Journal of Pulmonary Medicine & Respiratory Research Category: Medical Type: Review Article

Mechanisms of Interleukin -17 in the Pathogenesis of Neutrophilic Asthma

Nightingale Syabbalo1*
1 Professor of Medicine and Physiology, Copperbelt University, Kitwe, Zambia

*Corresponding Author(s):
Nightingale Syabbalo
Professor Of Medicine And Physiology, Copperbelt University, Kitwe, Zambia
Tel:+260 966486117,
Email:nightsyab@gmail.com

Received Date: May 15, 2020
Accepted Date: May 22, 2020
Published Date: May 30, 2020

Abstract

Asthma is a complex chronic airway disease with several distinct phenotypes characterized by different immunopathological pathways, clinical presentation, physiology, comorbidities, biomarker of allergic inflammation, and response to treatment. Approximately 10% of patients with asthma have severe refractory disease, which is difficult to control on high doses of inhaled corticosteroids, and long-acting β2-agonists. About 50% of these individuals suffer from neutrophilic asthma. Neutrophilic asthma is a phenotype of asthma that is severe and persistent, with frequent exacerbations, and is characterized by fixed airway obstruction. It is associated with comorbidities such as respiratory infections, obesity, gastroesophageal reflux disease, and obstructive sleep apnea. Immunopathologically, it is characterized by the presence of high levels of neutrophils in the lungs and airways. Interleukin-17 secreted by Th17 cells, plays a key role in the pathogenesis of neutrophilic asthma by expressing the secretion of chemoattractant cytokines, and chemokines for the recruitment and activation of neutrophils. Activated neutrophils produce oxidative bursts, releasing multiple proteinases, cytokines, chemokines, and reactive oxygen species which cause airway epithelial cell injury, inflammation, and hyperresponsiveness. During respiratory infections, and allergic inflammation, neutrophils can release neutrophil extracellular traps and cytoplasts, which can damage epithelial cells leading to further airway inflammation. Neutrophilic asthma is unresponsive to high dose inhaled corticosteroids, and probably to precision novel anti-IgE, interleukin and interleukin monoclonal antibody therapies. There is need for targeted precision biologics, and other treatment modalities for these patients.

Keywords

Chemokines; Cytokines; Interleukin-17; Monoclonal antibodies; Neutrophilic asthma

