Asthma and IL-17

Introduction: For the last two decades there has been great interest in cytokines specifically IL-17 in
the pathogenesis of Asthma. It has been the subject of possible therapeutic intervention. Though most
of the research has been conducted in murine and mice models, the potential for intervention in
humans is unbound. This review takes into account the work done till now and the projections into the
future.
Discussion
Asthma affects nearly 300 million people and one of every 250 deaths is attributed to this disease
worldwide. The cost of asthma hospitalizations, emergency room visits, lost school, and workdays is
significant. Asthma is a common airway disorder that is characterized by chronic airway
inflammation, mucus production, and airway hyper responsiveness

(AHR) with airway

remodelling(1). Numerous triggers can induce bronchoconstriction, including allergic responses,

respiratory infections, exercise, irritants, and non-steroidal anti-inflammatory drugs in select
patients(2). Accumulating evidence indicates that antigen-specific Th2 cells and their cytokines such
as IL-4, IL-5, IL-13 and IL-17-producing CD4 T cells (Th17 cells) and IL-23, an IL-12-related
cytokine that is essential for survival and functional maturation of Th17 cells, are involved in antigeninduced airway inflammation(3).
New Paradigm
The T helper 1 (Th1) cell and Th2 cell paradigm, first proposed by Mosmann and Coffman, has been
used to explain how hosts elicit different adaptive immune responses to eradicate the evasion of
various pathogens(4). Upon first encounter of foreign antigens presented by antigen-presenting cells
(APCs), naveCD4+ T cells can differentiate into either interferon-g (IFN-g)-producingTh1 cells or
IL-4-producing Th2 cells, and this differentiation is largely controlled by various environmental
factors, especially by signals coming directly from APCs(5). Uncontrolled and persistent effector T
cell responses, however, can drive the onset of autoimmunity, allergy, or atopy. Evidence from clinical
observations and from studies on experimental animals supports the idea that uncontrolled Th2 cell
responses, as well downstream cytokines IL-4, IL-5, and IL-13, are underlying the development of

atopic diseases, such as asthma(6, 7). On allergen sensitization, Th17 cells home to the lung and
enhance not only neutrophilic airway inflammation but also Th2 cell-mediated eosinophilic airway
inflammation in mouse models of asthma(8). These observations have indicated that investigation of
the differentiation, effector function, and regulation of Th17 cells may offer a new way to control
asthma(9). Helper 17 (Th17) cytokines are now widely believed to be critical for the regulation of
various chronic immune diseases. Investigations have revealed a significant role for IL-17 cytokines
in regulating inflammation and modulating lung and airway structural cells in asthma(10).
The Family
The IL-17 family consists of six members including IL-17 (now synonymous with IL-17A), IL-17B,
IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F(11, 12). IL-17, the most investigated
member in this family exerts a wide variety of biological activities due to ubiquitous distribution of its
receptor(13). The originally described IL-17 receptor (IL-17RA) is a Type I transmembrane protein
consisting of a 293 amino acid extracellular domain, a 21 amino acid transmembrane domain, and a
long 525 amino acid cytoplasmic tail. Its mRNA is extensively expressed in the lungs, kidneys, liver,
and spleen, as well as in isolated fibroblasts, epithelial cells, mesothelial cells, and various myeloid
cells from rats and mice. Among human cells, the mRNA for IL-17RA can be detected in epithelial
cells, fibroblasts, B and T lymphocytes, myelomonocytic cells, and marrow stromal cells. The
IL17RA protein is present on peripheral blood T lymphocytes and in vascular endothelial cells from
humans.
IL-17 in Asthma
IL-17A and IL-17F are mainly produced by a recently identified subpopulation of CD4 T cells,
namely Th17 cells, which seem to be involved in the pathogenesis of a variety of autoimmune
diseases. IL-17 is implicated in numerous immune and inflammatory responses primarily as a proinflammatory regulator by inducing the expression of various inflammatory mediators, such as
cytokines, chemokines, adhesion molecules, and growth factors(14). In asthmatic patients, IL-17
expression has been shown to increase in sputum, lung cells, bronchoalveolar lavage (BAL) fluids,
and peripheral blood. In mouse models, allergen sensitization causes Th17 cells to home to the lungs,
where

