Constitutive Host Resistance
Julius P. Kreier in Infection, Resistance, and Immunity, 2022
Cells of the mononuclear phagocyte lineage initially contain granules; these are lost during differentiation. The mononuclear phagocytes, which comprise from two to eight percent of the circulating leukocytes, contain enzymes similar to those present in neutrophils (Table 3.1). The enzymes are contained within bags bounded by membranes, called lysosomes. The mononuclear phagocyte is long-lived and continues to synthesize enzymes throughout its life. The acid hydrolases of mononuclear phagocytes act at acidic pH and cleave phosphate ester bonds that occur in proteins, polysaccharides, lipids, and nucleic acids. The enzymes are distinguished by their substrates and include fucosidase, 5′nucleotidase, galactosidase, arylsulfatase, mannosidase, N-acetyl-glucosaminidase, glucuronidase, and glycerophosphatase. Other enzymes included in this group are responsible for protein hydrolysis and are called cathepsins A, B, and C, and so on. Neutral proteases include cathepsin G, whose substrates are cartilage, proteoglycans, fibro-gen, and casein, and the enzymes, eiastase and collagenase. The latter two enzymes have been shown to play an important role in the destruction of normal tissues that may occur during an inflammatory response. The peroxidase enzyme catalase protects the phagocytes from the toxic effects of the hydrogen peroxide produced following the binding and phagocytosis of foreign substances.
Inflammation
George Feuer, Felix A. de la Iglesia in Molecular Biochemistry of Human Disease, 2020
Polymorphonuclear neutrophil elastase can hydrolyze a variety of proteins; it solubilizes elastin, cartilage proteoglycan, and several types of collagen molecules. The elastase cleaves Types I and II collagens at the nonhelical teleopeptide region of the molecules which contains the intermolecular cross-links. The resultant depolymerization facilitates further nonspecific proteolytic action. Types III and IV collagens are hydrolyzed by the polymorphonuclear neutrophil elastase across the helical portion of the tropocollagen portion. In addition to these structural tissue components, a variety of important proteins present at the inflammatory sites can also be destroyed by elastase, such as intermediates of the kallikrein-kinin system, complement system, clotting and fibrinolytic cascades, and immunoglobulins.26,133 Cathepsin G shows chymotrypsin-like properties, and it attacks the microfibrillar components of the elastic fiber, proteoglycan molecules, and certain components of the complement, clotting, and fibrinolytic systems.
Dysregulation of the PA/PAI System in Pulmonary Disease (ARDS and Fibrosis)
Pia Glas-Greenwalt in Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
Although nearly a half-century of work has implicated plasminogen-dependent fibrinolytic enzymes as the major tissue fibrinolysins, additional enzymes may be important. In particular, leukocytes have been demonstrated to participate in clot resolution by pig-independent pathways.53 Neutrophils release cathepsin G and elastase during blood coagulation and this may contribute to slow clot dissolution. One could envision that neutrophil accumulation at sites of active lung injury where fibrin deposition is prominent might also promote fibrinolysis. Alternative pathways for both fibrin formation and resorption by monocyte/macrophages have also been described.54-57 Following activation of monocytes, the Mac-1 (CD 11 b/CD 18) receptor has been demonstrated to bind factor X and facilitate prothrombinase formation. Furthermore, activated Mac-1 binds fibrinogen and fibrin, competitively with factor X, and the bound fibrin(ogen) is taken up and degraded by monocytic cells. Degradation appears to involve lysosomal enzymes, especially cathepsin D.57 Activation of these Mac-1-dependent pathways may contribute to the known accumulation of fibrin around macrophages in both lung injury and lung cancer,10,58 and to slow fibrin turnover under conditions where the pig-dependent pathway is suppressed by excess inhibitors. The expression and regulation of the Mac-1-dependent pathways in the lung remains to be established, however.
Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions
Published in Platelets, 2019
Rachel A. Rigg, Laura D. Healy, Tiffany T. Chu, Anh T. P. Ngo, Annachiara Mitrugno, Jevgenia Zilberman-Rudenko, Joseph E. Aslan, Monica T. Hinds, Lisa Dirling Vecchiarelli, Terry K. Morgan, András Gruber, Kayla J. Temple, Craig W. Lindsley, Matthew T. Duvernay, Heidi E. Hamm, Owen J. T. McCarty
Release of dense granule contents from activated platelets facilitates recruitment of leukocytes to the site of injury; this process is often dysregulated in inflammatory disease [9,10]. Given the described role of platelet PAR4 in supporting the phosphorylation and activation of a number of PKC substrates requisite for platelet dense granule release [7], we examined whether PAR4 plays a disproportionate role relative to PAR1 in dense granule release. Intriguingly, PAR4 inhibitors diminished dense granule release in response to α-thrombin, while the PAR1 inhibitor SCH 79797 on its own had no effect. Furthermore, upon stimulation with the inflammatory mediators cathepsin G or plasmin, PAR4 inhibitors fully blocked dense granule release, while SCH had no effect either alone or in combination with a PAR4 inhibitor. Given that cathepsin G and plasmin are proteases known to specifically cleave PAR4 [13,14] and are released during inflammation mediated by leukocytes or during fibrinolysis [32,33], this suggests a unique and important role for PAR4 in facilitating platelet dense granule release under the inflammatory conditions.
A two-decade journey in identifying high mobility group box 1 (HMGB1) and procathepsin L (pCTS-L) as potential therapeutic targets for sepsis
Published in Expert Opinion on Therapeutic Targets, 2023
Jianhua Li, Cassie Shu Zhu, Li He, Xiaoling Qiang, Weiqiang Chen, Haichao Wang
Cathepsins (CTS) refer to a family of intracellular peptide hydrolases that include cysteine proteases of the papain family (Cathepsin B, C, F, H, L, K, O, S, V, W, and X), serine carboxypeptidases (Cathepsin G) and aspartic proteases (Cathepsin D and E) [92]. As a primary lysosomal protease with >85% amino acid sequence homology between humans and rodents (Figure 3) [93,94], Cathepsin L (CTS-L) is mainly responsible for degrading endocytosed proteins to generate immunogenic antigens for adaptive immunity (Table 1) [95,96]. Like many other cathepsins, CTS-L is also first synthesized as an inactive proenzyme (procathepsin L, pCTS-L), and can be further processed to become mature and active CTS-L enzyme (Figure 3). Unlike other papain enzymes, however, CTS-L is up-regulated in some malignantly transformed tumor cells by various growth factors such as the platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), and the pro-region-containing procathepsin L (pCTS-L) can be secreted extracellularly (Table 3) [97] to facilitate tumor invasion and metastasis [109]. Even in non-transformed cells, many inflammatory (e.g. LPS or IFN-γ) [98–100] and noxious stimuli (e.g. alcohol consumption, cigarette smoking, and UV irradiation) [101–103] can similarly induce the expression and secretion of pCTS-L in both innate immune cells [98,102] and nonimmune cells that include hepatocytes [101], dermal fibroblasts [103], and synovial fibroblasts [99] (Table 3).
Regulatory role of thiol isomerases in thrombus formation
Published in Expert Review of Hematology, 2018
The major drawback of the above-described technique is that it can only identify substrates that are subject to disulfide reduction, as CXXA variants of the active motif can never exist in an oxidized state. To identify substrate proteins of PDI which require oxidation using kinetic substrate trapping, a PDI variant must retain both active site cysteine residues, but instead be modified to perform disulfide exchange much more slowly that the wild-type PDI, so that the PDI−substrate intermediates formed during the oxidoreductate reaction can be ‘frozen’ using alkylating agents, and subsequently isolated and identified. Using two such variants where His of CGHC motif was modified to either Pro (CGPC) or Arg (CGAC) in both a and a’ domains, multiple other substrates released from activated platelets have now been identified [82]. These include factor V, annexin V, heparanase, ERp57, kallekrein 14, serpin B6, tetranectin, and collagen VI, which show a bias for reduction, whereas cathepsin G, glutaredoxin-1, thioredoxin, GPIb, and fibrinogen show a bias for oxidation by PDI. Cathepsin G is an ∝-granule protein known to play a role in thrombosis [83,84]. Treating washed platelet releasate with oxidized PDI increases the activity of native cathepsin G, confirming the physiological importance of PDI-cathepsin G interaction. Similarly, inhibition of PDI activity with quercetin-3-rutinoside significantly reduced platelet factor Va generation following platelet activation, which paralleled the reduction in platelet-dependent thrombin generation, implying that PDI is involved in conversion of platelet factor V to Va, which in turn is involved in thrombin generation [85].
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