|Year : 2016 | Volume
| Issue : 2 | Page : 57-65
Role of proteases in pathophysiology of allergic diseases
Sagar Laxman Kale, Komal Agrawal, Naveen Arora
Allergy and Immunology Section, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
|Date of Web Publication||5-Dec-2016|
Room 509, Allergy and Immunology Section, CSIR-Institute of Genomics and Integrative Biology, Delhi University Campus, Mall Road, New Delhi - 110 007
Source of Support: None, Conflict of Interest: None
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 Apr 26];30:57-65. Available from: http://www.ijaai.in/text.asp?2016/30/2/57/195210
| Introduction|| |
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. ,, Proteases are also known to play an important role in the pathophysiology of diseases such as neurodegenerative and cardiovascular diseases, arthritis, and cancer. ,,, 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.  Earlier studies have demonstrated the role of protease-antiprotease imbalance in asthmatic airways.  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.  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|| |
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.  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.  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. 
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. ,,,
| Mast Cell Proteases|| |
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.  Proteases account for around 25% of total MC protein content and constitute the most conspicuous proteins released from the preformed granules upon degranulation.  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.  A two-fold increase in intraepithelial MCs rich in tryptase and CPA3 has been observed in high Th2 asthmatics.  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|
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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.  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. 
Tryptases interact with protease activated receptors (PAR-2) on airway smooth muscle cells leading to constriction.  It potentiates the action of known constrictors like histamine.  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. , Human β tryptase when instilled intratracheally leads to neutrophilic inflammation in guinea pigs.  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. ,, 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. 
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.  It degrades matrix proteins and activates matrix metalloproteases.  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. ,, Chymases also lead to cleavage and activation of proIL-1 β, proIL-18, CCL-6, CCL-9, and CCL-15. ,, An increasing number of chymase-positive MCs have been observed in the small pulmonary arteries of asthmatics.  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|| |
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.  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. , Although it can be secreted, it majorly functions intracellular and participates in activation of chymases, cathepsin G, and tryptases. ,, 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. 
| Protease Allergens|| |
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]. 
|Table 1: List of protease allergens from different source listed in the WHO/IUIS allergen nomenclature database|
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| Protease Allergens as TH2 Adjuvants|| |
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.  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.  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.  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. 
| Disruption of Protease-Antiprotease Balance|| |
There exists a correlation between severity of nasal allergen challenge and the amount of endogenous protease inhibitor.  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.  An imbalance between proteases and antiproteases was reported in the nasal mucosa of allergic rhinitis patients.  Der p 1 is known to cleave and inactivate α1-antitrypsin.  Disruption of protease-antiprotease balance at the epithelial surfaces might promote inflammatory responses.
| Disruption of Epithelial Barrier|| |
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.  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.  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.  Similar studies carried with pollen proteases showed that pollen peptidases disrupt epithelial barrier integrity by cleavage of tight junction proteins. , 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|| |
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.  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. , 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.  Der p 1 and Der p 5 activated human derived airway epithelial cells by both protease-dependent and protease-independent mechanisms.  Asokananthan et al. showed that Der p 1-induced proinflammatory cytokine release from the respiratory epithelial cells was in part mediated by PAR-2.  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.  Cockroach serine protease allergen Per a 10 has been shown to activate airway epithelial cells in a PAR-2-dependent manner.  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|| |
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. , These lowered IL-12 levels were associated with lower CD40 expression on DCs probably by cleavage of CD40 by Per a 10.  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.  Der p 1 has also been reported to lower IL-12 expression by monocyte-derived dendritic cells by CD40 cleavage.  A study has also demonstrated that Th2 response development after protease challenge requires a cooperation between DCs and basophils and it occurs through ROS.  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.  This early IL-4 is speculated to be involved in the establishment of type 2 immune responses. , 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.  Along with basophils, proteases can also activate MCs leading to the production and secretion of IL-4. 
| Cleavage of Cell Surface Receptors|| |
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.  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.  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.  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.  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. , DC-SIGN cleavage by Der p 1 can hamper Th1 responses thus favoring Th2 immune responses.  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. 
| Protease Inhibitors as Possible Therapeutic Adjuncts|| |
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.  MOL6131 a nonpeptide inhibitor of lung MC tryptase effectively reduces allergic features in an ovalbumin (OVA)-induced mice model of allergic airway inflammation.  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. 
Trasylol (aprotinin), a serine protease inhibitor was found to prevent trypsin induces shock.  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.  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.  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. , 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. ,, 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. 
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.  UTI, urinary trypsin inhibitor, purified from a human source improved allergic inflammatory symptoms in house dust mite challenged mouse model of chronic asthma. 
| Concluding Remarks|| |
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.
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