Effects of Granulocyte Neutral Proteases on Complement Components

Johnson, Ulf; Ohlsson, Kjell; Olsson, Inge

doi:10.1111/j.1365-3083.1976.tb00296.x

Cited by 95 publications

(43 citation statements)

References 17 publications

(10 reference statements)

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“…5G). These data are consistent with early demonstrations of PMN-derived cationic and neutral protease C3 cleavage and C3a generation (60,61), as well as recent studies of ELANE C3 cleavage and C3a generation (59). Critically, in this regard, inhibition of C3a generation by EDTA in our data does not necessarily reflect C3 convertase inhibition, as EDTA has been shown to bind and inhibit ELANE (62).…”

Section: Pmn-and Mf-cm Factorssupporting

confidence: 80%

Neutrophils Induce Astroglial Differentiation and Migration of Human Neural Stem Cells via C1q and C3a Synthesis

Hooshmand

Nguyen

Piltti

et al. 2017

The Journal of Immunology

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Inflammatory processes play a key role in pathophysiology of many neurologic diseases/trauma, but the effect of immune cells and factors on neurotransplantation strategies remains unclear. We hypothesized that cellular and humoral components of innate immunity alter fate and migration of human neural stem cells (hNSC). In these experiments, conditioned media collected from polymorphonuclear leukocytes (PMN) selectively increased hNSC astrogliogenesis and promoted cell migration in vitro. PMN were shown to generate C1q and C3a; exposure of hNSC to PMN-synthesized concentrations of these complement proteins promoted astrogliogenesis and cell migration. Furthermore, in vitro, Abs directed against C1q and C3a reversed the fate and migration effects observed. In a proof-of-concept in vivo experiment, blockade of C1q and C3a transiently altered hNSC migration and reversed astroglial fate after spinal cord injury. Collectively, these data suggest that modulation of the innate/humoral inflammatory microenvironment may impact the potential of cell-based therapies for recovery and repair following CNS pathology.

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Section: Pmn-and Mf-cm Factorssupporting

confidence: 80%

Neutrophils Induce Astroglial Differentiation and Migration of Human Neural Stem Cells via C1q and C3a Synthesis

Hooshmand

Nguyen

Piltti

et al. 2017

The Journal of Immunology

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“…Since granulocyte elastase in vitro not only inactivates C3 [6,7] but also IgG and IgM [10,11], it is conceivable that free granulocyte elastase in vivo leads to functional inactivation of these opsonins and thereby favors the persistence of microorganisms, a well known characteristic of P aeruginosa infections in these patients [2,3].…”

Section: Discussionmentioning

confidence: 99%

“…Since the activities of the three enzymes measured could possibly be attributed to the presence of PMN neutral proteases [6][7][8]29], correlations between enzymatic activities within each group were calculated. Group 1: a linear correlation was found between 125I-labeled C3-cleaving and granulocyte elastase-like activity (r = .49, P < .025) and between elastolytic and granulocyte elastaselike activity (r = .89, P < .001).…”

Section: Leukocyte Quantitation and Protein Concentra-mentioning

confidence: 99%

“…These enzymes are indeed able to destroy important structural proteins of the lung and its airways such as elastin, collagen, and proteoglycans [4,5] in vitro; in addition, they can inactivate important opsonins such as complement component C3 [6][7][8] and IgG and IgM immunoglobulins [9][10][11]. It is also well established that they are released extracellularly during phagocytosis [12].…”

mentioning

confidence: 99%

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Granulocyte Neutral Proteases and Pseudomonas Elastase as Possible Causes of Airway Damage in Patients with Cystic Fibrosis

Suter¹,

Schaad²,

Roux³

et al. 1984

Journal of Infectious Diseases

193

127

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We studied the possible role of granulocyte neutral proteases as mediators of airway destruction in patients with cystic fibrosis (CF) who were infected with Pseudomonas aeruginosa. We measured the enzymatic activities of bronchial secretions on purified radioactively labeled complement component three (C3), elastin, and a granulocyte elastase-specific substrate. Bronchial secretions from 18 patients with CF who were infected with P aeruginosa had a significantly higher mean value for C3 cleaving, elastolytic, and granulocyte elastase-like activity than did two control groups. High enzymatic activities were observed in patients with CF who have advanced bronchial disease (that had been determined by a clinical scoring system). Kinetics of proteolysis of radioactively labeled C3 and inhibition profiles of the activities of the three enzymatic activities studied suggest that they are mainly derived from granulocytes. In addition, 20 of 31 strains of P aeruginosa isolated from patients with CF inactivated purified o l-antiprotease in vitro. We postulate that granulocyte neutral proteases and P aeruginosa may act synergistically in the airways of patients with CF and may contribute to the destruction of elastin and inactivation of C3.Cystic fibrosis is a fatal hereditary disease, in which the leading cause of death is respiratory failure [I]. Patients with cystic fibrosis (CF) usually have a long history of purulent bronchitis leading to progressive destruction of small bronchioles and followed by involvement of the large airways [2]. The pathogens most frequently associated with these respiratory-tract infections are Staphylococcus aureus and Pseudomonas aeruginosa [2,3]. Clinical and pathological observations suggest that progressive airway destruction is accelerated during infections with P aeruginosa [2]. However, little information is available regarding the mechanisms involved in progressive bronchiolar and bronchial damage and the persistence of P aeruginosa in bronchial secretions.Bronchial secretions from patients with CF con- [4,5]. These enzymes are indeed able to destroy important structural proteins of the lung and its airways such as elastin, collagen, and proteoglycans [4,5] in vitro; in addition, they can inactivate important opsonins such as complement component C3 [6][7][8] and IgG and IgM immunoglobulins [9][10][11]. It is also well established that they are released extracellularly during phagocytosis [12]. Furthermore, P aeruginosa may secrete an elastase that destroys the two main inhibitors protecting the lung and its airways from the activity of PMN neutral proteases: al-antiprotease [13][14][15][16] and the bronchial mucosal proteinase inhibitor [17]. In addition, this bacterial elastase is also active on C3[18] and elastin [15].We therefore measured the enzymatic activities of bronchial secretions from patients with CF (who were infected with P aeruginosa) on purified human C3, bovine elastin, and a granulocyte elastase-specific substrate. Two groups of patients with bronchial secretions r...

