Home Print this page Email this page Small font size Default font size Increase font size
Users Online: 284
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 30  |  Issue : 2  |  Page : 57-65

Role of proteases in pathophysiology of allergic diseases


Allergy and Immunology Section, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India

Date of Web Publication5-Dec-2016

Correspondence Address:
Naveen Arora
Room 509, Allergy and Immunology Section, CSIR-Institute of Genomics and Integrative Biology, Delhi University Campus, Mall Road, New Delhi - 110 007
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-6691.195210

Rights and Permissions
  Abstract 

Prevalence of allergic diseases ranges from 20% to 30% worldwide and is increasing for the last few decades. Emerging studies have implicated proteases, both endogenous and exogenous in initiating, mediating, and exacerbating allergic responses. Mast Cells (MCs) are the critical effectors of the allergic diseases and upon activation release a wide variety of mediators and account for the majority of endogenous proteases including chymase, tryptase, and MC-carboxypeptidase A (MC-CPA). The substrates of MC proteases include extracellular matrix components, proenzymes, and cell surface receptors. These proteases are stored in a fully active state and upon release contribute to the tissue injury. Along with endogenous proteases, allergens having protease activity have also been implicated in the manifestation of allergic diseases. Protease allergens are known to modulate immune responses toward Th2 by (i) disrupting protease-antiprotease balance at the epithelial surfaces, (ii) disrupting airway epithelial barrier, (iii) activating airway epithelial cells, (iv) modulating the activity of immune cells, and (v) by cleaving cell surface receptors. As proteases play crucial roles in the manifestation of allergic reactions, they can be exploited as a target for the development of new generation therapies for allergic diseases.

Keywords: Allergy, allergens, proteases


How to cite this article:
Kale SL, Agrawal K, Arora N. Role of proteases in pathophysiology of allergic diseases. Indian J Allergy Asthma Immunol 2016;30:57-65

How to cite this URL:
Kale SL, Agrawal K, Arora N. Role of proteases in pathophysiology of allergic diseases. Indian J Allergy Asthma Immunol [serial online] 2016 [cited 2017 Nov 17];30:57-65. Available from: http://www.ijaai.in/text.asp?2016/30/2/57/195210


  Introduction Top


Proteases are proteolytic enzymes that catalyze the hydrolysis of peptide bonds in proteins in a precise way which results in an irreversible activation/inactivation and/or degradation of the target substrate protein. Proteases exist in diverse classes and play a crucial role in homeostasis including immunity, cell cycle progression, blood coagulation, apoptosis, inflammation, angiogenesis, and tissue remodeling. [1],[2],[3] Proteases are also known to play an important role in the pathophysiology of diseases such as neurodegenerative and cardiovascular diseases, arthritis, and cancer. [4],[5],[6],[7] A delicate balance between proteases and protease inhibitors (serpins) is involved in the maintenance of epithelial barriers in the skin and airways, disruption of which leads to allergic sensitization and inflammation. [8] Earlier studies have demonstrated the role of protease-antiprotease imbalance in asthmatic airways. [9] Immediate allergic responses including mast cell (MC) responses, as well as late phase responses that include leukocyte activation have shown to significantly increase the protease load in human airways following antigen exposure. [10] This increase in proteolytic activity is a major contributor to airway pathophysiology and airway remodeling associated with asthma. Studies have also linked genetic defects in proteases and their inhibitors to be the potential cause of allergic diseases. This review focuses on the role of endogenous and exogenous proteases involved in the initiation and exacerbation of allergic inflammation.


  Genetic Links Between Proteases and Allergic Disorders Top


High-density single nucleotide polymorphism (SNP) linkage disequilibrium map analysis revealed a SNP association limited to dipeptidyl peptidase gene 10 (DPP10) that cleaves terminal dipeptides from proallergic cytokines and chemokines such as exotaxin and RANTES and defects in DPP10 could increase these mediators. [11] Further, mutations in MC chymase promoter region (chromosome 14q11.2) have been linked to atopic dermatitis (AD) and elevated total serum IgE levels in AD. [12] Stratum corneum chymotryptic enzyme (SCCE) is reported to play a role in desquamation by cleavage of stratum corneum proteins and genetic association between 4 nucleotide insertion in the 3'UTR of SCCE and AD has been reported. [13]

Similarly, mutations in LETKI-1 (chromosome 5q32) have been linked to AD, α1-antichymotrypsin (chromosome 14q32.1) with asthma, C1 esterase inhibitor (chromosome 11q12-13.1) with hereditary angioedema, and plasminogen activator inhibitor 1 (chromosome 7q21.3-q22) with asthma. [14],[15],[16],[17]


  Mast Cell Proteases Top


MCs are critical effector cells in IgE-mediated type I hypersensitivity disorders such as asthma, rhinitis, and dermatitis, found localized within smooth muscle bundles in asthmatics as compared to normal subjects and its density correlates with bronchial hyperresponsiveness, pointing toward an important role of MCs in the pathophysiology of asthma. [18] Proteases account for around 25% of total MC protein content and constitute the most conspicuous proteins released from the preformed granules upon degranulation. [19] MC-specific proteases include tryptase and chymase belonging to serine protease family while MC-carboxypeptidase A (MC-CPA) is a zinc-dependent metalloprotease. Approximately, 16 μg of tryptase and chymase per 10 16 cells are present in human skin MCs. [19] A two-fold increase in intraepithelial MCs rich in tryptase and CPA3 has been observed in high Th2 asthmatics. [20] The proteases released from MCs play a central role in promoting airway remodeling and inflammation [Figure 1].
Figure 1: Model representing the central role of proteases released from mast cells after degranulation in inflammation and airway remodeling: Proteases cleave tight junction proteins increasing epithelial permeability; activates matrix metalloprotease; cleaves fibronectin leading to airway remodeling. Proteases lead to activation of various cytokines and chemokines such as interleukin-18, CCL-6, CCL-9; activates protease activated receptors leading to secretion of proinflammatory cytokines, interleukin-6, interleukin-8, granulocyte macrophage colony-stimulating factor, and promotes inflammation