ABBREVIATIONS

Act1: adaptor protein nuclear factor (NF)-κ activator

AHR: airway hyperresponsiveness

ARDS: adult respiratory distress syndrome

BAL: bronchoalveolar lavage

CF: cystic fibrosis

COPD: Chronic obstructive pulmonary disease

CXCL: C-X-C motif chemokine ligand

DPP-4: dipeptidyl peptidase-4

FEF 25-75%: forced expiratory flow at 25% to 75% points

FeNO: fractional expired nitric oxide

FEV1: forced expiratory volume in 1 sec

FVC: forced vital capacity

GERD: gastroeosophageal reflux disease

GM-CSF: granulocyte/monocyte colony-stimulating factor

GRO-α: growth-related oncogene α

ICS: inhaled corticosteroids

IFN-γ: interferon-γ

LABA: long acting beta-adrenoceptor agent

LAMA: long acting muscarinic antagonist

IL: interleukin

ILC-3: type 3 innate lymphoid cell

LTB4: leukotriene B4

MAP: mitogen-activated protein

MIP-1α: macrophage inflammatory protein 1-α

MMP: matrix metalloproteinases

MPO: myeloperoxidase

NETS: neutrophil extracellular traps

NF-?B: nuclear factor-?B

NO: nitric oxide

OCS: oral corticosteroids

OSA: obstructive sleep apnoea

PAF: platelet activating factor

PGE2: prostaglandin E2

RORγt: retinoic acid-related orphan receptor γ, thymus specific

ROS: reactive oxygen species

RV: rhinoviruses

SABA: short acting beta-adrenoceptor agent

TGF-β: transforming growth factor-β

Th2: T-helper type 2 cells

Th17: T-helper type 17 cells

TNF-α: tumour necrosis factor-α

TSLP: Thymic stromal lymphopoietin

TXB2: thromboxane B2

INTRODUCTION

Asthma is a significant public health problem, affecting more than 300 million individuals globally [1]. It is a complex chronic airway disease with several distinct phenotypes, characterized by different immunopathological pathways, clinical features, physiology, comorbidities, biomarker of allergic inflammation, and response to treatment [1-4]. It has now become common practice to phenotype asthma for precision and targeted therapies, because asthmatic patients respond to the standard treatment differently. There are several proposed distinct clinical phenotypes of asthma, such as childhood-onset allergic asthma, adult-onset eosinophilic asthma, neutrophilic asthma, Exercise-Induced Asthma (EIA), obesity-related asthma, and Aspirin-Exacerbated Respiratory Disease (AERD) [5-12]. Among these phenotypes of asthma, are patients with severe persistent asthma whose disease is refractory to the standard treatment, including high doses of Inhaled Corticosteroids (ICS), Long-Acting β2-Agonists (LABA), and Leukotriene Receptor Antagonists (LTRA) [5,7,9,14]. Severe asthma is a debilitating form of asthma, which afflicts about 10% of asthma patients [13]. It has a late-onset, and is related to respiratory infections, hormonal changes, or environmental exposures, but it can develop in childhood, often associated with allergies [13]. Patients with severe asthma typically have the lowest quality of life [14] the highest risk for morbidity and mortality [13-15] and consume the majority of healthcare resources [13].

Severe refractory asthma encompasses several cellular and molecular phenotypes of asthma, including eosinophilic, neutrophilic, paucigranulocytic, and mixed granulocytic asthma phenotypes [6]. Eosinophilic asthma is a very well defined and established phenotype of asthma [5,6,9,10] whereas, neutrophilic asthma is less defined, and has a complex pathogenesis.

Approximately 50% of patients with asthma have an eosinophilic inflammatory type [16], whereas the remaining patients show a non-eosinophilic phenotype, which include neutrophilic, paucigranulocytic, and mixed granulocytic. McGrath et al [17] have reported that non-eosinophilic asthma, including neutrophilic asthma can be observed in patients with severe asthma, but also in approximately half of patients with mild-to-moderate asthma.

Neutrophilic asthma is characterized by severe persistent disease, frequent exacerbations, and fixed airway obstruction. It is associated with comorbidities such as respiratory infections, obesity, Gastroesophageal Reflux Disease (GERD), and Obstructive Sleep Apnea (OSA) [14], which require treatment in order to achieve asthma control. Neutrophilic asthma is unresponsive to standard treatment with Inhaled Corticosteroids (ICS), Long-Acting β2-Agonists (LABA), Leukotriene Receptor Antagonists (LTRA), mast cell stabilizing agents [7,14,18,19] and probably to the new biologics [20]. The clinical, and diagnostic features of neutrophilic asthma are summarized in table 1.

Adult on-set, most cases after 20 years

Less atopic

Less severe exacerbations compared to eosinophilic asthma

Co-morbidities: obesity, smoking, GERD, OSA

Sputum neutrophil count, 40-70%; eosinophil count <2-3%

Low FeNO <30 ppb - biomamarker of eosinophilic asthma

Low periostin levels - indicator of IL-13 inflammatory activity

High hydrogen sulfide levels

Less subepithelial basement membrane thickness - indicator of IL-13 and IL-25 inflammatory activity

Fixed airway obstruction (low FEV1)

Low post-bronchodilator response to β2-gonists

Less responsive to methacholine bronchoprovocation tests

Corticosteroid unresponsiveness

Table 1: Clinical and diagnostic characteristics of neutrophilic asthma

Abbreviations: GRD, gastroeosophageal reflux disease; OSA, obstructive sleep apnoea; FeNO, fractional expired nitric oxide; FEV1, forced expired volume in 1 sec.

Interleukin-17 (IL-17 also termed IL-17A) plays a key role in the pathophysiology of neutrophilic asthma. IL-17 and other family members are produced mainly by Th17 cells, but other cell can also secrete IL-17 in the lungs. IL-17 induces the transcription of several cytokines, chemokines, adhesion molecules, and growth factors. Chemoattractant cytokines, and chemokines recruit and activate neutrophils into the airways leading to neutrophilic asthma.

The major role of neutrophils in the lung is respiratory defense against bacterial and fungi, but unfortunately, activated neutrophils can produce proteases, Reactive Oxygen Species (ROS), cytokines, and chemokines which can lead to epithelial injury, airway inflammation and hyperresponsiveness, culminating to severe neutrophilic asthma. Neutrophils upon provocation by viral and bacterial infections or allergic inflammation, can generate Neutrophils Extracellular Traps (NETs), inflammasomes, and cytoplasts, which can further orchestrate airway injury, hyperreactivity, and can lead to severe obstructive disease [21].

