Meprin β contributes to collagen deposition in lung fibrosis

Abstract

Lung fibrosis is a severe disease characterized by epithelial cell injury, inflammation and collagen deposition. The metalloproteases meprinα and meprinβ have been shown to enhance collagen maturation and inflammatory cell infiltration via cleavage of cell-cell contact molecules; therefore we hypothesized that meprins could play a role in lung fibrosis. An exhaustive characterization of bleomycin-treated meprinα, meprinβ and the double meprinsαβ knock-out (KO) with respective wt-littermates was performed by using several different methods. We observed no difference in lung function parameters and no change in inflammatory cells infiltrating the lung between wt and all meprins KO mice after 14 days bleomycin. No difference in epithelial integrity as assessed by e-cadherin protein level was detected in bleomycin-treated lungs. However, morphological analysis in the bleomycin-treated mice revealed decrease collagen deposition and tissue density in meprinβ KO, but not in meprinα and meprinαβ KO mice. This finding was accompanied by localization of meprinβ to epithelial cells in regions with immature collagen in mice. Similarly, in human IPF lungs meprinβ was mostly localized in epithelium. These findings suggest that local environment triggers meprinβ expression to support collagen maturation. In conclusion, our data demonstrate the in vivo relevance of meprinβ in collagen deposition in lung fibrosis.

Role of meprin metalloproteinases in cytokine processing and inflammation

“…Meprins are expressed in the lung epithelial and inflammatory cells in human and mouse lungs and meprin β is upregulated in a mouse model of idiopathic pulmonary fibrosis [87]. Meprin β-KO, but not meprin α-KO mice, subjected to bleomycin-induced lung fibrosis accumulated less collagen than bleomycin treated WT mice [43]. Taken together, these studies indicate that meprins play important roles in the fibrosis of lungs and skin.…”

“…CCL2/MCP1 meprin β (human), meprin α (rat), meprin A (rat) [20] FGF-19 meprin β (human) [21] Pro-IL-1β meprin α (human), meprin β (human), meprin A (rat) [22,23] IL-6 meprin α and β (human), meprin β (rat), meprin α (mouse) [24] IL-6R meprin α and β (human) [25] Pro-IL-18 meprin β (mouse) [26] Actin meprin β (rat), meprin α (mouse) [27] Pro-ADAM10 meprin β (human) [9] Angiotensin-I and -II meprin A (mouse), meprin A (human) [28][29][30] CD99 meprin β (mouse) [31] E-Cadherin meprin α and β (human) [32] Pro-Collagen-III meprin α and β (human) [33] Collagen-IV meprin A (rat), meprin α and β (human) [11,34] Fibronectin meprin A (rat), meprin α and β (human) [11,34] Insulin meprin A (mouse), meprin A (human) [28][29][30] Laminin-1 and −5 rec human meprin α [11,35] Nidogen-I meprin A (rat), meprin α and β (human) [34,36] Protein Kinase A meprin A (rat) [37] Thymosin-β4 meprin A (rat) [38] Villin meprin β (rat), meprin α (mouse) [27] Substrate identified in vivo Pro-IL-1β meprin A (mouse) [23,39] IL-6 meprin α and β (mouse) [24,40] IL-6R meprin β (human) [25] Pro-IL-18 meprin β (mouse) [26] Amyloid precursor protein meprin β (mouse) [41] CD99 meprin β (mouse) [42] Pro-Collagen-I meprin α and β (mouse) [43,…”

Streptococcus thermophilus alters the expression of genes associated with innate and adaptive immunity in human peripheral blood mononuclear cells

“…The p values are calculated based on a Student's t-test of the Triplicate 2^(-Delta CT) [(2^-ΔCT)] values for each gene in the treatment group vs. the control group [32,33,35,36].…”

PDGFRα and αSMA mark two distinct mesenchymal cell populations involved in parenchymal and vascular remodeling in pulmonary fibrosis

“…S3, A-D; https://doi.org/10.5281/zenodo.3532795), have increased coverage of distal pulmonary vessels by ␣SMAϩ cells with deposition of intra-/perivascular collagen (Supplemental Fig. S4, A-D; https://doi.org/10.5281/zenodo.3532795), and have impaired lung function with restrictive phenotype (2)(3)(4).…”