cathepsin-g and Psoriasis

Sterile inflammation is initiated by molecules released from necrotic cells, called damage-associated molecular patterns (DAMPs). Members of the extended IL-1 cytokine family are important DAMPs, are typically only released through necrosis, and require limited proteolytic processing for activation. The IL-1 family cytokines, IL-36α, IL-36β, and IL-36γ, are expressed as inactive precursors and have been implicated as key initiators of psoriatic-type skin inflammation. We have recently found that IL-36 family cytokines are proteolytically processed and activated by the neutrophil granule-derived proteases, elastase, and cathepsin G. Inhibitors of IL-36 processing may therefore have utility as anti-inflammatory agents through suppressing activation of the latter cytokines. We have identified peptide-based pseudosubstrates for cathepsin G and elastase, based on optimal substrate cleavage motifs, which can antagonize activation of all three IL-36 family cytokines by the latter proteases. Human psoriatic skin plaques displayed elevated IL-36β processing activity that could be antagonized by peptide pseudosubstrates specific for cathepsin G. Thus, antagonists of neutrophil-derived proteases may have therapeutic potential for blocking activation of IL-36 family cytokines in inflammatory conditions such as psoriasis.

Topics: Anti-Inflammatory Agents; Cathepsin G; HeLa Cells; Humans; Inflammation; Interleukin-1; Neutrophils; Pancreatic Elastase; Peptide Hydrolases; Psoriasis; Skin

Generalized pustular psoriasis (GPP) is an autoinflammatory skin disease whose pathogenesis has not yet been fully elucidated. Alpha-1-antichymotrypsin(ACT) is a protein encoded by the SERPINA3 gene and an inhibitor of cathepsin G. One study of a European sample suggested that the loss of ACT function caused by SERPINA3 mutation is implicated in GPP. However, the role of SERPINA3 in the pathogenesis of GPP in other ethnic populations is unclear. To explore this, seventy children with GPP were performed next-generation sequencing to identify rare variants in the SERPINA3 gene. Bioinformatic analysis and functional tests were used to determine the effects of the variants, and a comprehensive analysis was performed to determine the pathogenicity of the variants and whether they are associated with GPP. One rare deletion and three rare missense variants were identified in the SERPINA3 gene in GPP. The deletion variant c.1246_1247del was found to result in a mutant protein with an extension of 10 amino acids and a C-terminal of 20 amino acids that was completely different from the wild-type. This mutant was found to impede secretion of ACT, thus failing to function as an inhibitor of cathepsin G. Two missense variants were found to reduce the ability of ACT to inhibit cathepsin G enzymatic activity. The association analysis suggested that the deletion variant is associated with GPP. This study identified four rare novel mutations of SERPINA3 and demonstrated that three of these mutations result in loss of function, contributing to the pathogenesis of pediatric-onset GPP in the Asian population.

Topics: Cathepsin G; Child; Humans; Interleukins; Mutation; Psoriasis; Serpins; Skin Diseases

Growing evidence suggests the important role of IL-36 in the pathogenesis of psoriasis. Cathepsin G is a neutrophil-derived protease that can activate IL-36γ.. To assess the expression of IL-36γ and cathepsin G in psoriasis and to quantify the impact of treatment with narrow-band ultraviolet B phototherapy (NB-UVB) on their levels.. This case-control study involved 26 patients with moderate-severe psoriasis and 25 healthy volunteers. Psoriasis patients eligible for phototherapy received 24 NB-UVB sessions. Punch skin biopsies were obtained from all participants at recruitment and after phototherapy from patients. Real-time PCR was utilized for quantitative assessment of IL-36γ and cathepsin G expression in tissue samples.. The expression of IL-36γ and cathepsin G was significantly higher in psoriasis before NB-UVB therapy compared to controls (. IL-36γ and cathepsin G expression is upregulated in psoriatic lesions, supporting their role as mediators of inflammation in psoriasis. Downregulation of IL-36γ and cathepsin G is a possible mechanism for psoriasis improvement after NB-UVB therapy. IL-36 and cathepsin G can be considered as therapeutic targets for psoriasis.

Topics: Case-Control Studies; Cathepsin G; Down-Regulation; Humans; Interleukin-1; Interleukins; Phototherapy; Psoriasis; Ultraviolet Therapy

Psoriasis therapy remains an extremely relevant area of modern drug design, due to necessity of adverse reaction reduction, inherent for actual methods of therapy. It was established that two serine proteases-neutrophil elastase 1 (HNE1) and cathepsin G (CatG)-are the key agents in psoriasis development. The collected molecular data for the presented targets form the basis for the molecular modeling strategy for the search for and identification of new target-specific inhibitors. The result of this work is a group of high-priority small-molecule compounds with double-targeted affinity, which are able to suppress the pro-psoriatic processes induced by the considered serine proteases at the initial stage of the disease.