This review discusses the production of IL-17 and other IL-17 family members by Th17 cells; IL-17 immunopathological roles; IL-17 signaling pathways; and IL-17 collaborating cytokines (IL-1β, IL-6, IL-8, IL-21, and IL-23) in the pathophysiology of severe neutrophilic asthma.

T HELPER 17 CELLS

T helper 17 (Th17) cells were first identified in 2005 as the main producer of the IL-17 [22,23]. Th17 cells also produce IL-17F, IL-22, IL-21 and IL-26, and to a lesser extent IL-6, GM-CSF, and TNF-β [24-30]. The differentiation of Th17 cells from naïve T cells is regulated by the combination of IL-6 and Transforming Growth Factor (TGF)-β [31-37]. The presence of both IL-6 and TGF-β is required for the upregulation of a specific Th17 cell transcription factor, retinoic acid Receptor-related Orphan Receptor (ROR)-γt [33,34]. The transcription factor RORγt is necessary for Th17 cytokine production and for the expression of the IL-23 receptor complex [34]. Interleukin-23 is required for expansion, stabilization, and proliferation of Th17 cells in order to produce chemoattractant cytokines, and chemokines [38,39]. In addition, IL-23 prolongs the expression of Th17 cells signature cytokines, such as IL-17, IL-22, and GM-CSF that induce tissue pathology and mediates chronic inflammation. It also promotes the survival, and maintenance of Th17 cells [38,39]. Interleukin-21 produced by Th17 cells themselves, acts in a positive feedback loop to differentiate more Th17 cells [40]. Signal Transducer and Activator of Transcription 3 (STAT 3) appears to be essential for the differentiation of Th17 cells [40,41]. Interleukin-1β is essential in the early differentiation and conversion of Fox3+ T cells into IL-17-producing cells [42,43].

OTHER IL-17 PRODUCING CELLS

Interleukin-17 is also secreted by other activated immune cells, such as dendritic cells, CD8+ T cells, δγ T cells, natural killer cells, invariant natural killer T cells, lymphoid tissue inducer cells, and type 3 innate lymphoid cells [44-50]. Additionally, haematopoietic and non-haematopoietic cells, such as eosinophils, neutrophils, monocytes, macrophages, and bronchial fibroblasts can secrete IL-17, under certain circumstances [51-54]. Because of the large number of cells producing IL-17, it becomes very difficult to target any specific cell type. Moreover, most of these cells produce a plethora of inflammatory mediators, which could make precision therapeutic targeting difficult.

Interleukin-17

Interleukin-17 (IL-17) plays a key role in the pathogenesis of neutrophilic asthma, via induction and expression of cytokines, chemokines, adhesion molecule, and growth factors which propagate neutrophil recruitment and activation into the airways. Interleukin-17, synonymous to IL-17A was initially identified as Cytotoxic T-Lymphocyte-associated Antigen 8 (CTLA-8) in 1993 by Rouvier and colleagues [55]. Subsequent characterization revealed that this cytokine was produced by a special type of T helper cells different from Th1 and Th2 known as Th17 cells, and thus renamed as IL-17 [56-58]. Latter genomic sequencing led to the discovery of additional IL-17 family members totaling six, namely IL-17A (synonymous to IL-17), IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25), and IL-17F [59-63].

IL-17 is disulfide-linked homodimeric glycoprotein consisting of 155 amino acids with a molecular weight of 35 kDa; but heterodimers composed of IL-17A and IL-17F, as well as IL-17F homodimers exist [64,65]. IL-17A homodimer produce more pathophysiologic responses than the heterodimer or the IL-17F homodimer [62,64, 65]. Among the IL-17 family members, IL-17F has the highest homology (55%) with IL-17A [62,66,67] and IL-25 has the least homology (17%) [62,67]. Moreover, IL-25 immunopathologically behaves as a Th2 cytokine similar to the other “alarmin” cytokines, such as IL33 and TSLP. IL-17A and IL-17F have similar pathophysiological roles, although IL-17 is about 10-30 times as potent as IL-17F [64]. IL-17 is the most studied family member [59,62] particularly in the pathogenesis of rheumatoid arthritis [67-69] and psoriasis [70-73] and to a lesser extent in the immunopathology of neutrophilic asthma [6,9,10,16,20].

