Lack of cathepsin activities alter or prevent the development of lung granulomas in a mouse model of sarcoidosis
© Samokhin et al; licensee BioMed Central Ltd. 2011
Received: 9 September 2010
Accepted: 20 January 2011
Published: 1 December 2011
Remodeling of lung tissues during the process of granuloma formation requires significant restructuring of the extra-cellular matrix and cathepsins K, L and S are among the strongest extra-cellular matrix degrading enzymes. Cathepsin K is highly expressed in various pathological granulomatous infiltrates and all three enzymes in their active form are detected in bronchoalveolar lavage fluids from patients with sarcoidosis. Granulomatous inflammation is driven by T-cell response and cathepsins S and L are actively involved in the regulation of antigen presentation and T-cell selection. Here, we show that the disruption of the activities of cathepsins K, L, or S affects the development of lung granulomas in a mouse model of sarcoidosis.
Apolipoprotein E-deficient mice lacking cathepsin K or L were fed Paigen diet for 16 weeks and lungs were analyzed and compared with their cathepsin-expressing littermates. The role of cathepsin S in the development of granulomas was evaluated using mice treated for 8 weeks with a potent and selective cathepsin S inhibitor.
When compared to wild-type litters, more cathepsin K-deficient mice had lung granulomas, but individually affected mice developed smaller granulomas that were present in lower numbers. The absence of cathepsin K increased the number of multinucleated giant cells and the collagen content in granulomas. Cathepsin L deficiency resulted in decreased size and number of lung granulomas. Apoe-/- mice treated with a selective cathepsin S inhibitor did not develop lung granulomas and only individual epithelioid cells were observed.
Cathepsin K deficiency affected mostly the occurrence and composition of lung granulomas, whereas cathepsin L deficiency significantly reduced their number and cathepsin S inhibition prevented the formation of granulomas.
Cathepsins K, L and S are members of the papain family of cysteine proteases that have been recently implicated in the development of various lung diseases . It is believed that cathepsins participate in lung tissue remodeling based on their ability to degrade extra-cellular matrix, their involvement in the regulation of immune responses and their potential contribution to the kallikrein-kinin system [2–5]. In this study, we investigated the roles of cathepsins K, L, and S in the development of granulomas in mouse lungs that have features of human granulomas of sarcoidosis . Sarcoidosis is a systemic disease characterized by the presence of noncaseating epithelioid granulomas with a pulmonary involvement in ~90% of the patients [7, 8]. Cathepsins K, L, and S are expressed by lung macrophages, fibroblasts, and epithelial cells . Significant expression of cathepsin K was first found in granulomas induced by Echinococcus granulosus in bovine lung . A strong expression of cathepsin K was also observed in epithelioid and multinucleated giant cells (MGCs) in patients with sarcoidosis and tuberculosis [11, 12]. The presence of active forms of cathepsins K, L and S was found in bronchoalveolar lavage fluids from patients with sarcoidosis . Recently, we described that Apoe-/- mice fed a cholate-containing high fat diet develop lung granulomas that have many features of human granulomas of sarcoidosis . Epithelioid and MGCs in such granulomas have shown strong immunostaining for cathepsin K suggesting that this protease might be involved in granuloma formation or resorption (6).
Similarly to cathepsin K, cathepsins L and S are able to degrade major extracellular proteins  but they are also involved in immune responses [15, 16]. Since cathepsins L and S play significant role in antigen presentation and T cell selection [15, 17] and the formation of granulomas has been linked to T cell activation [18–21], the disruption of cathepsins L and S activities might affect the development of granulomas.
Thus, based on the strong expression of cathepsin K in granulomas and the pivotal role of cathepsins S and L in the antigen presentation and T-cell selection, we hypothesized that the disruption of these protease activities might interfere with lung granuloma formation. In this study, we investigated the effect of cathepsin K and L deficiencies and cathepsin S inhibition on the development of lung granulomas in Apoe-/- mice on Paigen diet.
Three groups of mice were used: apolipoprotein E-deficient (Apoe-/-) mice (Jackson Laboratories), double knockout mice lacking apolipoprotein E and cathepsin K (Apoe-/- Ctsk-/-) (n = 10) and double knockout mice lacking apolipoprotein E and cathepsin L (Apoe-/- Ctsl-/-) (n = 19). Double knockout Apoe-/- Ctsk-/- and Apoe-/- Ctsl-/- mice were generated by crossing Apoe-/- with the Ctsk-/- or Ctsl-/- mice as previously described . Ctsk-/- and Ctsl-/- mice were kindly provided by Drs. P. Saftig (University of Kiel, Germany) and C. Peters (University of Freiburg, Germany). The single cathepsin deficiencies have the following phenotypes: Cathepsin K-deficient mice show an osteopetrotic phenotype with excessive trabeculation of the bone-marrow space  and increased fibrosis in lungs after treatment with bleomycin . Cathepsin L-deficient mice deficient mice develop periodic hair loss and epidermal hyperplasia .
