Allergic Airway Inflammation in Mice Deficient for the Antigen-Processing Protease Cathepsin E

Pilzner, Carolin; Bühling, Frank; Reinheckel, Thomas; Chwieralski, Caroline E.; Rathinasamy, Anchana; Lauenstein, Hans-Dieter; Wex, Thomas; Welte, Tobias; Braun, Armin; Groneberg, David A.

doi:10.1159/000338288

Cited by 14 publications

(14 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…9,12 In humans, Cat E can be found in dendritic cells, epithelial cells, lymphocytes, osteoclasts, spleen, and lymph nodes. 9,45,46 To date, studies have found that Cat E plays an important role in antigen processing via the major histocompatibility complex class II pathway in host defense against cancer cells, microorganisms, gastric differentiation, and development of signet-ring cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Cathepsin E Promotes Pulmonary Emphysema via Mitochondrial Fission

Zhang

Shan

Homer

et al. 2014

The American Journal of Pathology

View full text Add to dashboard Cite

Emphysema is characterized by loss of lung elasticity and irreversible air space enlargement, usually in the later decades of life. The molecular mechanisms of emphysema remain poorly defined. We identified a role for a novel cathepsin, cathepsin E, in promoting emphysema by inducing mitochondrial fission. Unlike previously reported cysteine cathepsins, which have been implicated in cigarette smoke-induced lung disease, cathepsin E is a nonlysosomal intracellular aspartic protease whose function has been described only in antigen processing. We examined lung tissue sections of persons with chronic obstructive pulmonary disease, a clinical entity that includes emphysematous change. Human chronic obstructive pulmonary disease lungs had markedly increased cathepsin E protein in the lung epithelium. We generated lung epithelial-targeted transgenic cathepsin E mice and found that they develop emphysema. Overexpression of cathepsin E resulted in increased E3 ubiquitin ligase parkin, mitochondrial fission protein dynamin-related protein 1, caspase activation/apoptosis, and ultimately loss of lung parenchyma resembling emphysema. Inhibiting dynamin-related protein 1, using a small molecule inhibitor in vitro or in vivo, inhibited cathepsin E-induced apoptosis and emphysema. To the best of our knowledge, our study is the first to identify links between cathepsin E, mitochondrial fission, and caspase activation/apoptosis in the pathogenesis of pulmonary emphysema. Our data expand the current understanding of molecular mechanisms of emphysema development and may provide new therapeutic targets.

show abstract

Section: Discussionmentioning

confidence: 99%

Cathepsin E Promotes Pulmonary Emphysema via Mitochondrial Fission

Zhang

Shan

Homer

et al. 2014

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…and Bifidobacterium pseudocatenulatum B7003) in vitro (Marotti et al, 2012), modulation of inflammation (Pilzner et al, 2012), changes in mucin production (Leforestier et al, 2009) and a decreased occurrence of infection in the first six months of life (Arslanoglu et al, 2007).…”

Section: Prebioticsmentioning

confidence: 99%

“…Moreover, FOS ameliorated allergic peritoneal inflammation induced by ovalbumin (OVA), partially through the suppression of interleukin-5 (IL-5), and chemokine eotaxin in mice (Hosono et al, 2003;Yasuda et al, 2012). The IL-5 gene cluster and eotaxin are concomitant with the infiltration of eosinophils, neutrophils, mast cells and T lymphocytes into the airways of mice contributing to inflammation, particularly in Th2 type chronic inflammatory disease (Pilzner et al, 2012). Thus, it is likely that FOS influences cell populations such as T cells, basophils, mast cells, and epithelial cells (Hosono et al, 2003;Yasuda et al, 2012).…”

Section: Prebiotics and Inflammationmentioning

confidence: 99%

Prebiotics: A Potential Treatment Strategy for the Chemotherapy-damaged Gut?