Interleukin-17 signaling 

Interleukin-17 family cytokines signal via a receptor family that is distinct from other known cytokine receptors [57,74]. There are five IL-17 family member receptors, namely IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE, all of which are single-transmembrane receptors with conserved structural features [59]. Structurally, all the receptors have two extracellular fibronectin II-like domains, and a conserved cytoplasmic motif “SEFIR” domain. The SEFIR (similar expression to fibroblast growth factor genes and IL-17Rs protein family) is critical for triggering downstream signaling events [59]. 

Interleukin-17 acts by stimulating a heterodimer receptor complex constituted by an IL-17 receptor A (IL-17RA), and IL-17 receptor C (IL-17RC) receptor sub-units [62,75-80]. The signaling is via the adaptor protein nuclear factor (NF)-κ activator (Act1), and downstream to more generic intracellular signaling proteins [81-83]. The signaling compounds may include tumor necrosis factor receptor associated factor -2, -3, and -6; TGF-activated kinase-1 and mitogen-activated protein kinases, such as c-jun N-terminal kinase, extracellular-regulated kinase, and p38 [80,82-84]. Tumor-necrosis factor receptor associated factor (TRAF6) is critical for the activation of the NF-?B, and MAPK pathways [85]. The signaling adaptor Act1, which also contains the SEFIR domain, is essential for mediating IL-117R signaling [86,87]. Further downstream signaling pathways finally result in the induction of expression of cytokines, chemokines, and growth factors by IL-17.

The major role of IL-17 and IL-17F in the pathogenesis of neutrophilic asthma is to induce the expression of chemokines, cytokines, and growth factors, which recruit, activate and promote neutrophil degranulation in the airways [88,89]. Some of these mediators cause airway epithelial injury, goblet metaplasia and mucus hypersecretion, hyperresponsiveness, airway smooth muscle proliferation [90] and airway remodeling, which lead to severe airway obstruction and corticosteroid resistance. IL-17 per se plays a role in subepithelial fibrosis, and airway remodeling [91]. Table 2 shows the list of cytokines, chemokines, and lipid mediators induced by interleukin-17. 

Cytokines

Chemokines

Leukotrienes

Prostaglandins

Interleukin-6 (IL-6)

CXCL1 (Gro-α)

Leukotriene B4

Prostaglandin E2

IL-8 (CXCL8)

CXCL2 (Gro-β)

 

 

IL-21

CXCL5

 

 

Il-23

CXC6

 

 

IL-1β

CCL2, CCL20

 

 

Tumor necrosis factor-α (TNF-α)

 

 

 

Transforming growth factor-β (TGF-β)

 

 

 

Granulocyte colony-stimulating factor (G-CSF)

 

 

 

Granulocyte macrophage colony-stimulating factor (GM-CSF)

 

 

 

Table 2: Cytokines, and chemokines expressed by interleukin-17

ACTIVATED NEUTROPHILS IN NEUTROPHILIC ASTHMA

Neutrophils are polymorphonuclear leukocytes that have a fundamental role to play in innate immune response [88,92]. Neutrophils act as the first line of defense against pathogens, such as bacteria, fungi and perhaps viruses, and participate in the resolution of inflammation. However, neutrophils also contribute to immunopathology of many diseases including respiratory diseases, such as cystic fibrosis, Adult Respiratory Distress Syndrome (ARDS), and neutrophilic asthma.

Activated neutrophils produce oxidative bursts, releasing multiple proteases, cytokines, chemokines, lipid mediators, cathepsin G, myeloperoxidase, and cytotoxic Reactive Oxygen Species (ROS) that lead to airway epithelial cell injury, inflammation, and hyperresponsiveness. The mediators are also responsible for goblet cell hyperplasia and mucus hypersecretion, airway smooth muscle proliferation and remodeling [93]. The chemoattractant mediators, such as CXCL1, CXCL2, CXCL6, CXCL8 (IL-8), LTB4, PAF, thromboxane’s further orchestrate neutrophil recruitment, migration and activation, thus amplifying the neutrophilic airway inflammation [94]. Neutrophils produce ROS which lead to an increase in transcription of IL-8 by epithelial cells, further propagating the chemoattractant neutrophilic response [95]. Inflammatory mediators, such as neutrophil proteases (elastase, cathepsin G, metalloproteinase-9, proteinase-3), and ROS act synergistically to cause the immunopathological features of neutrophilic asthma outlined in table 3.