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“…Activation proceeds through the cleavage of native C3 by either the classical (C42) or the alternative (C3b, Bb) pathway convertase of C3 or both [2,3]. Recently it has been shown in vitro [4][5][6][7][8] that C3, as well as C5, can be split by complement-unrelated enzymes, such as purified neutral proteases from PMNLs. These reports have shown that the purified granular enzymes elastase, collagenase, and cathepsin G can act on C3 and C5 by splitting small fragments similar in size to C3a and C5a from the native molecules.…”

mentioning

confidence: 99%

Cleavage of C3 by Neutral Proteases from Granulocytes in Pleural Empyema

Suter

Nydegger

Roux

et al. 1981

Journal of Infectious Diseases

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The possibility of direct inactivation of C3 by granular enzymes from polymorphonuclear leukocytes (PMNLs) in pleural empyema was examined. As a group, pleural empyema from 10 patients with purulent effusions and a positive bacteriologic culture cleaved significantly more 125I-labeled C3 bound to Sepharose (18.4070 ± 7.3070) than did 19 sterile pleural effusions (2.4070 ± 0.9070; P« 0.001) and sonicates from bacterial strains commonly found in empyema (1.4070 ± 0.2070). Granular enzymes from 7 x 10 6 PMNLs cleaved 78.5070 of 125I-labeled C3 bound to Sepharose. When proteolysis of 125I-labeled C3 after incubation with pleural empyema or PMNL granular enzymes was examined with polyacrylamide gel electrophoresis, breakdown products were similar. Granulocyte elastase-like activity was detected in four samples of pleural empyema. Granulocyte elastase inhibitors, as well as 10070 human serum, effectively suppressed cleavage of C3 and elastase-like activity. In pleural empyemas, granular enzymes from PMNLs, especially elastase, apparently contribute to low complement-mediated opsonic activity by direct inactivation of C3.Pleural empyema is a closed-space infection defined by the simultaneous presence of large numbers of live microorganisms and polymorphonuclear leukocytes (PMNLs). The disease is further characterized by its chronic evolution and its poor response to medical and sometimes even surgical therapy.Work from our laboratory [1] has shown that the persistence of live microorganisms despite the presence of large numbers of PMNLs in pleural empyemas can be partially explained by a marked decrease in complement-mediated opsonic activity in culture-positive pleural effusions. This deficiency in opsonic activity was further shown to be accompanied by the local generation of increased amounts of C3d, the inactive breakdown product of C3.Serum complement is of major importance in the humoral immune response to pyogenic infections, and C3 is currently viewed as the target molecule of both the classical and the alternative pathways of complement activation [1][2][3]. Its acReceived for publication March 10, 1981, and in revised form June 22, 1981. This work was supported in part by grant no. 3.836-0.79 from the Swiss National Research Foundation.We thank Drs. M. Baggiolini and B. Dewald for advice, suggestions, and revision of the manuscript and F. Michaud for secretarial assistance.Please address requests for reprints to Dr. F. A. Waldvogel, Department of Medicine, University Hospital, 121I Geneva 4, Switzerland.499 tivation leads to the production of the biologically active fragment C3b, and the coating of microorganisms with C3b promotes their recognition by PMNLs. Activation proceeds through the cleavage of native C3 by either the classical (C42) or the alternative (C3b, Bb) pathway convertase of C3 or both [2,3]. Recently it has been shown in vitro [4][5][6][7][8] that C3, as well as C5, can be split by complement-unrelated enzymes, such as purified neutral proteases from PMNLs. These reports have shown that the...

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Effects of Granulocyte Neutral Proteases on Complement Components

Cited by 95 publications

References 17 publications

Neutrophils Induce Astroglial Differentiation and Migration of Human Neural Stem Cells via C1q and C3a Synthesis

Neutrophils Induce Astroglial Differentiation and Migration of Human Neural Stem Cells via C1q and C3a Synthesis

Granulocyte Neutral Proteases and Pseudomonas Elastase as Possible Causes of Airway Damage in Patients with Cystic Fibrosis

Cleavage of C3 by Neutral Proteases from Granulocytes in Pleural Empyema

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