Click here to view


Tryptases are released in large quantities along with histamine on allergen challenge. High levels of transcript and immunoreactive protein are found in asthmatic bronchial epithelial biopsies. [20] Basal level of tryptase concentration is higher in bronchoalveolar lavage fluid (BALF) of atopic asthmatics, and it further increases on the endobronchial challenge with allergen. [21]

Tryptases interact with protease activated receptors (PAR-2) on airway smooth muscle cells leading to constriction. [22] It potentiates the action of known constrictors like histamine. [23] It can also degrade vasoactive intestinal peptide (bronchodialating peptide), cleave extracellular matrix causing untethering of muscle from bronchial wall, and activate matrix cleaving proteases to further aid in bronchoconstriction. [22],[24] Human β tryptase when instilled intratracheally leads to neutrophilic inflammation in guinea pigs. [25] Tryptases can also act as mitogens for epithelium, fibroblasts, and airway smooth muscle cells which require activation of ERK1 and 2, depending partially on protease activity of tryptase and contributes to smooth muscle hyperplasia and fibrosis, leading to tissue remodeling. [26],[27],[28] It can also cause degranulation of nearby MCs thereby amplifying the stimulus. A recent study has shown that tryptases could cleave interleukin (IL)-33, a key cytokine in asthma to generate mature forms which are more potent than full length IL-33 for activation of innate lymphoid cells and tryptase inhibitor suppresses IL-33 dependent allergic airway inflammation in mice model. [29]

Chymases are abundantly present in skin MCs as compared to lungs. A higher fraction of chymase-positive MCs are found within 20 μm of submucosal glands. [30] It degrades matrix proteins and activates matrix metalloproteases. [31] Chymases may also cleave tight junction proteins such as ZO-1 and occludin thereby increasing epithelial permeability, further aiding in the process of sensitization by increasing access to foreign antigens. [32],[33],[34] Chymases also lead to cleavage and activation of proIL-1 β, proIL-18, CCL-6, CCL-9, and CCL-15. [35],[36],[37] An increasing number of chymase-positive MCs have been observed in the small pulmonary arteries of asthmatics. [38] The transcript levels of MC-CPA are found to be most overexpressed in the epithelium of asthmatics versus nonasthmatics, yet its role in lung diseases remained to be elucidated.


  Non Mast Cells-Specific Proteases Top


Cathepsin G is expressed in neutrophils, dendritic cells, and monocytes. In human, it is unique in a way that it can cleave both tryptic and chymotryptic substrates. Its function is similar to chymases in some respect like it can activate matrix metalloproteases. [39] Dipeptidyl peptidase I (Cathepsin C) expressed by a variety of granulated cells, is a thiol class peptidase which removes amino-terminal dipeptides from peptides and has endoproteolytic activity. [40],[41] Although it can be secreted, it majorly functions intracellular and participates in activation of chymases, cathepsin G, and tryptases. [41],[42],[43] It is found in abundance in the MCs of uninflamed airways. Matrix metalloprotease 9 is activated by chymases, and it participates in degradation of extracellular matrix. [44]


  Protease Allergens Top


Studies on a wide variety of allergenic proteins with a broad range of structures and functions have revealed that there is no unique structure or function responsible for allergenicity. An increasing number of studies have demonstrated that enzymatic activity (particularly protease activity) of some proteins contributes to allergenicity. Protease allergens from various clinically relevant sources such as house dust mite (HDM), cockroach, pollen, and fungi have been identified and characterized. A detailed list of protease allergens from various sources identified and listed in WHO/IUIS allergen nomenclature is summarized in [Table 1]. [45]
Table 1: List of protease allergens from different source listed in the WHO/IUIS allergen nomenclature database

Click here to view



  Protease Allergens as TH2 Adjuvants Top


Protease allergens induce allergic airway inflammation and are known to play a key role in the exacerbation of allergic responses by virtue of their protease activity. Allergen protease activity has been implicated in the development of allergic Th2 responses. [46] Exposure to active proteases also lead to the higher IL-33 levels in lungs whereas IL-33 deficient mice had reduced IgE/IgG1 levels with no eosinophilia demonstrating the role of IL-33 in protease-induced sensitization. [46] Further, studies have also showed that mice sensitized through the nasal mucosa with either active or inactive cysteine protease showed Th2 type lung hypersensitivity in active cysteine protease sensitized mice. This experiment also demonstrated that cysteine protease activity act as an adjuvant for other bystander antigens. [47] Similar studies with Per a 10 demonstrated that proteolytic activity of Per a 10 plays a major role in driving allergic response by providing an adjuvant effect to self and other antigens in the same microenvironment. [48]


  Disruption of Protease-Antiprotease Balance Top


There exists a correlation between severity of nasal allergen challenge and the amount of endogenous protease inhibitor. [49] Elastase inhibitors α1-antitrypsin, secretory leukoprotease inhibitor (SLPI), and elafin are secreted in the lung lining fluids and protect the respiratory tract from proteolysis by proteases. SLPI blocks and inactivates mast cells and leukocyte serine proteases that are implicated in allergic diseases. [50] An imbalance between proteases and antiproteases was reported in the nasal mucosa of allergic rhinitis patients. [51] Der p 1 is known to cleave and inactivate α1-antitrypsin. [52] Disruption of protease-antiprotease balance at the epithelial surfaces might promote inflammatory responses.