they

enhance

neutrophilic

infiltration

and

augment

Th2-mediated

eosinophilic

inflammation(15). Interleukin 17 up regulates a diverse set of cytokines, chemokines, adhesion

molecules, and growth factors. It has also been shown that IL-17A is expressed in the airways of
asthmatic patients and its expression is correlated with the severity of asthma(16). IL-17A has also
been shown to stimulate bronchial fibroblasts, epithelial cells, and smooth muscle cells and induce the
expression of a variety of cytokines and chemokines, which are important for granulopoiesis and
neutrophil recruitment (18). The IL-4/IL-13 signalling pathway accounts for the symptoms
experienced by a subset of severe asthmatics with allergen-associated symptoms and high serum
immunoglobulin E (IgE) levels, and these patients are generally responsive to anti-IgE treatment. The
IL-5/IL-33 signalling pathway is likely to play a key role in the disease pathogenesis of those who are
resistant to high doses of inhaled corticosteroid but responsive to systemic corticosteroids and antiIL5 therapy(17).
Neutrophil Migration
The ability of IL-17A to evoke migration of neutrophils makes it likely that IL-17A is involved in
severe asthma, of which neutrophil infiltration is one of the hallmarks. IL-17 appears to be an
important mediator of inflammation, especially in neutrophil-dominated responses to bacterial
challenge(18). This connection is intriguing given that expression of IL-17 is restricted to memory T
cells, which are associated with an adaptive immune response, while neutrophils are viewed primarily
as mediators of innate immunity(19). It has been hypothesized that by secreting IL-17, which
subsequently induces chemokines and granulopoietic factors, memory T cells may enhance faster and
more effective recruitment of neutrophils. In this respect IL-17 may serve as a modulator of early
immune responses to pathogens, and as such may be an important element of host defence. On the
other hand, the overproduction of IL-17 may aggravate inflammatory reactions and contribute to
tissue injury(20). Somewhat surprisingly, the IL-17 mRNA levels correlate positively with the IL-5
mRNA levels in sputum from asthmatic patients(21, 22). Both in plasma and in activated peripheral
blood mononuclear cells from allergic asthmatics, the increase in IL-17 concentration is accompanied
by the enhanced concentration of IL-23, which is a critical regulator of IL-17. In addition, an increase
in transcription factor RORt level is found in allergic asthmatics. These findings indicate that
increased expression of IL-23 and RORt may contribute to the increase in IL-17 expression in

asthmatic patients(23). Therefore, the results in asthmatic patients suggest that besides predominant
Th2 immunity, abnormal Th17 immunity is also involved in the pathogenesis of allergic asthma. IL17 may be viewed as a potential target for therapeutic intervention(24, 25). Furthermore, compared to
people with mild asthma, individuals with severe asthma not only have more IL-17, they tend to have
more of the cells known to secrete IL-17, namely Th17 cells. Research has also shown that mice with
more Th17 cells get little breathing relief from steroids, a common treatment for asthma but one to
which severe asthma patients rarely respond. Moreover, it has recently been shown that Th17 cellmediated neutrophilic airway inflammation is steroid-resistant(26).
IL-17 per se, however, does not cause chemotaxis of human neutrophils from peripheral blood,when
studied in vitro(27). In contrast, IL-17 enhances the production of IL-8 in human airway smooth
muscle cells, bronchial epithelial cells, and bronchial fibroblast, and the neutrophil chemotactic effect
of IL-1 is blocked by an anti-IL-8 antibody (Ab) in vitro. These data indicate that IL-17 exerts the
accumulation of neutrophils into the airways in an indirect manner, mainly via the

enhanced

production of IL-8, a potent neutrophilic chemoattractant by lung structural cells(28).