After perfusion with ice-cold phosphate-buffered saline (PBS), lungs and thymuses were fixed in 10% buffered formalin for 5 hours at 4°C, embedded in paraffin, and 5 μm sections were cut and mounted onto Superfrost/Plus slides (Fisher-Scientific, Ottawa, ON).
Sections were dewaxed, rehydrated, blocked with 10% goat serum in PBS, and incubated overnight at 4°C with the primary antibody in 1% BSA in PBS: affinity purified rabbit polyclonal anti-cathepsin K (1: 50) , mouse monoclonal antibody against SMC α-actin (1:100, Biomeda, Foster City, CA), rat anti-mouse Mac-3 antibody (1:100, Pharmingen, San Diego, CA), rabbit polyclonal anti-mouse osteopontin (1:100, ARP, Belmont, MA), rabbit polyclonal anti-CD4 (1:100, Abbiotec, San Diego, CA), rabbit polyclonal anti-CD8 (1:100, ANASPEC, San Jose, CA) or goat polyclonal anti-cathepsin S and anti-cathepsin L (Santa Cruz Biotechnology, Inc., Santa Cruz, CA). Sections stained for cathepsins S and L were blocked with 10% donkey serum in PBS. As negative controls, we used mouse, rabbit, rat or goat IgG at the same concentrations as the corresponding primary antibodies and for cathepsin K and L antibodies tissue sections from cathepsin K- and L-deficient mice were used. Tissue sections were then incubated with the appropriate secondary antibody: goat anti-rabbit Cy3-conjugated, goat anti-mouse Cy2-conjugated antibody (1:200, Rockland, Gilbertsville, PA), goat anti-rat FITC-conjugated antibody (1:200, Sigma-Aldrich, St. Louis, MO), and donkey anti-goat Texas Red-conjugated (1:200 v/v, Jackson ImmunoResearch Laboratories, West Grove, PA).
Gomori's trichrome staining
Sections were deparaffinized, hydrated with a graded alcohol series and distilled water, and placed in preheated Bouin's solution at 58°C for 10 min. Sections were stained in Weigert's iron hematoxylin solution for 5 min, washed under running water for 30 sec, stained with Gomori's trichrome solution (Sigma-Aldrich, St. Louis, MO) for 15 min, placed in 0.5% acetic acid for 10 sec, and then mounted for light microscopy.
Morphometry, collagen content, and cell composition of granulomas
The areas of granulomas stained positively for Mac-3, osteopontin, CD4 and CD8, and collagen were quantified using color threshold and calculated as percentage of granuloma area. The size of granulomas was measured in mm2. Trichrome stained sections were used for the measurement of granuloma size and for the quantification of collagen content. Images were captured with a Leica DMI 6000B microscope (Leica Microsystems, Inc, Richmond Hill, ON) and analyzed with Openlab 3 software.
Quantification of the number of granulomas, multinucleated giant cells and CD4-positive cells
Five sections 200 μm apart from each other were analyzed for each lung. For CD4-positive cell quantification three pictures per lung section were taken using a 40-fold magnification, avoiding areas with dominating tracheal or bronchial tissue. The average number of granulomas and multinucleated giant cells per section and the average number of CD4-positive cells per captured area for each mouse were used for statistical analyses.
Student's t-tests were performed when values past test for normal distribution. Data are presented as mean ± standard deviation. Discontinuous data (such as the number of granulomas) were analyzed using the Mann-Whitney U-test. Significance was concluded when P < 0.05.