  Disruption of Epithelial Barrier Top


The airway epithelium forms the first line of defense against the inhaled environmental insults comprised pollutants, irritants, pathogens, and aeroallergens. Intercellular epithelial junctions comprising of tight junctions, adherens junctions, and desmosomes maintain the epithelial barrier and protect the underlying tissue from the inhaled substances. A number of studies have reported a defective and disrupted epithelial barrier in allergic diseases such as asthma and dermatitis. Allergens with protease activity have been shown to disrupt airway epithelial barrier by cleaving tight junction proteins. Herbert et al. revealed that unfractionated growth medium extract from which Der p 1 is isolated along with Der p 1 was capable of cellular detachment of Madin-Darby canine kidney cells and canine tracheal respiratory cells grown on plastic substrata. [53] This study also demonstrated that application of Der p 1 or SGME caused epithelial injury and increased its permeability to serum albumin. Later, a study by Wan et al. showed that HDM fecal pellets (HDMFPs) increased epithelial permeability and disrupted tight junctions. [54] They demonstrated Der p 1 in HDMFP was responsible for disruption of epithelial barrier and Der p 1 cleavage sites are present on occludin and claudin 1. Further, it was shown that Der p 1 contributes to allergic sensitization by disrupting tight junction proteins, instigated by cleavage of ZO-1 and occludin proteins. [55] Similar studies carried with pollen proteases showed that pollen peptidases disrupt epithelial barrier integrity by cleavage of tight junction proteins. [56],[57] This disruption of epithelial barrier by protease allergens helps in allergic sensitization by facilitating the delivery of aeroallergens across the epithelium and might contribute to allergic inflammatory reactions.


  Activation of Airway and Bronchial Epithelial Cells Top


In vitro studies have shown that protease allergens from HDM, fungi, and pollens activate airway epithelial cells in activity-dependent manner to secrete proinflammatory cytokines. Mounting evidence suggests that sensitization occurs at mucosal surfaces and that proteolytic activity helps in breaking the normal state of tolerance. Kamijo et al. showed that repeated exposure of airway mucosa with protease allergens leads to lung eosinophilia and higher IgE/IgG1 production in a protease activity-dependent manner. [46] Airway epithelial cells exposed to mite, timothy grass pollen, or birch pollen extracts showed secretion of IL-6, IL-8, granulocyte macrophage colony-stimulating factor, and monocyte chemotactic protein-1. [58],[59] Use of purified proteases Der p 1and Der p 9 demonstrated that this release of cytokines from the airway epithelial cells was dependent on the protease activity of the allergens. [60] Der p 1 and Der p 5 activated human derived airway epithelial cells by both protease-dependent and protease-independent mechanisms. [61] Asokananthan et al. showed that Der p 1-induced proinflammatory cytokine release from the respiratory epithelial cells was in part mediated by PAR-2. [62] However, other reports have suggested that though Der p 1 is capable of cleaving PAR-2 peptide, it activates airway epithelial cells in a PAR-2-independent manner. [63] Cockroach serine protease allergen Per a 10 has been shown to activate airway epithelial cells in a PAR-2-dependent manner. [64] Either through PAR-2 or not, all these reports suggest the role of protease activity of the allergens in activating airway epithelial cells. Once activated, these epithelial cells secrete a myriad of cytokines and chemokines that promote Th2 responses and allergic inflammation through several mechanisms.


  Modulation of Functions of Immune Cells Top


After crossing the epithelial barrier, protease allergens interact with cells of immune system and can modulate their functioning. Per a 10 has been shown to potentiate dendritic cells derived T-cell polarization toward type II by upregulating CD86, OX40 L expression and lowered IL-12 secretion. [65],[66] These lowered IL-12 levels were associated with lower CD40 expression on DCs probably by cleavage of CD40 by Per a 10. [67] Priming of naive CD4+ T-cells with active Per a 10 pulsed DCs showed high Th2 cytokines IL-4, IL-5, and IL-13 and lowered IL-12 secretion as compared to inactive Per a 10 pulsed DCs. [68] Der p 1 has also been reported to lower IL-12 expression by monocyte-derived dendritic cells by CD40 cleavage. [68] A study has also demonstrated that Th2 response development after protease challenge requires a cooperation between DCs and basophils and it occurs through ROS. [69] Protease allergens can also induce basophils in an IgE-independent manner to produce IL-4 and IL-13. Basophils may act as an early source of IL-4. [70] This early IL-4 is speculated to be involved in the establishment of type 2 immune responses. [71],[72] Naive T-cells can also act as an early source of IL-4 as they have been shown to express PAR-2 receptors and secrete IL-4 on interaction with papain. [73] Along with basophils, proteases can also activate MCs leading to the production and secretion of IL-4. [72]


  Cleavage of Cell Surface Receptors Top


Protease allergens promote Th2 responses by hampering Th1 and Treg responses, and this is achieved by cleavage of a myriad of receptors on different cells. Der p 1 a major cysteine protease from HDM may enhance IgE responses by cleaving CD23 from the surface of activated B-cells. [74] Membrane-bound CD23 sends a negative feedback signal when bound to IgE that downregulates IgE secretion, cleavage of CD23 switches off this negative feedback signal thereby increasing IgE synthesis. [75] Subsequently, it has also been demonstrated that Der p 1 can cleave CD25, α-subunit of IL-2 receptor which inhibits IL-2 mediated T-cell proliferation and interferon-γ production thereby shifting the Th1/Th2 balance toward Th2. [76] Der p 1 has also been shown to cleave DC-SIGN and DC-SIGNR. Cleavage of DC-SIGN reduces binding of DC-SIGN to ICAM-3. [77] ICAM-3 is an endogenous DC-SIGN receptor expressed by naive T-cells and along with ICAM-1 is involved in DC trafficking, DC-T-cell interaction, and polarization of immune response toward Th1. [78],[79] DC-SIGN cleavage by Der p 1 can hamper Th1 responses thus favoring Th2 immune responses. [77] Recently, cysteine protease allergen papain has been shown to cleave CD123 (IL-3α), an IL-3 receptor and suppress IL-3 mediated expansion of basophils. However, the implications of CD123 cleavage in allergic responses need further studies. [80]