Cytokines

Chemokines

Lipid derivatives

Interleukin 1α (IL-1α)

CXCL1 (GRO-α)

Leukotriene B4 (LTB4)

IL-1β

CXCL (GRO-β)

Prostaglandin E2 (PGE2)

IL-6

CXCL2

Platelet activating factor

IL-8 (CXCL8)

CXCL5

Thromboxane B2 (TXB2)

IL-17 and IL-17F

CXCL6

 

Interferon-γ (IFN-γ)

CXCL10

 

Tumor necrosis factor-α (NF-α)

 

 

Macrophage inflammatory protein 1-α (MIP-1α)

 

 

Table 3: Chemoattractant mediators associated with neutrophilic airway inflammation

There is sufficient evidence to support the roles of mediators secreted by neutrophils in the pathogenesis of severe neutrophilic asthma. Several studies have documented increased concentrations of neutrophil active mediators, such as IL-8, elastase, Matrix Metalloproteinase-9 (MMP-9), Leukotriene B4 (LTB4), IL-17A, TNF-α, and GM-CSF in plasma, BAL fluid, and bronchial epithelial-conditioned media derived from patients with severe neutrophilic asthma [6,96-103]. In an elegant study, Grunwell et al [104] have demonstrated that children with neutrophilic-predominant asthma have proinflammatory neutrophils with enhanced survival. They have also reported that, children with neutrophilic asthma have quantitatively significantly increased levels of a wide variety of cytokines (IL-1β, IL-6, IL-8); chemokines (CXCL2, CXCL3, CXCL4), myeloperoxidase, and elastase in their BAL fluid.

a. Metalloproteases

Metalloprotease-9 is one of the most investigated inflammatory mediators in asthma. Elevated levels of MMP-9 have been found in induced sputum, and BAL fluid from patients with asthma, and the levels correlated with neutrophil numbers [104] and the severity of asthma [105] Wenzel et el [106] have suggested that localized tissue MMP-9 deposition in the lungs may lead to subepithelial basement membrane thickening, fixed airflow obstruction, and severe asthma.

b. Neutrophil elastase

Neutrophil elastase is one of the most cytotoxic proteins produced by activated neutrophils forms the primary granules. It has been implicated in all the pathophysiological aspects of severe neutrophilic asthma. The immunopathological roles of elastase include airway epithelial injury, increased vascular permeability, hyperplasia of bronchial sub mucus glands and hypersecretion of mucus, bronchoconstriction, and hyperresponsiveness [107]. Neutrophil elastase can induce goblet cell metaplasia, mucus hypersecretion, which is a hallmark of severe asthma. It can also induce airway smooth muscle proliferation [108] and has been implicated in airway remodeling [109].

Neutrophil elastase level has been shown to be elevated in bronchial secretions, and in induced sputum in asthmatic patients compared to healthy controls, especially during exacerbations [110,111].

c. Myeloperoxidase

Myeloperoxidase (MPO) released from neutrophil primary granules can react with hydrogen peroxide (H2O2) generated during respiratory bursts, producing hypochlorous acid (HOCl), and other reactive oxygen species [112]. The ROS are crucial for microbial activity, and antigen presentation, but play deleterious role in causing injury to lung tissue during neutrophilic inflammatory process [89,90]. MPO levels have been shown to be elevated in the BAL fluid of patients with asthma compared to healthy subjects [113,114].

d. Lipid mediators

Neutrophils can synthesize lipid mediators such as and leukotrienes (LTB4), and platelet activating factor (PAF). They are also able to produce prostaglandins (PGE2), and thromboxane’s (TXB2) via cyclooxygenase enzyme systems [115,116]. Lipid mediators play an important role in neutrophil migration and activation in the airway inflammation process.

e. Reactive oxygen species 

Activated neutrophils are the major source of reactive oxygen species, such as hydrogen peroxide (H2O2), hypochlorous acid (HOCl), and superoxide radical (O2-) in allergic inflammation. ROS act synergistically with neutrophil proteases to cause lung tissue damage, sub mucus gland hyperplasia and mucus secretion, and airway hyperreactivity [117-121].