Wang

Geier

Howarth

2014

Critical Reviews in Food Science and Nutrition

View full text Add to dashboard Cite

Mucositis, characterized by ulcerative lesions along the alimentary tract, is a common consequence of many chemotherapy regimens. Chemotherapy negatively disrupts the intestinal microbiota, resulting in increased numbers of potentially pathogenic bacteria, such as Clostridia and Enterobacteriaceae, and decreased numbers of "beneficial" bacteria, such as Lactobacilli and Bifidobacteria. Agents capable of restoring homeostasis in the bowel microbiota could therefore be applicable to mucositis. Prebiotics are indigestible compounds, commonly oligosaccharides, which seek to reverse chemotherapy-induced intestinal dysbiosis through selective colonization of the intestinal microbiota by probiotic bacteria. In addition, evidence is emerging that certain prebiotics contribute to nutrient digestibility and absorption, modulate intestinal barrier function through effects on mucin expression, and also modify mucosal immune responses, possibly via inflammasome-mediated processes. This review examines the known mechanisms of prebiotic action and explores their potential to reduce the severity of chemotherapy-induced mucositis in the intestine. MUCOSITISThe treatment of cancer by chemotherapy, sometimes in combination with radiotherapy, is associated with an array of acute side-effects, including alopecia, neutropenia and nausea (Logan et al., 2007). Furthermore, these treatments can also induce inflammation and deterioration of the mucosal membranes of the alimentary tract, a condition referred to as mucositis. Mucositis can occur throughout the entire gastrointestinal tract (Gibson et al., 2005); however, it most commonly affects the mucosa of the mouth (oral mucositis) and small intestine (gastrointestinal mucositis), with symptoms including pain, vomiting, bloating, and diarrhoea. Severe cases are often associated with secondary complications such as malnutrition and septicaemia, resulting in poor patient outcomes. Indeed, the pathobiology of mucositis is influenced by the nature of the causative agent (Logan et al., 2009), with temporal variations in pathogenesis, in addition to the location and severity of damage (Logan et al., 2009). Consequently, the multi-factorial nature of mucositis makes it a difficult condition to understand, and subsequently treat.Despite mucositis being one of the most common side-effects of cancer treatment (Choi et al., 2007) its incidence and severity is highly variable, and is dependent on the treatment regimen and individual variation in terms of tolerability . Approximately 40% of all patients undergoing chemotherapy develop mucositis (Gibson et al., 2002; with this number rising to between 60% and 100% in patients receiving high-dose chemotherapy regimens for conditions such as the haematological malignancies (Gibson et al., 2002;. To date, effective treatments for intestinal mucositis have been elusive. Potential treatment options are limited by the requirement for treatments to protect the mucosa and promote the repair process, without compromising cytotoxic effects on the ...

show abstract

“…both have been implicated in antigen processing using inhibitors and knockout mice (34,(37)(38)(39)(40)(41)(42). Even though none of these studies reported any effects on MHCII expression levels, they did not rule out a role of CatD and/or CatE in MHCII protein turnover.…”

Section: Introductionmentioning

confidence: 99%

Quality control of HLA-DR molecules by the lysosomal aspartyl protease, cathepsin D

Shah

McDonald

Parker

et al. 2020

Preprint

View full text Add to dashboard Cite

words)Major histocompatibility complex class II (MHCII) 1 molecules display peptides on antigen-presenting cells (APCs) for inspection by CD4+ T cells. MHCII surface levels and life span are regulated post-translationally by peptide loading and ubiquitindependent lysosomal targeting, but proteases responsible for MHCII protein degradation remain unidentified. Here, we examined the role of aspartyl proteases in MHCII protein degradation and characterised the form of MHCII that is degraded. Exposure of immature monocyte-derived dendritic cells (MoDCs) and KG-1 acute myeloid leukaemia cells to the aspartyl protease inhibitor, pepstatin A (PepA), caused accumulation of human leukocyte antigen (HLA)-DR molecules in intracellular vesicles. Statistically significant PepA effects on MHCII protein expression were also observed in murine APCs. In KG-1 cells, cathepsin D (CatD) was the sole expressed aspartyl protease, and shRNA-mediated knockdown ablated the PepA effect, providing formal proof of CatD involvement. In vitro, CatD initiated specific cleavage of recombinant DR at F54, a site flanking the peptide-binding groove. Immunochemical characteristics of PepA-rescued DR molecules in KG-1 cells were consistent with selective CatD attack on HLA-DR molecules that lack association with the MHCII chaperone, invariant chain, or with stably bound peptide. We propose that CatD has a critical role in the selective lysosomal disposal of mature HLA-DR molecules that have lost, or never acquired, bound peptide, explaining how MHCII protein life span is coupled to peptide loading.

show abstract

Allergic Airway Inflammation in Mice Deficient for the Antigen-Processing Protease Cathepsin E

Cited by 14 publications

References 77 publications

Cathepsin E Promotes Pulmonary Emphysema via Mitochondrial Fission

Cathepsin E Promotes Pulmonary Emphysema via Mitochondrial Fission

Prebiotics: A Potential Treatment Strategy for the Chemotherapy-damaged Gut?

Quality control of HLA-DR molecules by the lysosomal aspartyl protease, cathepsin D

Contact Info

Product

Resources

About