  Protease Inhibitors as Possible Therapeutic Adjuncts Top


A balance between endogenous proteases and serine/cysteine protease inhibitors is necessary for normal homeostasis and is involved in the maintenance of skin and airway epithelial barrier. A disruption in this balance either due to genetic defects in the genes encoding these proteases and the inhibitors or due to excessive exposure to exogenous protease allergens leads to the disruption of epithelial barrier culminating into allergic sensitization and inflammation. Proteases owing to their role in the exacerbation of allergic diseases are a potential targets for developing novel therapeutics or ameliorating allergic diseases.

Tryptase inhibitor, bis-amidines when used with peptidic inhibitors, was found effective in alleviation of airway inflammation in a sheep model. [81] MOL6131 a nonpeptide inhibitor of lung MC tryptase effectively reduces allergic features in an ovalbumin (OVA)-induced mice model of allergic airway inflammation. [82] Studies with tryptase inhibitor have shown a reduction in bronchoconstriction in mild atopic asthmatics. APC366, a tryptase inhibitor reduced antigen-induced late asthmatic response in individuals with atopic asthma. [83]

Trasylol (aprotinin), a serine protease inhibitor was found to prevent trypsin induces shock. [84] Gabexate mesylate (FOY) and nafamostat mesilate (6-amidino-2-naphthyl p-guanidinobenzoate dimethane sulfonate; FUT), synthetic serine protease inhibitors attenuated allergen-induced airway eosinophilia and decreased allergen-induced IgE production, IL-4, and tumor necrosis factor-α levels, while augmented IL-12 and IL-10 levels in BALF of murine model of asthma. [85] The follow-up study demonstrated that these protease inhibitors attenuated Der p 1-induced airway hyperresponsiveness (AHR), airway remodeling, and allergic airway inflammation by downregulating Th2 cytokines and Th17 cell function along with inhibition of nuclear factor-κB activation in the lungs. [86] Studies evaluating therapeutic and prophylactic potential of AEBSF (4-[2-aminoethyl] benzenesulfonyl fluoride hydrochloride), a serine protease inhibitor, demonstrated it to be effective in reducing allergic airway inflammatory parameters in both OVA and cockroach extract-induced allergic airway inflammatory mice model. [87],[88] It was also shown that administration of AEBSF reduced oxidative stress in these models.

Chymase inhibitors SUN C-8257, Y-40613, and SUN C-8077 have shown a therapeutic potential in AD in animal models. [89],[90],[91] Human chymase and cathepsin G inhibitors reduce airway hyperresponsiveness in a sheep model sensitized to Ascaris suum and challenged with an allergen. These have shown to reduce airway neutrophilia in a mice model exposed to tobacco smoke. [92]

Apart from synthetic protease inhibitors, naturally occurring protease inhibitors such as SLPI and urinary trypsin inhibitor (UTI) have been evaluated potential therapeutic agents. SLPI, a secretory leukocyte protease inhibitor, prevented allergen-induced pathophysiologic airway responses that included early and late phase bronchoconstriction, AHR, and airway inflammation in animal models of asthma. [50] UTI, urinary trypsin inhibitor, purified from a human source improved allergic inflammatory symptoms in house dust mite challenged mouse model of chronic asthma. [86]


  Concluding Remarks Top


Although both endogenous and exogenous proteases have been implicated in initiation and aggravating allergic symptoms, the detailed mechanism of their action and the differences between endogenous and exogenous proteases in mediating the allergic responses are not known. An insight into these mechanisms can lead to the development of new targets for therapeutic intervention of allergic diseases. Corticosteroids are the first choice of medications used for alleviating allergic symptoms because of their effectiveness but are associated with a myriad of side effects. There is an increased recognition of the need for the development of effective therapeutic agents for ameliorating allergic symptoms and provide long-term relief to allergic patients with a minimum of low-risk side effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000;407:258-64.  Back to cited text no. 1
    
2.
Lu P, Takai K, Weaver VM, Werb Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol 2011;3. pii: A005058.  Back to cited text no. 2
    
3.
Heutinck KM, ten Berge IJ, Hack CE, Hamann J, Rowshani AT. Serine proteases of the human immune system in health and disease. Mol Immunol 2010;47:1943-55.  Back to cited text no. 3
    
4.
Singh RB, Dandekar SP, Elimban V, Gupta SK, Dhalla NS. Role of proteases in the pathophysiology of cardiac disease. Mol Cell Biochem 2004;263:241-56.  Back to cited text no. 4
    
5.
Siklos M, BenAissa M, Thatcher GR. Cysteine proteases as therapeutic targets: Does selectivity matter? A systematic review of calpain and cathepsin inhibitors. Acta Pharm Sin B 2015;5:506-19.  Back to cited text no. 5
    
6.
Ferrell WR, Lockhart JC, Kelso EB, Dunning L, Plevin R, Meek SE, et al. Essential role for proteinase-activated receptor-2 in arthritis. J Clin Invest 2003;111:35-41.  Back to cited text no. 6
    