Cathepsins K, L and S are expressed in mouse lung granulomas
Cathepsin K deficiency increased the incidence of granulomatous infiltrations in lungs
Percentage of mice with granulomas, proteinosis or iBALT in lungs
(cat S inh)
Cathepsins K and L deficiencies and cathepsin S inhibition decreases the number and size of lung granulomas
Effect of cathepsins on thymus hypertrophy
Accumulation of CD4-positive cells in lungs is affected by cathepsin S inhibitor and cathepsin L deficiency
The formation of lung granulomas results in an extensive extracellular matrix remodeling. Collagen and elastin are the major components of the pulmonary matrix and it is believed that a cooperative action of multiple enzymes is required for its turnover. Cathepsin K has a unique ability to cleave highly efficiently triple helical collagen at multiple sites and to act as a potent elastase as well . Its strong expression in lung granulomas suggested an important role in granuloma formation and resolution, and indeed, lungs of Apoe-/- Ctsk-/- mice showed significant differences in granuloma appearance, size, and composition. The increased incidence of lung granulomas in cathepsin K-deficient mice (88% vs. 41%) correlates with the increased collagen fibers deposition (10% vs 20%) that may consequently result in a delayed granuloma resolution. Lung granuloma formation and their spontaneous resolution as commonly observed in patients with sarcoidosis  require remodeling of the extracellular matrix. It is tempting to speculate that the increased amount of collagen in granulomas (Figure 4H) and the presence of abundant collagen fibers between epithelioid cells in areas without well-formed granulomas (Figure 3F, G) in Ctsk-/- mice is due to the lack of the collagenase activity of cathepsin K. This accumulation of collagen fibers might also be responsible for the smaller number and size of granulomas. In our measurements, accumulations of epithelioid cells were considered as granulomas only when they were present as well-formed and ball-shaped structures that are characteristic for sarcoidosis. In Apoe-/- Ctsk-/- mice, epithelioid cells were often observed forming ring-like structures with dispersed collagen fibers, or were randomly distributed in fibrotic areas (Figure 3D, H).
The cell composition of granulomas in cathepsin K-deficient mice was also changed. They contained a significantly higher number of MGCs. This type of cells is formed by the fusion of cells from the monocyte-macrophage lineage . In atherosclerotic plaques from Apoe-/- Ctsk-/- mice, macrophages have an increased size  and microarray analyses have revealed the upregulation of several macrophage genes, including CD36 . Since CD36 participates in macrophage fusion , we suggest that it might be responsible for the increased number of MGCs in cathepsin K-deficient mice. The disruption of cathepsins L and S activities resulted in a more significant effect on granuloma formation. Cathepsin L deficiency reduced the size and the number of lung granulomas whereas mice treated with the cathepsin S inhibitor did not develop well-formed granulomas.
Analysis of available literature data suggests that the preventive effect of cathepsin L deficiency or cathepsin S inhibition on lung granuloma development may not only depend on their extracellular matrix-degrading activities, but on their involvement in antigen presentation as well [17, 38]. Cathepsin S is expressed in B cells, macrophages, and dendritic cells and is required for invariant chain (li) degradation and antigen processing . Cathepsin S-deficient mice have decreased MHC class II presentation in B and dendritic cells, and a reduced number of CD4+ T-cells . On the other hand, cathepsin L is expressed in cortical thymic epithelial cells and macrophages and is responsible for li degradation in CD4+ T cell selection in the thymus . Cathepsin L-deficient mice have a reduction in their numbers of CD4+ cells in thymus and peripheral organs . The roles of cathepsins S and L on the functions of CD4+ may have a direct influence on sarcoidosis development. T cell activation is mandatory for the development of granulomatous reactions and CD4+ T cells of the Th1-type are essential for the formation and the maintenance of granulomas [18–21]. The decreased amount of CD4+ cells in lungs of mice lacking cathepsin L or treated with cathepsin S inhibitor (Figure 7B, C) supports the suggestion that the effect of these two cathepsins on the granuloma formation is related to their role in antigen presentation and T-cell selection.
In addition to its involvement in antigen presentation, cathepsin L has been described to play a role in T-cell actin polymerization, shape polarization, chemotaxis. Cathepsin L deficiency significantly decreases the expression of laminin, fibronectin, and collagens I and II in thymus of cathepsin L-deficient mice . This might partially explain why Apoe-/- Ctsl-/- mice had significantly smaller thymi compared to Apoe-/- mice (Figure 7D, E).
In conclusion, our results show that the disruption of cathepsin L and S activities prevents the development of lung granulomas, whereas cathepsin K deficiency results in altered granuloma composition in mice. These results suggest that interventions in cathepsin S and L activities may yield a therapeutic benefit for patients with sarcoidosis, i.e., a potential prevention of disease progression. Such an approach, however, would require extreme caution as both cathepsins have been described as critical participants in antigen presentation and their inhibition may result in increased infection and cancer rates.
The authors gratefully acknowledge Drs. Paul Saftig (University of Kiel, Germany) and Christoph Peters (University of Freiburg, Germany) for providing the mouse strains for cathepsin K and L-deficiencies. We also gratefully acknowledge Stephanie Alleyn, Aleksandar Popovic, Simon Wong, Denis Normandin and Réné St-Jacques from Merck-Frosst for their excellent technical assistance and assistance with animal care during this study. This work was supported by the CIHR grant C04-0435 and a Canada Research Chair Award (D. B.).
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