Autophagic dysfunction in patients with Papillon-Lefèvre syndrome is restored by recombinant cathepsin C treatment

Bullón, Pedro; Castejón-Vega, Beatriz; Román-Malo, Lourdes; Jiménez-Guerrero, Maripaz; Cotán, David; Forbes-Hernández, Tamara Y.; Varela‐López, Alfonso; Pérez-Pulido, Antonio J.; Giampieri, Francesca; Quiles, José L.; Sánchez-Alcázar, José A.; Cordero, Mario D.

doi:10.1016/j.jaci.2018.01.018

Cited by 25 publications

(18 citation statements)

References 32 publications

(26 reference statements)

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“…NET formation is also considered a potential factor changing the influence of the individual course of periodontitis [82]. Periodontitis in Papillon-Lefèvre (PLS) syndrome arises from the failure to eliminate periodontal pathogens because of cathepsin C deficiency [83]. PLS neutrophils reduced the capacity for NET production, characterized by the absence of the NET-related proteins such as chorionic gonadotropin, MPO and NE.…”

Section: Defective Neutrophils and Impaired Net Formation In Periodonmentioning

confidence: 99%

Neutrophil Extracellular Traps in Periodontitis

Magán‐Fernández

Al-Bakri

O’Valle

et al. 2020

Cells

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Neutrophils are key cells of the immune system and have a decisive role in fighting foreign pathogens in infectious diseases. Neutrophil extracellular traps (NETs) consist of a mesh of DNA enclosing antimicrobial peptides and histones that are released into extracellular space following neutrophil response to a wide range of stimuli, such as pathogens, host-derived mediators and drugs. Neutrophils can remain functional after NET formation and are important for periodontal homeostasis. Periodontitis is an inflammatory multifactorial disease caused by a dysbiosis state between the gingival microbiome and the immune response of the host. The pathogenesis of periodontitis includes an immune-inflammatory component in which impaired NET formation and/or elimination can be involved, contributing to an exacerbated inflammatory reaction and to the destruction of gingival tissue. In this review, we summarize the current knowledge about the role of NETs in the pathogenesis of periodontitis.

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Section: Defective Neutrophils and Impaired Net Formation In Periodonmentioning

confidence: 99%

Neutrophil Extracellular Traps in Periodontitis

Magán‐Fernández

Al-Bakri

O’Valle

et al. 2020

Cells

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“…CatC inhibition could activate this process at least in promyelocytes. Furthermore, Bullon et al (42) recently reported that PLS fibroblasts accumulated autophagosomes, which results in an autophagic dysfunction. This observation could well explain the elimination of several proteins in PLS neutrophils, including NSP zymogens and mutated CatC.…”

Section: Cathepsin C Inactivation and Membrane-bound Proteinasementioning

confidence: 99%

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

Seren

Abouzaid

Eulenberg-Gustavus

et al. 2018

Journal of Biological Chemistry

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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.

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“…Recently Bullon et al in a landmark paper designed a recombinant CstC protein by means of baculovirus expression vector system (BEVS) coupled to an insect cell culture system. This protein was able to repair autophagic dysfunction in skin fibroblast isolated from Papillon-Lefèvre syndrome patients in vitro (Bullon et al, 2018). Papillon-Lefèvre syndrome is an extremely rare autosomal recessive genetic disorder characterised by a NET-driven severe destruction of periodontium (Van Dyke et al, 1984, Hahn et al, 2018.…”

Section: Novel Directions Of Autophagy Research In Pdsmentioning

confidence: 97%

Autophagy in periodontal disease: Evidence from a literature review

Lorenzo-Pouso¹,

Castelo‐Baz²,

Pérez‐Sayáns³

et al. 2019

Archives of Oral Biology

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Objective: To summarize evidence and data in relation to the implications of autophagy in periodontal disease (PD) and describe potential nutraceuticals or pharmaceuticals able to modulate this subtype of cell death. Design: Literature searches of different electronic databases (Medline via PubMed, SCOPUS, Web of Science, and EMBASE) using appropriate keywords (e.g. periodontal disease, periodontitis, alveolar bone loss, periodontal infection, tooth loss, autophagy, programmed cell death, type 2 cell death) were performed. Then, a comprehensive literature review of the current understanding of this link was elaborated. Results: Autophagy plays a pivotal role in PD and it seems that its regulation may be an interesting avenue for future periodontal research according to several in vivo and in vitro reports. Conclusion: Nowadays research has ascertained the role of autophagy in PD, specially its role in the host defence against periodontal disease drivers. A bulk of research has recognized several pharmaceuticals and nutraceuticals that can potentially modulate this kind of cell death and serve as useful therapies. However, further research is warranted in order to reach a clinical translation, which could be of help in the discovery of novel host modulation therapies for PD.

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Autophagic dysfunction in patients with Papillon-Lefèvre syndrome is restored by recombinant cathepsin C treatment

Abstract: Our data provide a novel molecular mechanism underlying PLS. Impaired autophagy caused by insufficient lysosomal function might represent a new therapeutic target for PLS.

Cited by 25 publications

References 32 publications

Neutrophil Extracellular Traps in Periodontitis

Neutrophil Extracellular Traps in Periodontitis

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

Autophagy in periodontal disease: Evidence from a literature review

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