7.
Wojtukiewicz MZ, Hempel D, Sierko E, Tucker SC, Honn KV. Protease-activated receptors (PARs) - Biology and role in cancer invasion and metastasis. Cancer Metastasis Rev 2015;34:775-96.  Back to cited text no. 7
    
8.
Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, Moustafa M, et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 2009;129:1892-908.  Back to cited text no. 8
    
9.
Kesic MJ, Hernandez M, Jaspers I. Airway protease/antiprotease imbalance in atopic asthmatics contributes to increased influenza A virus cleavage and replication. Respir Res 2012;13:82.  Back to cited text no. 9
    
10.
Welle M. Development, significance, and heterogeneity of mast cells with particular regard to the mast cell-specific proteases chymase and tryptase. J Leukoc Biol 1997;61:233-45.  Back to cited text no. 10
    
11.
Allen M, Heinzmann A, Noguchi E, Abecasis G, Broxholme J, Ponting CP, et al. Positional cloning of a novel gene influencing asthma from chromosome 2q14. Nat Genet 2003;35:258-63.  Back to cited text no. 11
    
12.
Weidinger S, Rümmler L, Klopp N, Wagenpfeil S, Baurecht HJ, Fischer G, et al. Association study of mast cell chymase polymorphisms with atopy. Allergy 2005;60:1256-61.  Back to cited text no. 12
    
13.
Vasilopoulos Y, Cork MJ, Murphy R, Williams HC, Robinson DA, Duff GW, et al. Genetic association between an AACC insertion in the 3′UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis. J Invest Dermatol 2004;123:62-6.  Back to cited text no. 13
    
14.
Walley AJ, Chavanas S, Moffatt MF, Esnouf RM, Ubhi B, Lawrence R, et al. Gene polymorphism in Netherton and common atopic disease. Nat Genet 2001;29:175-8.  Back to cited text no. 14
    
15.
Malerba G, Patuzzo C, Trabetti E, Lauciello MC, Galavotti R, Pescollderungg L, et al. Chromosome 14 linkage analysis and mutation study of 2 serpin genes in allergic asthmatic families. J Allergy Clin Immunol 2001;107:654-8.  Back to cited text no. 15
    
16.
Bowen B, Hawk JJ, Sibunka S, Hovick S, Weiler JM. A review of the reported defects in the human C1 esterase inhibitor gene producing hereditary angioedema including four new mutations. Clin Immunol 2001;98:157-63.  Back to cited text no. 16
    
17.
Bucková D, Izakovicová Hollá L, Vácha J. Polymorphism 4G/5G in the plasminogen activator inhibitor-1 (PAI-1) gene is associated with IgE-mediated allergic diseases and asthma in the Czech population. Allergy 2002;57:446-8.  Back to cited text no. 17
    
18.
Bradding P. The role of the mast cell in asthma: A reassessment. Curr Opin Allergy Clin Immunol 2003;3:45-50.  Back to cited text no. 18
    
19.
Schwartz LB, Irani AM, Roller K, Castells MC, Schechter NM. Quantitation of histamine, tryptase, and chymase in dispersed human T and TC mast cells. J Immunol 1987;138:2611-5.  Back to cited text no. 19
    
20.
Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, et al. Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma. J Allergy Clin Immunol 2010;125:1046-53.e8.  Back to cited text no. 20
    
21.
Jarjour NN, Calhoun WJ, Schwartz LB, Busse WW. Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with increased airway obstruction. Am Rev Respir Dis 1991;144:83-7.  Back to cited text no. 21
    
22.
Schmidlin F, Amadesi S, Vidil R, Trevisani M, Martinet N, Caughey G, et al. Expression and function of proteinase-activated receptor 2 in human bronchial smooth muscle. Am J Respir Crit Care Med 2001;164:1276-81.  Back to cited text no. 22
    
23.
Johnson PR, Ammit AJ, Carlin SM, Armour CL, Caughey GH, Black JL. Mast cell tryptase potentiates histamine-induced contraction in human sensitized bronchus. Eur Respir J 1997;10:38-43.  Back to cited text no. 23
    
24.
Caughey GH, Leidig F, Viro NF, Nadel JA. Substance p and vasoactive intestinal peptide degradation by mast cell tryptase and chymase. J Pharmacol Exp Ther 1988;244:133-7.  Back to cited text no. 24
    
25.
McNeil HP, Adachi R, Stevens RL. Mast cell-restricted tryptases: Structure and function in inflammation and pathogen defense. J Biol Chem 2007;282:20785-9.  Back to cited text no. 25
    
26.
Ruoss SJ, Hartmann T, Caughey GH. Mast cell tryptase is a mitogen for cultured fibroblasts. J Clin Invest 1991;88:493-9.  Back to cited text no. 26
    
27.
Cairns JA, Walls AF. Mast cell tryptase is a mitogen for epithelial cells. Stimulation of IL-8 production and intercellular adhesion molecule-1 expression. J Immunol 1996;156:275-83.  Back to cited text no. 27
    
28.
Brown JK, Jones CA, Rooney LA, Caughey GH. Mast cell tryptase activates extracellular-regulated kinases (p44/p42) in airway smooth-muscle cells: Importance of proteolytic events, time course, and role in mediating mitogenesis. Am J Respir Cell Mol Biol 2001;24:146-54.  Back to cited text no. 28
    
29.
Lefrançais E, Duval A, Mirey E, Roga S, Espinosa E, Cayrol C, et al. Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells. Proc Natl Acad Sci U S A 2014;111:15502-7.  Back to cited text no. 29
    
30.
Matin R, Tam EK, Nadel JA, Caughey GH. Distribution of chymase-containing mast cells in human bronchi. J Histochem Cytochem 1992;40:781-6.  Back to cited text no. 30
    