In vitro stimulation of neutrophils from atopic asthmatic patients with inophore A2318, and the chemoattractant fMLP have been shown to produce higher level of ROS compared to non-atopic subjects [117,119]. Tanazawa et al [120] have reported that the production of free oxygen radicals was inversely proportional to measures of airway obstruction, e.g., FEV1. The levels of O2-, however, are related to bronchial hyperresponsiveness to methacholine challenge [120]. Furthermore, higher levels of ROS have been reported during asthma attacks and exacerbations, thus implicating ROS in the pathogenesis of severe neutrophilic asthma, and in promoting exacerbations. Loukides and colleagues [121] have reported an increase in hydrogen peroxide in expired breath condensates from patients with asthma, which correlated with airway inflammation and asthma severity.

Neutrophil proteases, such as elastase, cathepsin G, and protease-3 may induce airway inflammation through activation of eosinophils to produce superoxide’s, cytokines, and chemokines, thus aggravating neutrophilic asthma [122]. Thus, during neutrophilic asthma, there is collaborative cross-talk between neutrophils and eosinophils, leading to more severe neutrophilic airway inflammation.

f. Treatment options for neutrophilic asthma

Neutrophilic asthma is a very difficult phenotype of asthma to treat. It is unresponsive to high dose inhaled corticosteroids, and to the new biologics targeted at IgE (omalizumab), and Th2 cytokines, such as IL-5 (mepolizumab, reslizumab, benralizumab), and IL-4/IL-13 (dupilumab), which are effective in the treatment of eosinophilic asthma, and are steroid-sparing [123-127].

Neutrophilic asthma is characterized by chronic neutrophilic airway inflammation, frequent exacerbation and fixed airflow obstruction. It is therefore, logical to add-on treatment with long-acting drug with broad pharmacodynamic and therapeutic actions, such as Long-acting Muscarinic Antagonists (LAMA), and selective long-acting theophyllines (Table 4).

Cytokine/mediator

Intervention

Drugs

IL-17

IL-7R, IL-17 mAbs

Brodalumab, secukinumab

IL-23

p19 subunit of IL-23

Risankizumab

IL-8 (CXCL8)

CXCLR2 blockade

AZD5069, SCH527123

IL-1β

IL-1β blockade

Anakinra, canakinumab

TNF-β

TNF-β blockade

Etanercept, golimumab

Kinases

p38 kinase blockade

Losmapimod

Phosphodiesterase 4

Phosphodiesterase 4 inhibition

Roflumilast

Macrolide antibiotics

Immunomodulation

Azithromycin, clarithromycin

Acetylcholine

Muscarinic receptor blockade

Tiotropium

Table 4: Pharmacological interventions in neutrophilic asthma

Abbreviations: IL, interleukin; mAb, monoclonal antibody; CXC, C-X-C chemokine motif ligand; GRO-α: growth-related oncogene α; TNF-β, tumor necrosis factor-β; TK, tyrosine kinase receptor cKit (KIT).

LONG-ACTING MUSCARINIC ANTAGONIST

Tiotropium bromide is a Long-acting Muscarinic Antagonist (LAMA) that cause bronchodilation by blocking the actions of cholinergic muscarinic receptors in the airway [128]. It is a selective LAMA, and antagonizes only M1 and M3 muscarinic subtypes, and has a 20-fold higher affinity than the nonselective LAMAs, such as ipratropium [128]. It slowly dissociates from M3 receptors, which confers it a half-life of approximately 35 hours and thus permits once-daily dosing [128-130]. Tiotropium has demonstrated clinical efficacy in patients with neutrophilic asthma [131], and other phenotypes of asthma [132]. Itis the only LAMA recommended as an add-on therapy to ICS in patients with severe refractory asthma [132-134], particularly patients with neutrophilic asthma [131].

a. Theophyllines

Theophyllines have a long noble history in the management of patients with asthma because of their broad pharmacological effects and immunomodulatory actions. Selective phosphodiesterase 4 inhibitors such as roflumilast have been shown to decrease the levels of the key cytokines involved in the pathogenesis of neutrophilic asthma, such as TNF-α, IL-6, IL-8, and IL-17. Roflumilast treatment has been shown to decrease levels of IL-6 in patients with Asthma-COPD Overlap Syndrome (ACOS) [135], and IL-8 in patients with mild asthma [136]. Similarly, roflumilast has been shown to decrease IL-17 levels in patient with asthma [137]. 

