scholarly journals Role of Polymorphonuclear Leukocyte-Derived Serine Proteinases in Defense against Actinobacillus actinomycetemcomitans

2006 ◽  
Vol 74 (9) ◽  
pp. 5284-5291 ◽  
Author(s):  
Susanne F. de Haar ◽  
Pieter S. Hiemstra ◽  
Martijn T. J. M. van Steenbergen ◽  
Vincent Everts ◽  
Wouter Beertsen
Keyword(s):  
Polymorphonuclear Leukocyte ◽  
Serine Proteases ◽  
Pathogenic Bacteria ◽  
Cell Damage ◽  
Severe Form ◽  
Cathepsin G ◽  
Actinobacillus Actinomycetemcomitans ◽  
Periodontal Pocket ◽  
Serine Proteinases ◽  
Loss Of Function

ABSTRACT Periodontitis is a chronic destructive infection of the tooth-supportive tissues, which is caused by pathogenic bacteria such as Actinobacillus actinomycetemcomitans. A severe form of periodontitis is found in Papillon-Lefèvre syndrome (PLS), an inheritable disease caused by loss-of-function mutations in the cathepsin C gene. Recently, we demonstrated that these patients lack the activity of the polymorphonuclear leukocyte (PMN)-derived serine proteinases elastase, cathepsin G, and proteinase 3. In the present study we identified possible pathways along which serine proteinases may be involved in the defense against A. actinomycetemcomitans. Serine proteinases are capable to convert the PMN-derived hCAP-18 into LL-37, an antimicrobial peptide with activity against A. actinomycetemcomitans. We found that the PMNs of PLS patients released lower levels of LL-37. Furthermore, because of their deficiency in serine proteases, the PMNs of PLS patients were incapable of neutralizing the leukotoxin produced by this pathogen, which resulted in increased cell damage. Finally, the capacity of PMNs from PLS patients to kill A. actinomycetemcomitans in an anaerobic environment, such as that found in the periodontal pocket, seemed to be reduced. Our report demonstrates a mechanism that suggests a direct link between an inheritable defect in PMN functioning and difficulty in coping with a periodontitis-associated pathogen.

scholarly journals A rare CTSC mutation in Papillon-Lefèvre Syndrome results in abolished serine protease activity and reduced NET formation but otherwise normal neutrophil function

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261724
Author(s):  
Felix P. Sanchez Klose ◽  
Halla Björnsdottir ◽  
Agnes Dahlstrand Rudin ◽  
Tishana Persson ◽  
Arsham Khamzeh ◽  
...  
Keyword(s):  
Protease Activity ◽  
Serine Proteases ◽  
Fungal Infections ◽  
Active Form ◽  
Neutrophil Function ◽  
Amino Acid Replacement ◽  
Cathepsin G ◽  
Monogenic Disease ◽  
Loss Of Function ◽  
Palmoplantar Hyperkeratosis

Papillon-Lefèvre Syndrome (PLS) is an autosomal recessive monogenic disease caused by loss-of-function mutations in the CTSC gene, thus preventing the synthesis of the protease Cathepsin C (CTSC) in a proteolytically active form. CTSC is responsible for the activation of the pro-forms of the neutrophil serine proteases (NSPs; Elastase, Proteinase 3 and Cathepsin G), suggesting its involvement in a variety of neutrophil functions. In PLS neutrophils, the lack of CTSC protease activity leads to inactivity of the NSPs. Clinically, PLS is characterized by an early, typically pre-pubertal, onset of severe periodontal pathology and palmoplantar hyperkeratosis. However, PLS is not considered an immune deficiency as patients do not typically suffer from recurrent and severe (bacterial and fungal) infections. In this study we investigated an unusual CTSC mutation in two siblings with PLS, a 503A>G substitution in exon 4 of the CTSC gene, expected to result in an amino acid replacement from tyrosine to cysteine at position 168 of the CTSC protein. Both patients bearing this mutation presented with pronounced periodontal pathology. The characteristics and functions of neutrophils from patients homozygous for the 503A>G CTSC mutation were compared to another previously described PLS mutation (755A>T), and a small cohort of healthy volunteers. Neutrophil lysates from patients with the 503A>G substitution lacked CTSC protein and did not display any CTSC or NSP activity, yet neutrophil counts, morphology, priming, chemotaxis, radical production, and regulation of apoptosis were without any overt signs of alteration. However, NET formation upon PMA-stimulation was found to be severely depressed, but not abolished, in PLS neutrophils.

