Molecular mechanisms in the development of asthma
Immune system cells migrate to the lungs and display their functional
properties to develop asthma.58 It was demonstrated
that Th2 resident memory T cells and circulating memory Th2 traffic into
the lung parenchyma and initiate a perivascular inflammation to promote
eosinophil and CD4+ T cell recruitment. Th2 resident
memory cells proliferate near airways and induce mucus metaplasia, AHR
and airway eosinophil activation. Transcriptional analysis revealed that
Th2 resident memory cells and circulating memory Th2 cells share a core
Th2 gene signature, but also exhibit distinct transcriptional profiles
(Figure 1).58
Braga et al.59 described the cellular landscape of
airway lining at the single-cell level. This comprehensive analysis in
asthma identified dominance of TH2 cells interacting
with structural and inflammatory cells. The presented data open new
perspective on lung biology and molecular mechanisms of
asthma.59 A Th1/Th2 imbalance is commonly seen in
allergic asthma and it is shifted back towards Th1 by Protein S. Protein
S, an anticoagulant, anti-inflammatory and anti-apoptotic glycoprotein
is associated with a reduction of AHR, lung tissue inflammatory cell
infiltration, Th2 cytokines in the lung and IgE levels. Asayama et al.
showed that it could inhibit allergic asthma by upregulating the type 1
cytokines TNF-α and IL-12 while downregulating IL-5+Th2 cells.60 A downregulation of Th2 cells is also
achieved by intraperitoneal injection of cysteamine, along with
IL17+ Th17 and
IL13+IL17+ Th2/Th17 cells, thus
effectively inhibiting AHR in an allergic mouse model upon retreatment
with the allergen.61 Lu et al. reported high ILC2
levels in type 2 asthmatics, while non-type 2 asthmatics showed higher
levels of Th17 cells and an inversed Th1/Th17 ratio.62The pathways of Th2-high and Th17-high inflammation were reciprocally
regulated.
The type 2 immunity is mainly driven by IL-4 and IL-13 signaling which
share the common receptor subunit interleukin-4 receptor alpha (IL-4Rα)
(Figure 2). Withdrawal of IL-4Rα signaling prevents the development of
AHR, eosinophilia, and goblet cell metaplasia in allergen-sensitized
mice. However, the IL-4Rα-deficient mice does not develop type 17
immunity after allergic sensitization.63
The increased serum IL-33 levels in asthma patients has been linked to
the activation of mast cells. To characterise the mechanisms of IL-33
contribution to asthma development, Ro et al.64 used
knockdown or pharmacological inhibitors in bone marrow-derived mast
cells and animal model. The study revealed that the
‘MyD88-5-/12-LO-BLT2-NF-κB’ cascade contributes to the IL-33 signaling
to induce IL-13 synthesis in mast cells, which may represent a new
therapeutic target for severe asthma.64
Lv et al. investigated the role and the mechanisms of IL-37 in type
2-mediated allergic lung inflammation in HDM-induced murine asthma
model. They found IL-37 impairs HDM-induced asthma, most likely by
preventing IL4/IL13-induced chemokine ligand (CCL)11 production from
fibroblasts and airway smooth muscle cells through its direct effect on
tracheobronchial epithelial cells.65
In a murine allergic asthma model, IL-4 receptor α blockade decreased
serum IgE and IL-5 levels and increased the level of IgG1, IgG2a, IgG2b
and IgG3 prior/during sensitization. Thus following the IL-4 receptor α
blockage, an immediate immunoglobulin response is induced accompanying
the suppression of type 2 cytokines with a potential long-lasting
reduction in Th2-biased T-regulatory (Treg) cells.66
Chitotriosidase (chitinase 1, Chit1) has been known as regulator and
stimulator in Th2 responses. Hong et. al. studied the possible
mechanisms and its role in the pathogenesis of allergic
asthma.67 Significantly elevated levels of Chit1 in
the sputum of patients with childhood asthma were reported. Moreover, in
the absence of Chit1 molecule, forkhead box P3
(Foxp3)+ Treg cell frequency decreased in the lungs of
mice besides TGF-β1 levels, which suggests a protective role in
asthmatic airway responses by regulating TGF-β secretion and
Foxp3+ Treg cells.
A neutrophilic inflammatory response or Th17 response is classified as
non‐type 2 asthma. The potential mechanisms of non‐type 2 asthma have
been well-described in a comprehensive review
article.68 Th17 cells are shown to play a key
role in allergic asthma by the secretion of inflammatory cytokines,
including IL-17A, IL-17F, IL-21, and IL-23. Worth et al.successfully demonstrated that genetic variants in IL17F, L17A, and
IL-23 signaling genes (IL23A, IL23R, IL12B) are associated with asthma.