31.
Johnson JL, Jackson CL, Angelini GD, George SJ. Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques. Arterioscler Thromb Vasc Biol 1998;18:1707-15.  Back to cited text no. 31
    
32.
Scudamore CL, Jepson MA, Hirst BH, Miller HR. The rat mucosal mast cell chymase, RMCP-II, alters epithelial cell monolayer permeability in association with altered distribution of the tight junction proteins ZO-1 and occludin. Eur J Cell Biol 1998;75:321-30.  Back to cited text no. 32
    
33.
Ebihara N, Funaki T, Murakami A, Takai S, Miyazaki M. Mast cell chymase decreases the barrier function and inhibits the migration of corneal epithelial cells. Curr Eye Res 2005;30:1061-9.  Back to cited text no. 33
    
34.
McDermott JR, Bartram RE, Knight PA, Miller HR, Garrod DR, Grencis RK. Mast cells disrupt epithelial barrier function during enteric nematode infection. Proc Natl Acad Sci U S A 2003;100:7761-6.  Back to cited text no. 34
    
35.
Mizutani H, Schechter N, Lazarus G, Black RA, Kupper TS. Rapid and specific conversion of precursor interleukin 1 beta (IL-1 beta) to an active IL-1 species by human mast cell chymase. J Exp Med 1991;174:821-5.  Back to cited text no. 35
    
36.
Omoto Y, Tokime K, Yamanaka K, Habe K, Morioka T, Kurokawa I, et al. Human mast cell chymase cleaves pro-IL-18 and generates a novel and biologically active IL-18 fragment. J Immunol 2006;177:8315-9.  Back to cited text no. 36
    
37.
Berahovich RD, Miao Z, Wang Y, Premack B, Howard MC, Schall TJ. Proteolytic activation of alternative CCR1 ligands in inflammation. J Immunol 2005;174:7341-51.  Back to cited text no. 37
    
38.
Shiang C, Mauad T, Senhorini A, de Araújo BB, Ferreira DS, da Silva LF, et al. Pulmonary periarterial inflammation in fatal asthma. Clin Exp Allergy 2009;39:1499-507.  Back to cited text no. 38
    
39.
Son ED, Kim H, Choi H, Lee SH, Lee JY, Kim S, et al. Cathepsin G increases MMP expression in normal human fibroblasts through fibronectin fragmentation, and induces the conversion of proMMP-1 to active MMP-1. J Dermatol Sci 2009;53:150-2.  Back to cited text no. 39
    
40.
Turk D, Janjic V, Stern I, Podobnik M, Lamba D, Dahl SW, et al. Structure of human dipeptidyl peptidase I (cathepsin C): Exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases. EMBO J 2001;20:6570-82.  Back to cited text no. 40
    
41.
Wolters PJ, Laig-Webster M, Caughey GH. Dipeptidyl peptidase I cleaves matrix-associated proteins and is expressed mainly by mast cells in normal dog airways. Am J Respir Cell Mol Biol 2000;22:183-90.  Back to cited text no. 41
    
42.
Wolters PJ, Pham CT, Muilenburg DJ, Ley TJ, Caughey GH. Dipeptidyl peptidase I is essential for activation of mast cell chymases, but not tryptases, in mice. J Biol Chem 2001;276:18551-6.  Back to cited text no. 42
    
43.
Adkison AM, Raptis SZ, Kelley DG, Pham CT. Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. J Clin Invest 2002;109:363-71.  Back to cited text no. 43
    
44.
Ohnishi K, Takagi M, Kurokawa Y, Satomi S, Konttinen YT. Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema. Lab Invest 1998;78:1077-87.  Back to cited text no. 44
    
45.
WHO/IUIS Allergen Nomenclature. Available from: http://www.allergen.org. [last accessed on 2016 Sep 15].  Back to cited text no. 45
    
46.
Kamijo S, Takeda H, Tokura T, Suzuki M, Inui K, Hara M, et al. IL-33-mediated innate response and adaptive immune cells contribute to maximum responses of protease allergen-induced allergic airway inflammation. J Immunol 2013;190:4489-99.  Back to cited text no. 46
    
47.
Cunningham PT, Elliot CE, Lenzo JC, Jarnicki AG, Larcombe AN, Zosky GR, et al. Sensitizing and Th2 adjuvant activity of cysteine protease allergens. Int Arch Allergy Immunol 2012;158:347-58.  Back to cited text no. 47
    
48.
Sudha VT, Arora N, Singh BP. Serine protease activity of Per a 10 augments allergen-induced airway inflammation in a mouse model. Eur J Clin Invest 2009;39:507-16.  Back to cited text no. 48
    
49.
Rudolph R, Dölling J, Kunkel G, Staud RD, Baumgarten C. The significance of nasal protease inhibitor concentrations in house dust allergy. Allergy 1978;33:310-5.  Back to cited text no. 49
    
50.
Wright CD, Havill AM, Middleton SC, Kashem MA, Lee PA, Dripps DJ, et al. Secretory leukocyte protease inhibitor prevents allergen-induced pulmonary responses in animal models of asthma. J Pharmacol Exp Ther 1999;289:1007-14.  Back to cited text no. 50
    
51.
Tomazic PV, Birner-Gruenberger R, Leitner A, Obrist B, Spoerk S, Lang-Loidolt D. Nasal mucus proteomic changes reflect altered immune responses and epithelial permeability in patients with allergic rhinitis. J Allergy Clin Immunol 2014;133:741-50.  Back to cited text no. 51
    