Modulation of tissue factor and tissue factor pathway inhibitor-1 by neutrophil proteases

2008 ◽  
Vol 100 (12) ◽  
pp. 1068-1075 ◽  
Author(s):  
Birgit A. Steppich ◽  
Isabell Seitz ◽  
Gabi Busch ◽  
Andreas Stein ◽  
Ilka Ott
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Tissue Factor ◽  
Serine Proteases ◽  
Tissue Factor Pathway Inhibitor ◽  
Cell Damage ◽  
Umbilical Vein ◽  
Neutrophil Activation ◽  
Cathepsin G ◽  
Tissue Factor Pathway

SummaryDuring systemic inflammation, neutrophil activation is accompanied by endothelial cell damage and hypercoagulability. Activated neutrophils release serine proteases that participate in tissue injury.We sought to investigate the effects of neutrophil proteases on proinflammatory and procoagulant changes in endothelial cells.The effects of elastase (HNE), cathepsin G (CG), and proteinase 3 (PR3) on expression of tissue factor (TF) and tissue factor pathway inhibitor-1 (TFPI) were examined in human umbilical vein endothelial cells. Flow cytometry demonstrated that these proteases proteolytically degraded endothelial cell-bound TFPI. TFPI mRNA expression was reduced by HNE and CG. PR3, but not HNE or CG, increased surface expression of TF and TF mRNA.Yet, increased TF expression did not enhance TF activity suggesting induction of encrypted TF. Using antibodies and siRNA to inhibit and silence PAR-1 and PAR-2, we observed that PR3 upregulation of TF is at least in part mediated by PAR-1.Although CG and HNE cleaved PAR-1, antibody reactivity to the PAR-1 hirudin-like sequence demonstrated inactivating cleavage, accounting for the selective ability of PR3 to induce PAR-1-mediated procoagulant effects.This was supported by induction of p42/44 MAPK by PR3. In conclusion, PR3 degradation of TFPI increases the procoagulant activity of endothelial cells. Release of PR3 after neutrophil activation may represent an important step in neutrophil-mediated vascular injury.

Precursor processing by SBT3.8 and phytosulfokine signaling contribute to drought stress tolerance in Arabidopsis

2021 ◽  
Author(s):  
Nils Stührwohldt ◽  
Eric Bühler ◽  
Margret Sauter ◽  
Andreas Schaller
Keyword(s):  
Drought Stress ◽  
Osmotic Stress ◽  
Stress Tolerance ◽  
Serine Proteases ◽  
Loss Of Function ◽  
Lateral Root Development ◽  
Osmotic Stress Tolerance ◽  
Stress Symptoms ◽  
C Terminus ◽  
Peptide Precursor

Abstract Increasing drought stress poses a severe threat to agricultural productivity. Plants, however, evolved numerous mechanisms to cope with such environmental stress. Here we report that the stress-induced production of a peptide signal contributes to stress tolerance. The expression of phytosulfokine (PSK) peptide precursor genes, and transcripts of three subtilisin-like serine proteases, SBT1.4, SBT3.7 and SBT3.8 were found to be up-regulated in response to osmotic stress. Stress symptoms were enhanced in sbt3.8 loss-of-function mutants and could be alleviated by PSK treatment. Osmotic stress tolerance was improved in plants overexpressing the precursor of PSK1 (proPSK1) or SBT3.8 resulting in higher fresh weight and improved lateral root development in the transgenic compared to wild-type plants. We further showed that SBT3.8 is involved in the biogenesis of the bioactive PSK peptide. ProPSK1 was cleaved by SBT3.8 at the C-terminus of the PSK pentapeptide. Processing by SBT3.8 depended on the aspartic acid residue directly following the cleavage site. ProPSK1 processing was impaired in the sbt3.8 mutant. The data suggest that increased expression in response to osmotic stress followed by the post-translational processing of proPSK1 by SBT3.8 leads to the production of PSK as a peptide signal for stress mitigation.

Amniotic Stem Cell-Conditioned Media for the Treatment of Nerve and Muscle Pathology: A Systematic Review

2021 ◽  
Author(s):  
Chukwuweike Gwam ◽  
Ahmed Emara ◽  
Nequesha Mohamed ◽  
Noor Chughtai ◽  
Johannes Plate ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Tissue Regeneration ◽  
Cell Damage ◽  
Conditioned Media ◽  
Nerve Tissue ◽  
Muscle Pathology ◽  
Loss Of Function ◽  
Cell Based Therapy

