upregulation of proteins secreted by neutrophils (azurocidin, S100, annexin A, neutrophil gelatinase-associated lipocalin, myeloperoxidase) (80). Interestingly, in a hypothesis-based approach, Barbaro et al detected the exhaled matrix metalloprotease-9 (MMP9) in different phenotypes of asthma and found it elevated in severe neutrophilic asthma (89), echoing the results of both the aforementioned study by Schofield et al, where MMP9 was associated with neutrophilic inflammation in bronchial mucosa from asthmatic patients (86), and those of a previous study in the field of lung transplantation that showed that the serum MMP9 level was predictive of bronchiolitis obliterans syndrome in lung transplant recipients, a condition also related to airway neutrophilia and bronchial remodeling (90).…”

TLR3 promotes MMP-9 production in primary human airway epithelial cells through Wnt/β-catenin signaling

“…Recent literature highlighted the major role of AEC in the remodeling processes associated with chronic diseases, infections or transplantation [ 1 ]. Although modulation of TGF-β induced remodeling by inflammatory environment has been described [ 14 – 16 ], the direct interaction between TGF-β and TLR signaling in AEC remains unexplored. AEC were cultured with low dose of TGF-β (1 ng/ml) to emphasize the synergy with TLR3 signaling.…”

“…AEC were isolated and cultured as already described [ 16 ]. Briefly, human primary BEC were obtained from lung donor trachea or bronchi, included within the multicentre COLT (Cohort in Lung Transplantation, NCT00980967) study (Comité de Protection des Personnes Ouest 1-Tours, 2009-A00036–51).…”

“…However, TGF-β is a pleiotropic growth factor expressed in the normal lung [ 13 ], and its ability to drive EMT is largely dependent on the microenvironment in which it is produced. Inflammatory cytokines like TNFα and IL-1β [ 14 , 15 ], or chemokines like CCL-2 [ 16 ] produced by macrophages or activated T cell have thus been shown to promote TGF-β-induced EMT.…”

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies

“…162 CCL2 also supports TGF-β-induced matrix metallopeptidase 9 (MMP-9) production by airway epithelial cells, which is important to fibroplasia and remodeling. 163 However, the pathogenesis of CLAD is considerably more complex than what can be explained by the simple Th1/Th2 paradigm.…”