52.
Kalsheker NA, Deam S, Chambers L, Sreedharan S, Brocklehurst K, Lomas DA. The house dust mite allergen Der p1 catalytically inactivates alpha 1-antitrypsin by specific reactive centre loop cleavage: A mechanism that promotes airway inflammation and asthma. Biochem Biophys Res Commun 1996;221:59-61.  Back to cited text no. 52
    
53.
Herbert CA, King CM, Ring PC, Holgate ST, Stewart GA, Thompson PJ, et al. Augmentation of permeability in the bronchial epithelium by the house dust mite allergen Der p1. Am J Respir Cell Mol Biol 1995;12:369-78.  Back to cited text no. 53
    
54.
Wan H, Winton HL, Soeller C, Tovey ER, Gruenert DC, Thompson PJ, et al. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest 1999;104:123-33.  Back to cited text no. 54
    
55.
Wan H, Winton HL, Soeller C, Gruenert DC, Thompson PJ, Cannell MB, et al. Quantitative structural and biochemical analyses of tight junction dynamics following exposure of epithelial cells to house dust mite allergen Der p 1. Clin Exp Allergy 2000;30:685-98.  Back to cited text no. 55
    
56.
Runswick S, Mitchell T, Davies P, Robinson C, Garrod DR. Pollen proteolytic enzymes degrade tight junctions. Respirology 2007;12:834-42.  Back to cited text no. 56
    
57.
Vinhas R, Cortes L, Cardoso I, Mendes VM, Manadas B, Todo-Bom A, et al. Pollen proteases compromise the airway epithelial barrier through degradation of transmembrane adhesion proteins and lung bioactive peptides. Allergy 2011;66:1088-98.  Back to cited text no. 57
    
58.
Vroling AB, Duinsbergen D, Fokkens WJ, van Drunen CM. Allergen induced gene expression of airway epithelial cells shows a possible role for TNF-alpha. Allergy 2007;62:1310-9.  Back to cited text no. 58
    
59.
Tomee JF, van Weissenbruch R, de Monchy JG, Kauffman HF. Interactions between inhalant allergen extracts and airway epithelial cells: Effect on cytokine production and cell detachment. J Allergy Clin Immunol 1998;102:75-85.  Back to cited text no. 59
    
60.
King C, Brennan S, Thompson PJ, Stewart GA. Dust mite proteolytic allergens induce cytokine release from cultured airway epithelium. J Immunol 1998;161:3645-51.  Back to cited text no. 60
    
61.
Kauffman HF, Tamm M, Timmerman JA, Borger P. House dust mite major allergens Der p 1 and Der p 5 activate human airway-derived epithelial cells by protease-dependent and protease-independent mechanisms. Clin Mol Allergy 2006;4:5.  Back to cited text no. 61
    
62.
Asokananthan N, Graham PT, Stewart DJ, Bakker AJ, Eidne KA, Thompson PJ, et al. House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: The cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. J Immunol 2002;169:4572-8.  Back to cited text no. 62
    
63.
Adam E, Hansen KK, Astudillo Fernandez O, Coulon L, Bex F, Duhant X, et al. The house dust mite allergen Der p 1, unlike Der p 3, stimulates the expression of interleukin-8 in human airway epithelial cells via a proteinase-activated receptor-2-independent mechanism. J Biol Chem 2006;281:6910-23.  Back to cited text no. 63
    
64.
Kale SL, Arora N. Per a 10 activates human derived epithelial cell line in a protease dependent manner via PAR-2. Immunobiology 2015;220:525-32.  Back to cited text no. 64
    
65.
Agrawal K, Kale SL, Arora N. Protease activity of Per a 10 potentiates Th2 polarization by increasing IL-23 and OX40L. Eur J Immunol 2015;45:3375-85.  Back to cited text no. 65
    
66.
Goel C, Govindaraj D, Singh BP, Farooque A, Kalra N, Arora N. Serine protease Per a 10 from Periplaneta americana bias dendritic cells towards type 2 by upregulating CD86 and low IL-12 secretions. Clin Exp Allergy 2012;42:412-22.  Back to cited text no. 66
    
67.
Goel C, Gaur SN, Bhati G, Arora N. DC type 2 polarization depends on both the allergic status of the individual and protease activity of Per a 10. Immunobiology 2015;220:1113-21.  Back to cited text no. 67
    
68.
Ghaemmaghami AM, Gough L, Sewell HF, Shakib F. The proteolytic activity of the major dust mite allergen Der p 1 conditions dendritic cells to produce less interleukin-12: Allergen-induced Th2 bias determined at the dendritic cell level. Clin Exp Allergy 2002;32:1468-75.  Back to cited text no. 68
    
69.
Tang H, Cao W, Kasturi SP, Ravindran R, Nakaya HI, Kundu K, et al. The T helper type 2 response to cysteine proteases requires dendritic cell-basophil cooperation via ROS-mediated signaling. Nat Immunol 2010;11:608-17.  Back to cited text no. 69
    
70.
Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol 2008;9:310-8.  Back to cited text no. 70
    
71.
Phillips C, Coward WR, Pritchard DI, Hewitt CR. Basophils express a type 2 cytokine profile on exposure to proteases from helminths and house dust mites. J Leukoc Biol 2003;73:165-71.  Back to cited text no. 71
    
72.
Rosenstein RK, Bezbradica JS, Yu S, Medzhitov R. Signaling pathways activated by a protease allergen in basophils. Proc Natl Acad Sci U S A 2014;111:E4963-71.  Back to cited text no. 72
    
73.
Liang G, Barker T, Xie Z, Charles N, Rivera J, Druey KM. Naive T cells sense the cysteine protease allergen papain through protease-activated receptor 2 and propel TH2 immunity. J Allergy Clin Immunol 2012;129:1377-86.e13.  Back to cited text no. 73
    