Muscle and nerve tissue damage can elicit a significant loss of function and poses as a burden for patients and healthcare providers. Even for tissues, such as the peripheral nerve and skeletal muscle, that harbor significant regenerative capacity, innate regenerative processes often lead to less than optimal recovery and residual loss of function. The reasons for poor regeneration include significant cell damage secondary to oxidative stress, poor recruitment of resident stem cells, and an unfavorable microenvironment for tissue regeneration. Stem cell-based therapy was once thought as a potential therapy in tissue regeneration, due to its self-renewal and multipotent capabilities. Early advocates for cellular-based therapy pointed to the pluripotent nature of stem cells, thus eluding to its ability to differentiate into resident cells as the source of its regenerative capability. However, increasing evidence has revealed a lack of engraftment and differentiation of stem cells, thereby pointing to stem cell paracrine activity as being responsible for its regenerative potential. Stem cell-conditioned media houses biomolecular factors that portray significant regenerative potential. Amniotic-derived stem cell-conditioned media (AFS-CM) has been of particular interest because of its ease of allocation and in vitro culture. The purpose of this review is to report the results of studies that assess the role of AFS-CM for nerve and muscle conditions. In this review, we will cover the effects of AFS-CM on cellular pathways, genes, and protein expression for different nerve and muscle cell types.

scholarly journals The Mouse Testis Is the Source of Various Serine Proteases and Serine Proteinase Inhibitors (SERPINs): Serine Proteases and SERPINs Identified in Leydig Cells Are under Gonadotropin Regulation

Endocrinology ◽  
2006 ◽  
Vol 147 (9) ◽  
pp. 4374-4383 ◽  
Author(s):  
Fanny Odet ◽  
Adélie Verot ◽  
Brigitte Le Magueresse-Battistoni
Keyword(s):  
Extracellular Matrix ◽  
Plasminogen Activator ◽  
Serine Proteases ◽  
Leydig Cells ◽  
Proteinase Inhibitors ◽  
Primary Cultures ◽  
Serine Proteinases ◽  
Rt Pcr ◽  
Positive Effects ◽  
Extracellular Matrix Components

The occurrence of various serine proteinases and serine proteinases inhibitors (SERPINs) was investigated by RT-PCR in whole testes of 1-, 3-, and 8-wk-old mice in crude and enriched germ cell fractions, mouse Leydig tumor cells (mLTC-1), and primary cultures of 3- and 8-wk-old enriched fractions of Leydig cells and 3-wk-old Sertoli cells. New members were identified in the testis protease repertoire. Within the Leydig repertoire, a PCR product was found for plasminogen activators urokinase plasminogen activator (uPA) and tissue plasminogen activator (8-wk-old cells), matriptase-2 (mLTC-1), kallikrein-21, SERPINA5, SERPINB2 (primary cultures), and serine peptidase inhibitor Kunitz type 2 (SPINT2). The gonadotropin regulation was explored by semiquantitative RT-PCR, using steroidogenic acute regulatory protein (StAR) as a positive control. Matriptase-2, kallikrein-21, SPINT2, and SERPINA5 were down-regulated, whereas uPA and its receptor were up-regulated by human chorionic gonadotropin (hCG) via cAMP in the mLTC-1 cells. Positive effects were observed transiently after 1–8 h of hCG exposure, and negative effects, first evidenced after 6 h, lasted 48 h. The hCG-induced effects were confirmed in primary cultures. In addition, SERPINB2 was augmented by hCG in primary cultures. Addition of either trypsin or protease inhibitors did not alter the hCG-induced surge of StAR. Because hCG regulated proteases and SERPINs (whereas testosterone did not), it could alter the proteolytic balance of Leydig cells and consequently the metabolism of extracellular matrix components. Therefore, even though a direct interplay between the early hCG-induced surge of uPA and StAR is unlikely, our data together with the literature suggest that extracellular matrix proteins alter Leydig cell steroidogenesis.

scholarly journals The Evolutionary History of the Chymase Locus -a Locus Encoding Several of the Major Hematopoietic Serine Proteases

2021 ◽  
Vol 22 (20) ◽  
pp. 10975
Author(s):  
Srinivas Akula ◽  
Zhirong Fu ◽  
Sara Wernersson ◽  
Lars Hellman
Keyword(s):  
Mast Cell ◽  
T Cell ◽  
Serine Proteases ◽  
Phylogenetic Trees ◽  
Granzyme B ◽  
Large Family ◽  
Cathepsin G ◽  
Immune Functions ◽  
New Class ◽  
History Of