Clinical studies have demonstrated the beneficial and efficacy of roflumilast in the treatment of neutrophilic asthma [136,138-142]. Themechanisms of theophyllines in relieving bronchoconstriction in patients with neutrophilic asthma are summarized in table 5.

Reduces airway inflammation

Reduces airway hyperresponsiveness

Reduces bronchochonstriction

Enhances mucociliary clearance

Prevents excessive airway remodeling with persistent airflow obstruction

Decreases the levels of Th17 associated cytokines, and chemokines

Indirectly decreases airway neutrophilia

Table 5: Pharmacological mechanisms of theophyllines in patients with neutrophilic asthma

b. Macrolides

Macrolide antibiotics have been demonstrated to be effective as add-on therapy for neutrophilic asthma [143-146]. In the AMAZES (Asthma and Macrolide: Azithromycin Efficacy and Safety) study, azithromycin reduced asthma exacerbations, and significantly improved asthma-related quality of life [145]. The mechanism of macrolides in neutrophilic asthma is related to their immunomodulatory and anti-inflammatory effects [145]. Macrolides have been shown to reduce neutrophil migration, and to decrease airway neutrophilia, and IL-8 levels [145, 146]. Macrolides have also been reported to inhibit NF-?B, and other transcription factors [146,147] and attenuate TNF-α, and IL-17 immune responses [146]. Cigana et al [148] have shown that azithromycin significantly reduces NF-?B expression, TNF-α mRNA levels and TNF-α secretion in cystic fibrosis-derived cell line. Marjanovi? and colleagues [147] have reported that macrolide antibiotics inhibit cytokine, and chemokine production, including IL-1β, IL-6, TNF-α, CXCL1, CXCL5, and CXCL8. This would of course, reduce neutrophil recruitment and influx into the asthmatic airways. Additionally, macrolides have antiviral action [149] and solithromycin has been reported to have the ability to restore corticosteroid sensitivity by inhibiting the phosphoinositide 3-kinase pathway [150]. In a pilot randomized, double-blind, placebo-controlled study in premature infants, azithromycin prophylaxis reduced postnatal steroid requirements, and duration of mechanical ventilation, although the incidence of bronchopulmonary dysplasia, and mortality were unaffected [151]. Short courses of macrolide antibiotics are useful during bacterial and viral-exacerbated asthma, and in patients with neutrophilic asthma, particularly with steroid- resistance asthma. However, long-term macrolide therapy for severe asthma should be avoided due to the risk of increased carriage of macrolide, and tetracycline resistance by airway microbiomes [152]. 

c. Bronchial thermoplasty

Severe neutrophilic asthma is characterized by airway smooth muscle hypertrophy and hyperplasia. Patients with severe refractory asthma who are not responsive to precise personalized anti-eosinophilic asthma biologics targeted at specific Th2 interleukins [153], may benefit from bronchial thermoplasty. Bronchial thermoplasty utilizes radio frequency thermal energy to reduce airway smooth muscle mass [154,155]. Thermoplasty improves symptoms control, and reduces exacerbation, emergency room visits, and hospitalization in patients with severe uncontrolled asthma and chronic airway obstruction. The procedure also improves the quality of life for the patients [156-160].

CONCLUSION

Neutrophilic asthma is a complex phenotype of asthma that is severe and persistent, with frequent exacerbations, and is characterized by fixed airway obstruction. Immunopathologically, it is characterized by the presence of high levels of neutrophils in the lungs and airways. Interleukin-17 secreted by Th17 cells, plays a key role in the pathogenesis of neutrophilic asthma by expressing the secretion of chemoattractant cytokines, and chemokines for the recruitment, and activation of neutrophils. Activated neutrophils produce oxidative bursts, releasing multiple proteinases, cytokines, chemokines, and reactive oxygen species which cause airway epithelial cell injury, inflammation, hyperresponsiveness, and airway remodeling. Neutrophilic asthma is unresponsive to high dose inhaled corticosteroids, and probably to precision novel anti-IgE, interleukin and interleukin monoclonal antibody therapies. There is need for targeted precision biologics and other treatment modalities for these patients, such as LAMA, long-acting phosphodiesterase inhibitors, and bronchial thermoplasty.

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Citation: Syabbalo N (2020) Mechanisms of Interleukin -17 in The Pathogenesis of Neutrophilic Asthma. J Pulm Med Respir Res 6: 032.

Copyright: © 2020  Nightingale Syabbalo, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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