Consequences of cathepsin C inactivation for membrane exposure of proteinase 3, the target antigen in autoimmune vasculitis

Abstract

Membrane-bound proteinase 3 (PR3) is the main target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis, a systemic small-vessel vasculitis. Binding of ANCA to PR3 triggers neutrophil activation with the secretion of enzymatically active PR3 and related neutrophil serine proteases, thereby contributing to vascular damage. PR3 and related proteases are activated from pro-forms by the lysosomal cysteine protease cathepsin C (CatC) during neutrophil maturation. We hypothesized that pharmacological inhibition of CatC provides an effective measure to reduce PR3 and therefore has implications as a novel therapeutic approach in granulomatosis with polyangiitis. We first studied neutrophilic PR3 from 24 patients with Papillon-Lefèvre syndrome (PLS), a genetic form of CatC deficiency. PLS neutrophil lysates showed a largely reduced but still detectable (0.5-4%) PR3 activity when compared with healthy control cells. Despite extremely low levels of cellular PR3, the amount of constitutive PR3 expressed on the surface of quiescent neutrophils and the typical bimodal membrane distribution pattern were similar to what was observed in healthy neutrophils. However, following cell activation, there was no significant increase in the total amount of PR3 on PLS neutrophils, whereas the total amount of PR3 on healthy neutrophils was significantly increased. We then explored the effect of pharmacological CatC inhibition on PR3 stability in normal neutrophils using a potent cell-permeable CatC inhibitor and a CD34 hematopoietic stem cell model. Human CD34 hematopoietic stem cells were treated with the inhibitor during neutrophil differentiation over 10 days. We observed strong reductions in PR3, cellular PR3 protein, and proteolytic PR3 activity, whereas neutrophil differentiation was not compromised.

Lung Protection by Cathepsin C Inhibition: A New Hope for COVID-19 and ARDS?

“… 24 , 25 Loss of function mutations in the CatC gene (gene symbol CTSC ) in humans cause Papillon–Lefèvre syndrome (PLS, OMIM 245000) characterized by a severe prepubertal periodontitis and palmoplantar keratoderma without marked immunodeficiency. 26 , 27 The lack of CatC activity results in an almost total elimination of elastase-related serine proteases in neutrophils from PLS patients 25 , 28 , 29 ( Figure 3 A). Moreover, PLS cells are incapable of producing neutrophil extracellular traps (NETs), networks of fibers, primarily composed of DNA.…”

“…The blood samples and pictures were taken after informed consent was obtained, and the study was conducted according to Declaration of Helsinki principles. 29 (B) Pharmacological inactivation of CatC by prolonged administration of IcatC XPZ-01 in a Macaca fascicularis experimental model of acute lung inflammation. The image shows broncho-alveolar lavage of an anesthetized macaque.…”

Papillon-Lefèvre Syndrome and Basal Cell Carcinoma: A Case Study

“…However, in our patient, cancer developed on the face; this could be either be an incidental finding or cathepsin C may play a role in cancer development. Cook (2009) mentioned that although cathepsin C mutation impaired the cytotoxic lymphocyte activity in PLS, leading to immunodeficiency and the possibility of tumor progression at a cellular level, immunodeficiency was not one of the main clinical features for PLS, as explained by cathepsin C-independent pathways [5, 9]. The role of cathepsin C could be the reason for the multiple cancer cases and severe infections like liver abscess reported in PLS patients [5, 9].…”

“…Cook (2009) mentioned that although cathepsin C mutation impaired the cytotoxic lymphocyte activity in PLS, leading to immunodeficiency and the possibility of tumor progression at a cellular level, immunodeficiency was not one of the main clinical features for PLS, as explained by cathepsin C-independent pathways [5, 9]. The role of cathepsin C could be the reason for the multiple cancer cases and severe infections like liver abscess reported in PLS patients [5, 9]. The role of cathepsin C in the development of dermatological conditions in PLS is still unclear and may explain the nonsignificant correlation between the severity of skin disease and severity of oral infection [5, 7, 8, 9].…”

CTSC compound heterozygous mutations in two Chinese patients with Papillon–Lefèvre syndrome

“…In polymorphonuclear leucocytes (PMNs) of PLS patients, impaired chemotactic and phagocytic function and an impaired response to T and B cell mitogens have been reported (Roberts et al, ). Seren et al () recently reported that inactive cathepsin C could reduce the amount of membrane‐bound proteinase 3 (PR3 m ), a main target antigen of anti‐neutrophil cytoplasmic autoantibodies (ANCA), indicating a new treatment for granulomatosis with polyangiitis (GPA).…”