Their results also confirmed that IgE levels could influence the
Th17-related gene expression.69 Moreover, the
IL-17 levels and leukotriene (LT)B4 were shown to increase with disease
severity in serum and sputum. Ro et al. investigated the role of
LTB4 receptors, BLT1 and BLT2, in a neutrophil‐dominant pulmonary
inflammation murine model. BLT1 and BLT2 were proven as important in
asthma development, and IL‐17 was identified as a key cytokine
synthesized through the BLT1/2‐cascade.70 In
humans, neutrophils released from the bone marrow express low
levels of CD16 and high levels of CD62L. This
CD16dimCD62Lhigh subset is
considered representing the immature neutrophil, whereas the
CD16highCD62Ldim subset is thought
to be mature and induced systemic
inflammation.71 Ekstedt et al.recently found that this novel neutrophil subset,
CD16highCD62Ldim, is increased in
the blood following an inhaled allergen bronchial challenge
bronchoprovocation test. They proposed that increasing neutrophil
subgroups in allergic asthma might offer new opportunities in advancing
allergic asthma research (Figure 3).71
‘Eat me’ and ‘Don’t eat me’ signals are an integral part of phagoptosis
and thus, in neutrophils, they are important for the resolution of
pulmonary inflammation as prolonged survival of airway neutrophils is
directly related to asthma severity.72 In allergic
donors, neutrophils showed an upregulation of CD47 (‘don’t eat me’) and
a simultaneous downregulation of CD36 and CD43 (‘eat me’) compared to
healthy controls (Figure 3).73 Additionally, less mRNA
for CCL4 and CCL20 (homing cytokines for macrophages) was found in
airway neutrophils of asthmatic donors than in healthy controls.
A study performed by Guan et al.74 has reported that
reduced monocytic myeloid-derived suppressor cells (M-MDSC) may result
in abnormal T responses with the increase in Th2 and Th17 cells and
decrease in Treg cells in asthma patients. These results suggest a new
immune regulatory mechanism in the pathogenesis of asthma open for
further research.74 To define whether there is a
deficiency in Breg subsets, Wirz et al.75 compared the
percentages of IL-10-producing Breg subsets in peripheral blood from
patients with asthma and AR. They demonstrated that there is no
difference in numbers of Bregs in the patients when compared to healthy
controls.75
Current research suggests that several receptors involving in asthma
pathophysiology, including PGD2 receptor 2 (DP2 or
CRTH2), as well as, colony‐stimulating factor 1 receptor (CSF1R). The
DP2 receptor is an essential regulator in allergic asthma because it can
be activated by both allergic and nonallergic
stimuli.76 The activation of the DP2 receptor pathway
increases both the airway smooth muscle mass and vascularization in
airway walls, resulting in downstream effects on asthma development.
Interestingly, airway epithelial cells secrete CSF1 into the alveolar
space in response to aeroallergen. Moon et al. demonstrated that
inhibition of the CSF1‐CSF1R signaling pathway could suppress
sensitization to aeroallergens and subsequent allergic lung inflammation
in mice with chronic asthma. They conclude that inhibition of CSF1R is a
potential new target for the medical treatment of allergic
asthma.77
Kim et al78 showed that the
ceramide/sphingosine-1-phosphate ratio can discriminate between two
different asthma endotypes. Sphingosine-1-phosphate (S1P) was found to
positively correlate with the percentage of platelet adherent
eosinophils, indicating eosinophilic inflammation. The percentage of
CD66+ activated neutrophils positively correlates with
C16:0 ceramide levels, indicating neutrophilic inflammation. An
upregulation of ceramide-mediated pro-apoptotic signals were found in
patients with higher CD66+ neutrophils. For both
eosinophilic and neutrophilic pathways, genetic SNPs were found.
Increased ceramide levels may also contribute to the development of
obese asthma. Choi et al.79 found multiple ceramides
(C16:0, C18:0 and C20:0) to accumulate in obese mice as a result of a
high fat diet, inducing AHR and inflammation. Increased expression of
ceramide synthase (CerS)1 and CerS6 were found in the lungs, and CerS6
was identified as a potential future therapeutic target for obese
asthma.
Felix and Kuschnir80 pointed out that Arginase
inhibitors could act beneficial for obese asthma patients by
upregulating the L-Arginine/asymmetric dimethylarginine ratio as an
addition to a previous article by Meurs et al.81 The
reply by Meurs et al.82 agreed and suggested an even
more direct link in pointing to the previously known increased arginase
expression and activity in obese asthma patients. However, the mechanism
behind this is still unknown, opening up avenues for future research.
One of the characteristics of asthmatic lung is airway remodeling.
Whether airway inflammation and remodeling in asthmatics can be related
to persistent airflow obstruction was evaluated in a recent study that
showed in asthmatics with persistent airflow obstruction increased
airway smooth muscle area, decreased periostin and transforming growth
factor beta (TGF-β) and chymase positive cells compared to patient with
non-persistent obstruction.83 Asaduzzaman et
al.84 studied cockroach-induced chronic murine asthma
models by using a specific inhibitor of proteinase-activated receptor-2
(PAR2) to identify a role of PAR2signalling on AHR and airway inflammation/remodelling. They showed that
administration of an anti-PAR2 antibody significantly
inhibited AHR, inflammation and collagen accumulation in the lung
tissue. The authors suggest that PAR2 blockade may be a
successful therapeutic strategy for human allergic airway
diseases.84
A recent study has introduced an in vivo molecular platform to
elucidate both disease mechanisms and therapeutic targets of virus
associated and non-virus-associated asthma exacerbations. A group of
exacerbation-related modules included SMAD3 signaling, epidermal growth
factor receptor signaling, extracellular matrix production, mucus
hypersecretion, and eosinophil activation.85 Another
study in infants suffering from rhinovirus bronchiolitis showed that
concentrations of IL‐4, IL‐5, IL‐13, and TSLP, were correlated with a
higher risk of asthma onset in childhood.86 In a study
with 5-year-old children demonstrated that the development of atopic
asthma in children with early rhinovirus-induced wheezing was associated
with differentially methylated genomic regions. The strongest
methylation changes were observed in the SMAD3 gene promoter
region at chr 15q22.33 and in introns of the DDO/METTL24 genes at
6q21.87
Respiratory syncytial virus (RSV) infection affects a large number of
the population in the early years of their life and is associated with
an increased asthma risk. Schuler et al. show that uric acid and IL-1β
play a role in the mechanism, and their inhibition can prevent the
development of asthma after neonatal RSV infection, thus being a
possible therapeutic target.88 A prospective study
suggested infants suffering from bronchiolitis at less than 6 months of
age, have a twice higher risk of doctor-diagnosed asthma after follow-up
for 11-13 years compared to general Finnish population, and that the RSV
was the main reason for bronchiolitis in these
infants.89 The EAACI Influenza in Asthma Task Force
performed a scoping review about the influenza burden, prevention, and
treatment in asthma. In this review, vaccination conferred a degree of
protection against influenza illness and asthma-related morbidity to
children with asthma, but not to adults with asthma. Although influenza
vaccines appeared to be safe for asthmatic patients, there is a lack of
data regarding efficacy in adults.90
A few studies have been performed to reveal the effects of medical
treatments with ILCs in allergic airway diseases so far. The mechanisms
in action of glucocorticoid therapy on ILCs were assessed in a
prospective study by Yu et al.91 Their data showed the
administration of glucocorticoids regulates ILC2s via MEK/JAK-STAT
signalization pathways in asthma patients.
To test the role of MUC1 membrane mucin in uncontrolled severe asthma,
the recent study analysed the association of MUC1-CT (cytoplasmic tail
in the C-terminal subunit) with corticosteroid efficacy in in
vitro and in vivo models. The results suggested that MUC1-CT has
an important role in the modulation of the anti-inflammatory effects of
corticosteroids and may be a promising new approach for the treatment of
asthma.92
MicroRNAs (miRNA) are secreted in extracellular vesicles and regulate
signaling pathways by being transferred between cells. Recently, Bartel
et al. characterized the miRNA secretion in extracellular vesicles from
normal bronchial epithelial cells treated with IL‐13 to induce an
asthma‐like epithelium. They observed that miR‐34a, miR‐92b, and miR‐210
were involved in the early development of a Th2 response in the airways
and asthma93.
Suojalehto et al. examined the protein expressions from nasal brush
samples from work-related asthma patients and healthy controls using the
proteomic approach. Work-related asthma patients often are exposed to
welding fumes, aerosols composed of hazardous metals and gases. The
nasal brush samples are a relatively non-invasive specimen containing
proteins secreted from epithelial and inflammatory cells. Their results
indicated that the nasal epithelial proteome of the work-related asthma
patients is highly enriched in processes related to inflammatory and
calcium signalling, free radical scavenging and oxidative stress
response, and metabolism.94
Uwadiae et al.95 studied the role of T follicular
helper (TFH) cells of allergen airway disease in a mouse model of
allergic asthma. They found that TFH cells accumulate beside the
germinal center B cells with constant allergen exposure. Furthermore,
blocking the inducible costimulatory (ICOS) signaling disrupted the TFH
cell response; however, it did not have an impact on the differentiating
of other CD4+ T-cell subsets. Based on these observations, the authors
suggest that TFH cells have critical roles in the regulation and the
ICOS/ICOS-L pathway can be a novel therapeutic target in allergic airway
disease.95