Several hematopoietic cells of the immune system store large amounts of proteases in cytoplasmic granules. The absolute majority of these proteases belong to the large family of chymotrypsin-related serine proteases. The chymase locus is one of four loci encoding these granule-associated serine proteases in mammals. The chymase locus encodes only four genes in primates, (1) the gene for a mast-cell-specific chymotryptic enzyme, the chymase; (2) a T-cell-expressed asp-ase, granzyme B; (3) a neutrophil-expressed chymotryptic enzyme, cathepsin G; and (4) a T-cell-expressed chymotryptic enzyme named granzyme H. Interestingly, this locus has experienced a number of quite dramatic expansions during mammalian evolution. This is illustrated by the very large number of functional protease genes found in the chymase locus of mice (15 genes) and rats (18 genes). A separate expansion has also occurred in ruminants, where we find a new class of protease genes, the duodenases, which are expressed in the intestinal region. In contrast, the opossum has only two functional genes in this locus, the mast cell (MC) chymase and granzyme B. This low number of genes may be the result of an inversion, which may have hindered unequal crossing over, a mechanism which may have been a major factor in the expansion within the rodent lineage. The chymase locus can be traced back to early tetrapods as genes that cluster with the mammalian genes in phylogenetic trees can be found in frogs, alligators and turtles, but appear to have been lost in birds. We here present the collected data concerning the evolution of this rapidly evolving locus, and how these changes in gene numbers and specificities may have affected the immune functions in the various tetrapod species.

scholarly journals Detection of highly and minimally leukotoxic Actinobacillus actinomycetemcomitans strains in patients with periodontal disease

2003 ◽  
Vol 17 (2) ◽  
pp. 183-188 ◽  
Author(s):  
Sheila Cavalca Cortelli ◽  
Antonio Olavo Cardoso Jorge ◽  
José Roberto Cortelli ◽  
Shawn Francis Jordan ◽  
Violet Ibyola Haraszthy
Keyword(s):  
Periodontal Disease ◽  
Strong Association ◽  
Aggressive Periodontitis ◽  
Actinobacillus Actinomycetemcomitans ◽  
Periodontal Pocket ◽  
Chain Reaction ◽  
Chi Square ◽  
Pocket Depth ◽  
Polymerase Chain ◽  
Brazilian Cohort

This study examined the prevalence of highly and minimally leukotoxic Actinobacillus actinomycetemcomitans in patients with periodontal disease. Pooled subgingival plaque samples from 136 patients with some form of periodontal disease were examined. Subjects were between 14 and 76 years of age. Clinical examinations included periodontal pocket depth (PD), plaque index (PI) and bleeding index (BI). The obtained plaque samples were examined for the presence of highly or minimally leukotoxic A. actinomycetemcomitans strains by the polymerase chain reaction (PCR). Chi-square and logistic regression were performed to evaluate the results. Forty-seven subjects were diagnosed with gingivitis, 70 with chronic periodontitis and 19 with aggressive periodontitis. According to chi-square there was no significant correlation detected between PD (chi2 = 0.73), PI (chi2 = 0.35), BI (chi2 = 0.09) and the presence of the highly leukotoxic A. actinomycetemcomitans. The highly leukotoxic A. actinomycetemcomitans strains were correlated with subjects that were 28 years of age and younger (chi2 = 7.41). There was a significant correlation between highly leukotoxic A. actinomycetemcomitans and aggressive periodontitis (chi2 = 22.06). This study of a Brazilian cohort confirms the strong association between highly leukotoxic A. actinomycetemcomitans strains and the presence of aggressive periodontitis.

scholarly journals Leigh Syndrome Due to NDUFV1 Mutations Initially Presenting as LBSL

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1325
Author(s):  
Nurun Nahar Borna ◽  
Yoshihito Kishita ◽  
Norio Sakai ◽  
Yusuke Hamada ◽  
Koji Kamagata ◽  
...  
Keyword(s):  
Brain Mri ◽  
Leigh Syndrome ◽  
Rare Condition ◽  
Psychomotor Retardation ◽  
Dorsal Column ◽  
Severe Form ◽  
Cerebral White Matter ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Loss Of Function ◽  
Radiological Features

Leigh syndrome (LS) is most frequently characterized by the presence of focal, bilateral, and symmetric brain lesions Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare condition, characterized by progressive pyramidal, cerebellar, and dorsal column dysfunction. We describe a case with infantile-onset neurodegeneration, psychomotor retardation, irritability, hypotonia, and nystagmus. Brain MRI demonstrated signal abnormalities in the deep cerebral white matter, corticospinal and dorsal column tracts, and pyramids, which resemble the MRI pattern of a severe form of LBSL, and involvement of basal ganglia and thalamus that resemble the radiological features of LS. We identified biallelic loss-of-function mutations, one novel (c.756delC, p.Thr253Glnfs*44) and another reported (c.1156C > T, p.Arg386Cys), in NDUFV1 (NADH:Ubiquinone Oxidoreductase Core Subunit V1) by exome sequencing. Biochemical and functional analyses revealed lactic acidosis, complex I (CI) assembly and enzyme deficiency, and a loss of NDUFV1 protein. Complementation assays restored the NDUFV1 protein, CI assembly, and CI enzyme levels. The clinical and radiological features of this case are compatible with the phenotype of LS and LBSL associated with NDUFV1 mutations.

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