Topics: Cathepsin G; Drug Discovery; Leukocyte Elastase; Models, Molecular; Molecular Targeted Therapy; Protein Conformation; Psoriasis; Serine Proteinase Inhibitors

IL-36γ is considered to be a valuable biomarker in psoriatic patients, which is expressed as an inactive precursor that needs to be proteolytically processed and activated, and neutrophil-derived proteases seemed to be potent activating enzymes of IL-36γ.. This study aims to investigate the activation of IL-36γ by cathepsin G (CG) and neutrophil elastase (NE).. We used inactive recombinant full-length (FL)-IL-36γ with different doses of NE or CG to stimulate HaCaT cells; neutrophil extracellular traps (NETs) were prepared to act on FL-IL-36γ and then stimulate HaCaT cells. Real-time quantitative PCR and ELISA were performed to detect CXCL-1 and CXCL-8 expression. We developed imiquimod-induced psoriasis-like mouse model to evaluate the effect of hypodermic injection of neutrophil-derived protease or its inhibitor. Histopathology and Western blotting were conducted for effect assessment.. Purified CG cleaved and activated recombinant human FL-IL-36γ to promote CXCL-1 and CXCL-8 expression by human keratinocytes, and NETs activated FL-IL-36γ and the activation was inhibited by serpin A3. CG induced expression of a more truncated IL-36γ in psoriasiform lesion of mice and aggravated the psoriasis-like lesion induced by imiquimod, whereas recombinant serpin A3 alleviated the severity of the psoriasis-like mouse mode.. CG has the ability to cleave and activate IL-36γ and aggravate imiquimod-induced mouse psoriasiform lesion. Thus, CG-specific inhibitors might be promising therapeutic drugs for psoriasis.

Topics: Animals; Cathepsin G; Female; Humans; Inflammation; Interleukin-1; Leukocyte Elastase; Mice; Mice, Inbred BALB C; Psoriasis; Tumor Cells, Cultured

Ten patients were treated with repeated leukophereses performed one to three times per week for 2-5 weeks. Two of the patients was cleared completely, four exhibited regression of more than one-half of the lesions, and four showed only a slight improvement. The therapy did not markedly affect the granulocyte count in peripheral blood, and the beneficial clinical response was not related to the number of polymorphonuclear leukocytes (PMNs) removed by leukophereses. During therapy, the activities of elastase, cathepsin G, lysozyme, and myeloperoxidase in PMNs were determined by spectrophotometry. PMNs isolated using a Haemonetics 30 blood-cell separator were about 50% deficient in these activities in comparison to cells obtained directly from peripheral blood. Thus, leukopheresis induces a marked degranulation of PMNs. Repeated leukophereses were found to generate significant variations in the activities of circulating PMN granule enzymes and in the levels of acid-soluble proteins. Remission or great improvement were observed in patients who, during therapy, exhibited decreased PMN elastase and cathepsin G activities, whereas a poor clinical response was accompanied by high enzymatic activities.

Topics: Adult; Cathepsin G; Cathepsins; Endopeptidases; Female; Humans; Leukapheresis; Male; Middle Aged; Muramidase; Neprilysin; Neutrophils; Pancreatic Elastase; Peroxidase; Psoriasis; Serine Endopeptidases

The activities of elastase, cathepsin G, lysozyme and myeloperoxidase of polymorphonuclear leukocytes were determined by spectrophotometry in thirty-six patients with psoriatic lesions, twelve symptom-free patients with psoriasis and fifteen normal controls. The mean activities of cathepsin G, elastase and lysozyme were found to be increased by 55 to 70% in patients with actively spreading plaque lesions compared with healthy controls (P less than 0.01). Most patients with guttate lesions had total enzyme activities within the normal range. Those with stationary plaque psoriasis had activities of both neutral proteinases (cathepsin G and elastase) which were about 40% lower than normal controls (P less than 0.05). In the lesion-free psoriatics, the activities of neutral proteinases were about 70% of control values. Our findings emphasize the importance of assessment of disease activity in this sort of investigation. The present data may help to resolve much of the confusion regarding PMN function in psoriasis.

Topics: Cathepsin G; Cathepsins; Cytoplasmic Granules; Endopeptidases; Humans; Muramidase; Neutrophils; Pancreatic Elastase; Peroxidase; Psoriasis; Serine Endopeptidases; Time Factors