Consistent with previous in vitro studies, studies with a murine model of asthma has shown that
inhibition of IL-17 activity with an anti-IL-17 Ab remarkably reduces the increase in airway
infiltration of neutrophils and expression of KC (a functional murine homolog of IL-8) protein
and mRNA induced by allergen inhalation (29). Moreover, IL-17 augments the release of IL-6 from
human bronchial fibroblasts and expression of G-CSF in bronchial epithelial cells, inducing
neutrophil development and granulopoiesis (30, 31). Thus, IL-17 in asthma orchestrates neutrophilic
airway inflammation by inducing the release of neutrophilic chemoattractant and activating factors
from local cells in the lungs(32). In contrast, IL-17 appears to inhibit the TNFa- and interferon (IFN)g-stimulated production of RANTES, a chemokine that acts mainly on mononuclear leukocytes. Since
RANTES is a potent chemoattractant for lymphocytes, it has been speculated that the inhibition of
RANTES secretion by lymphocyte-derived IL-17 may represent a regulatory mechanism limiting
lymphocyte infiltration(33). IL-17 can also exert its action via induced release of endogenous
tachykinins, which contribute to neutrophil recruitment by acting on NK-1 receptors. Just like the

effect on neutrophil recruitment, IL-17 can exert an indirect stimulatory effect on neutrophil activity
in the airways. It is likely that IL-17 activates airway neutrophils through the induced release of
neutrophil-activating cytokines, such as IL-6 and IL-8, which are known to be released from the
bronchial epithelium and fibroblasts by IL-17(34). Interestingly, IL-1b, another cytokine that is
increased in obstructive airways disease does potentiate the stimulatory effect of IL-17 on neutrophil
activation(35). It can be speculated that IL-17 stimulates the release of IL-1b from airway
macrophages and that this IL-1b potentiates the IL-17-induced release of IL-6 and IL8 in bronchial
epithelial cells. In short The IL-17 signaling pathway is thought to contribute to 'neutrophilic
asthma'(17).
IL-17 and Eosinophils
These results have suggested that IL-17 has a dual role in the regulation of eosinophilic airway
inflammation in asthma. Thus, IL-17 promotes eosinophilic airway inflammation by mounting Th2
responses during antigen sensitization while inhibiting eosinophilic airway inflammation by acting as
a down-regulator of the dendritic cell-derived Th2 chemoattractant TARC during the effector phase
(36) . However, more recent studies have reported that administration of anti-IL-17 Ab to OVAinhaled mice in the challenge phase reduces antigen- induced airway infiltration of eosinophil
and Th2 cytokine levels in BAL fluids by using different sensitization and challenge protocols(37) .
In addition, an enhancing effect of IL-17 on CCL11 mRNA expression and protein release in
human airway smooth muscle cells has been reported . Moreover, IL-17 activates NF- B pathway
that can subsequently induce CCL11 and TARC expression, suspecting the presence of an indirect
regulatory pathway (38). These observations suggest that IL-17 is associated with Th2 cell-mediated
eosinophilic inflammation in asthma. IL-17 seems to contribute to neutrophilic inflammation as well
as Th2 cell-mediated and eosinophilic inflammation in asthma(39).
Implicating IL-17 in asthma and proposing new disease subtypes has solved several puzzles. For
example, in many asthmatic patients, other types of white blood cell called eosinophils accumulate in
the lungs, but individuals with the most severe form of asthma harbour neutrophils, yet another type
of immune cell(40). Normally, these neutrophils surround the site of an acute infection or injury, lured

there by IL-17, to protect the body. It appears that in asthma, IL-17 is drawing neutrophils into the
lung but they are not there to protect. Instead, they make asthma attacks worse.

Mucus Hypersecretion

Mucus hypersecretion and persistent airway inflammation are common features of asthma. Chen et
al have found that IL-17 stimulates the expression of mucin genes, MUC5B and MUC5AC, in
the airway epithelial cells and that its effect on MUC5B expression is at least partly mediated by
IL-6 in a JAK2-dependent pathway(41). As the contribution of excessive airway mucus to asthma
pathology is clear, the increase in mucus production can be an action mechanism of IL-17 in
asthma(42). The potential significance of Th17 responses in asthma stems partly from the effects of
Th17 cells on the function of regulatory T cells controlling effector T cell responses. Thus, the
inhibition of IL-17 can be a way to control inflammation but also to restore regulatory T cell functions
in asthma(43)

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Figure no 1: The many pathways to asthma(44)

Figure no 2: The Role of Th2 Immune Pathway Modulation in the Treatment of Severe
Asthma and Its Phenotypes(45)

Figure 3: The pathogenesis of Asthma(46)

Figure 4: