Asthma- an inflammatory tour on the key players causing pathology
Introduction
Asthma is a highly prevalent lung disease which in 2019 affected over 295 million people and caused
a staggering 455, 000 deaths. Asthma is a long term chronic inflammatory condition which affects both
children and adults and it is one of the most common chronic diseases within children (WHO, 2022).
The prevalence of this condition has been increasing in both children in adults and it is thought that
there is going to be an additional 100 million more asthmatic by 2025. Asthma also has a significant
cost to society through direct and indirect costs with hospitalizations and medication being the most
important factors. Asthma cases also increase with co-morbidities including smoking and obesity
(Bahadori et al., 2009). This reveals how huge economic burden asthma has and how it can impact the
costs is society. Moreover this high prevalence and rising costs giving means that further research into
better treatments and control of the disease is vital.
Asthma is now being considered a heterogeneous condition with many contributing factors to the
underlying inflammatory processes. Clinically, asthma is identified by the tightening of airways leading
to airway hyper responsiveness (AHR) and tissue remodelling (WHO, 2022). Moreover, there are two
main types of asthma, called atopic and ectopic (allergen and non-allergen). Atopic asthma is caused
by an allergen which triggers an inflammatory response. These allergens could be anything such as
house dust mite (HDM), pollen and mould. T helper type 2 high (Th2- high) inflammation is a type of
inflammation which causes asthmatic pathology when introduced to an allergens. Around 50% of mild
to moderate asthma and a larger proportion of severe asthmatics are dependent on this Th2- high
inflammation which is mediated by cytokines such as IL-4, IL-5 and IL-13 (Habib, Pasha and Tang,
2022). Whereas non-allergic asthma will have triggers which are usually environmental factors. These
could include factors such as exercise and stress. This type of asthma is not as well understood or as
easy to detect (Bansal, 2022). Moreover, it is driven by a Th2- low inflammatory response which are
mediated by cytokines such as IL-17.Despite the different asthmatic phenotypes the types of cells and
components involved within the inflammatory process are comparable. Both have in common a
complex interplay between the surrounding epithelial tissues, inflammatory innate immune cells, T-
helper cell and many inflammatory cytokines and alarmins (Gillisen and Paparoupa, 2015). Overall this
process is highly complex and understanding in great detail is crucial to more personalised treatments.
Overall this review will explore the main mechanisms in which inflammation occurs through Th2- high
and Th2- low inflammation within different endotypes of asthma. It will explore the controversies
which arise in these inflammatory responses and the difficulties and barriers which still faces in
understanding these molecular mechanisms. Next it will explore different view with a neuro-immune
regulation of inflammation that has come to light in the past couple of years. Finally it will explore
different biomarkers used to identify specific treatments for asthmatics and the limitations due to the
heterogeneous nature of the disease. Lastly, how increasing our awareness of biomarkers is
important for the further personalised treatment overall reducing the impact on public health and the
economy.
Classic type 2 inflammatory response in asthma to an allergen
The most common form of asthma is atopic, leading to type 2 inflammation in response to an allergen
with complex intricate interplay of several individual pathways (figure 1). Firstly a disrupted epithelial
barrier is seen within most asthmatics in which there has been evidence of a loss of E- cadherin (Hijink
et al., 2007) as well as claudin- 18 ( Sweerus et al., 2017), which are important for mediating tight
junctions. This creates a reduced barrier integrity which is important in the pathogenesis of asthma
acting as the orchestrator of inflammation. This allows the facilitation of allergen and microbes to
, access the stromal tissues leading to sensitisation (Folkerts and Nijkamp, 1998). This contact of
allergens to the epithelium causes the release of alarmins: TSLP, IL-25 and IL-33. Specifically IL-25 and
Il-33 can activate innate lymphoid cells 2 (ILC2s). Where are TSLP primes antigen presenting cells
(APCs) such as dendritic cells to promote type 2 immunity by activation B cell and T cells acting as a
linkage between the epithelial barrier and type 2 inflammation (Ying et al., 2005). These cytokines
polarising naive CD4 T cells to Th2 cells. These Th2 cells then release type 2 cytokines such as IL-4, IL-
5 and IL-13 causing further activation and filtration of eosinophils, basophiles and epithelial
differentiation to mucus secretion as well as hyper-proliferative states (Kuruvilla, Lee and Lee, 2019).
Figure 1: Classic Th2 – high inflammatory process pulmonary epithelium exposed to insults causing
the release of cytokines and mediators polarising a Th2 response. Activating inflammatory innate
immune cells acting on smooth muscle epithelium within the lung (Made in Bio render. Com)
Th2 inflammatory cell and mediators
Alarmins IL-25 and IL-33 each originate from epithelial cells which promote a key role in allergic
asthma. For example in mouse models with transgenic over expression of Il-25 and IL33 generate
airway eosinophilia, up-regulation of type 2 cytokines expression and elevated IgE serum, AHR and
hypersecretion ( Yao et al., 2014)( Zhiguang et al., 2010). IL-33 has been seen to be a crucial amplifier
of T2 asthma. In studies it has been seen to can induce degranulation, expansion of eosinophils and
pro inflammatory cytokine production in IgE- sensitized mast cells as well as mediating anaphylactic
shock in mice. It also acts in synergy with the IgE receptor in mast cells and basophiles (Silver et al.,
2010).
Innate Lymphoid Cells
Normal conventional treatments are targets type 2 inflammatory cells however recent studies have
shown that ILC2S could have a more critical role in allergic response within asthma. It has been shown
that intranasal administration of ILC2s in mice resulted in the development of AHR and goblet cell
hyperplasia’s (Barlow et al., 2012). These ILC2 cells are also involved rapidly in producing type 2
cytokines. For example exposure of an allergen in a Rag 1 -/- mice to ILC2s induced a rapid increase in
Introduction
Asthma is a highly prevalent lung disease which in 2019 affected over 295 million people and caused
a staggering 455, 000 deaths. Asthma is a long term chronic inflammatory condition which affects both
children and adults and it is one of the most common chronic diseases within children (WHO, 2022).
The prevalence of this condition has been increasing in both children in adults and it is thought that
there is going to be an additional 100 million more asthmatic by 2025. Asthma also has a significant
cost to society through direct and indirect costs with hospitalizations and medication being the most
important factors. Asthma cases also increase with co-morbidities including smoking and obesity
(Bahadori et al., 2009). This reveals how huge economic burden asthma has and how it can impact the
costs is society. Moreover this high prevalence and rising costs giving means that further research into
better treatments and control of the disease is vital.
Asthma is now being considered a heterogeneous condition with many contributing factors to the
underlying inflammatory processes. Clinically, asthma is identified by the tightening of airways leading
to airway hyper responsiveness (AHR) and tissue remodelling (WHO, 2022). Moreover, there are two
main types of asthma, called atopic and ectopic (allergen and non-allergen). Atopic asthma is caused
by an allergen which triggers an inflammatory response. These allergens could be anything such as
house dust mite (HDM), pollen and mould. T helper type 2 high (Th2- high) inflammation is a type of
inflammation which causes asthmatic pathology when introduced to an allergens. Around 50% of mild
to moderate asthma and a larger proportion of severe asthmatics are dependent on this Th2- high
inflammation which is mediated by cytokines such as IL-4, IL-5 and IL-13 (Habib, Pasha and Tang,
2022). Whereas non-allergic asthma will have triggers which are usually environmental factors. These
could include factors such as exercise and stress. This type of asthma is not as well understood or as
easy to detect (Bansal, 2022). Moreover, it is driven by a Th2- low inflammatory response which are
mediated by cytokines such as IL-17.Despite the different asthmatic phenotypes the types of cells and
components involved within the inflammatory process are comparable. Both have in common a
complex interplay between the surrounding epithelial tissues, inflammatory innate immune cells, T-
helper cell and many inflammatory cytokines and alarmins (Gillisen and Paparoupa, 2015). Overall this
process is highly complex and understanding in great detail is crucial to more personalised treatments.
Overall this review will explore the main mechanisms in which inflammation occurs through Th2- high
and Th2- low inflammation within different endotypes of asthma. It will explore the controversies
which arise in these inflammatory responses and the difficulties and barriers which still faces in
understanding these molecular mechanisms. Next it will explore different view with a neuro-immune
regulation of inflammation that has come to light in the past couple of years. Finally it will explore
different biomarkers used to identify specific treatments for asthmatics and the limitations due to the
heterogeneous nature of the disease. Lastly, how increasing our awareness of biomarkers is
important for the further personalised treatment overall reducing the impact on public health and the
economy.
Classic type 2 inflammatory response in asthma to an allergen
The most common form of asthma is atopic, leading to type 2 inflammation in response to an allergen
with complex intricate interplay of several individual pathways (figure 1). Firstly a disrupted epithelial
barrier is seen within most asthmatics in which there has been evidence of a loss of E- cadherin (Hijink
et al., 2007) as well as claudin- 18 ( Sweerus et al., 2017), which are important for mediating tight
junctions. This creates a reduced barrier integrity which is important in the pathogenesis of asthma
acting as the orchestrator of inflammation. This allows the facilitation of allergen and microbes to
, access the stromal tissues leading to sensitisation (Folkerts and Nijkamp, 1998). This contact of
allergens to the epithelium causes the release of alarmins: TSLP, IL-25 and IL-33. Specifically IL-25 and
Il-33 can activate innate lymphoid cells 2 (ILC2s). Where are TSLP primes antigen presenting cells
(APCs) such as dendritic cells to promote type 2 immunity by activation B cell and T cells acting as a
linkage between the epithelial barrier and type 2 inflammation (Ying et al., 2005). These cytokines
polarising naive CD4 T cells to Th2 cells. These Th2 cells then release type 2 cytokines such as IL-4, IL-
5 and IL-13 causing further activation and filtration of eosinophils, basophiles and epithelial
differentiation to mucus secretion as well as hyper-proliferative states (Kuruvilla, Lee and Lee, 2019).
Figure 1: Classic Th2 – high inflammatory process pulmonary epithelium exposed to insults causing
the release of cytokines and mediators polarising a Th2 response. Activating inflammatory innate
immune cells acting on smooth muscle epithelium within the lung (Made in Bio render. Com)
Th2 inflammatory cell and mediators
Alarmins IL-25 and IL-33 each originate from epithelial cells which promote a key role in allergic
asthma. For example in mouse models with transgenic over expression of Il-25 and IL33 generate
airway eosinophilia, up-regulation of type 2 cytokines expression and elevated IgE serum, AHR and
hypersecretion ( Yao et al., 2014)( Zhiguang et al., 2010). IL-33 has been seen to be a crucial amplifier
of T2 asthma. In studies it has been seen to can induce degranulation, expansion of eosinophils and
pro inflammatory cytokine production in IgE- sensitized mast cells as well as mediating anaphylactic
shock in mice. It also acts in synergy with the IgE receptor in mast cells and basophiles (Silver et al.,
2010).
Innate Lymphoid Cells
Normal conventional treatments are targets type 2 inflammatory cells however recent studies have
shown that ILC2S could have a more critical role in allergic response within asthma. It has been shown
that intranasal administration of ILC2s in mice resulted in the development of AHR and goblet cell
hyperplasia’s (Barlow et al., 2012). These ILC2 cells are also involved rapidly in producing type 2
cytokines. For example exposure of an allergen in a Rag 1 -/- mice to ILC2s induced a rapid increase in