74.
Schulz O, Sutton BJ, Beavil RL, Shi J, Sewell HF, Gould HJ, et al. Cleavage of the low-affinity receptor for human IgE (CD23) by a mite cysteine protease: Nature of the cleaved fragment in relation to the structure and function of CD23. Eur J Immunol 1997;27:584-8.  Back to cited text no. 74
    
75.
Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol 2008;8:205-17.  Back to cited text no. 75
    
76.
Schulz O, Sewell HF, Shakib F. Proteolytic cleavage of CD25, the alpha subunit of the human T cell interleukin 2 receptor, by Der p 1, a major mite allergen with cysteine protease activity. J Exp Med 1998;187:271-5.  Back to cited text no. 76
    
77.
Furmonaviciene R, Ghaemmaghami AM, Boyd SE, Jones NS, Bailey K, Willis AC, et al. The protease allergen Der p 1 cleaves cell surface DC-SIGN and DC-SIGNR: Experimental analysis of in silico substrate identification and implications in allergic responses. Clin Exp Allergy 2007;37:231-42.  Back to cited text no. 77
    
78.
Geijtenbeek TB, Torensma R, van Vliet SJ, van Duijnhoven GC, Adema GJ, van Kooyk Y, et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 2000;100:575-85.  Back to cited text no. 78
    
79.
Su SV, Hong P, Baik S, Negrete OA, Gurney KB, Lee B. DC-SIGN binds to HIV-1 glycoprotein 120 in a distinct but overlapping fashion compared with ICAM-2 and ICAM-3. J Biol Chem 2004;279:19122-32.  Back to cited text no. 79
    
80.
Nishikado H, Fujimura T, Taka H, Mineki R, Ogawa H, Okumura K, et al. Cysteine protease antigens cleave CD123, the a subunit of murine IL-3 receptor, on basophils and suppress IL-3-mediated basophil expansion. Biochem Biophys Res Commun 2015;460:261-6.  Back to cited text no. 80
    
81.
Clark JM, Abraham WM, Fishman CE, Forteza R, Ahmed A, Cortes A, et al. Tryptase inhibitors block allergen-induced airway and inflammatory responses in allergic sheep. Am J Respir Crit Care Med 1995;152(6 Pt 1):2076-83.  Back to cited text no. 81
    
82.
Oh SW, Pae CI, Lee DK, Jones F, Chiang GK, Kim HO, et al. Tryptase inhibition blocks airway inflammation in a mouse asthma model. J Immunol 2002;168:1992-2000.  Back to cited text no. 82
    
83.
Krishna MT, Chauhan A, Little L, Sampson K, Hawksworth R, Mant T, et al. Inhibition of mast cell tryptase by inhaled APC 366 attenuates allergen-induced late-phase airway obstruction in asthma. J Allergy Clin Immunol 2001;107:1039-45.  Back to cited text no. 83
    
84.
Balldin G, Ohlsson K. Trasylol prevents trypsin-induced shock in dogs. Hoppe Seylers Z Physiol Chem 1979;360:651-6.  Back to cited text no. 84
    
85.
Chen CL, Wang SD, Zeng ZY, Lin KJ, Kao ST, Tani T, et al. Serine protease inhibitors nafamostat mesilate and gabexate mesilate attenuate allergen-induced airway inflammation and eosinophilia in a murine model of asthma. J Allergy Clin Immunol 2006;118:105-12.  Back to cited text no. 85
    
86.
Lin CC, Lin LJ, Wang SD, Chiang CJ, Chao YP, Lin J, et al. The effect of serine protease inhibitors on airway inflammation in a chronic allergen-induced asthma mouse model. Mediators Inflamm 2014;2014:879326.  Back to cited text no. 86
    
87.
Saw S, Kale SL, Arora N. Serine protease inhibitor attenuates ovalbumin induced inflammation in mouse model of allergic airway disease. PLoS One 2012;7:e41107.  Back to cited text no. 87
    
88.
Saw S, Arora N. Protease inhibitor reduces airway response and underlying inflammation in cockroach allergen-induced murine model. Inflammation 2015;38:672-82.  Back to cited text no. 88
    
89.
Imada T, Komorita N, Kobayashi F, Naito K, Yoshikawa T, Miyazaki M, et al. Therapeutic potential of a specific chymase inhibitor in atopic dermatitis. Jpn J Pharmacol 2002;90:214-7.  Back to cited text no. 89
    
90.
Tomimori Y, Tsuruoka N, Fukami H, Saito K, Horikawa C, Saito M, et al. Role of mast cell chymase in allergen-induced biphasic skin reaction. Biochem Pharmacol 2002;64:1187.  Back to cited text no. 90
    
91.
Watanabe N, Tomimori Y, Saito K, Miura K, Wada A, Tsudzuki M, et al. Chymase inhibitor improves dermatitis in NC/Nga mice. Int Arch Allergy Immunol 2002;128:229-34.  Back to cited text no. 91
    
92.
Maryanoff BE, de Garavilla L, Greco MN, Haertlein BJ, Wells GI, Andrade-Gordon P, et al. Dual inhibition of cathepsin G and chymase is effective in animal models of pulmonary inflammation. Am J Respir Crit Care Med 2010;181:247-53.  Back to cited text no. 92
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Genetic Links Be...
Mast Cell Proteases
Non Mast Cells-S...
Protease Allergens
Protease Allerge...
Disruption of Pr...
Disruption of Ep...
Activation of Ai...
Modulation of Fu...
Cleavage of Cell...
Protease Inhibit...
Concluding Remarks
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed800    
    Printed19    
    Emailed0    
    PDF Downloaded95    
    Comments [Add]    

Recommend this journal