Main text:
Asthma is a chronic inflammatory disease of the airways that causes
bronchial hyperreactivity, mucus overproduction, airway remodelling and
narrowing. Allergic asthmatic patients generally present a
predisposition toward T helper (Th) 2 inflammation that is maintained by
allergen-driven innate factors and downstream activation of Th2 cells.
In this regard, Notch signalling activates the key Th2 transcription
factor Gata-3. In fact, Notch is considered as a master regulator of Th
cells to terminally differentiate into Th1, Th2, Th17 lineages by
directly inducing the respective transcription factors and
cytokines.1 The latest findings by Harb et al.,further report how Notch signalling enables an inflammatory response in
the allergic airways by altering T-regulatory (Treg) cells into effector
Th2 and Th17 cells.2
The Notch family is formed by 4 transmembrane protein receptors
(Notch1-4) which regulate different cell signalling
pathways.1 Notch4 is involved in a number of cell fate
decisions, and its dysregulation has been associated with several
diseases, such as cancer. However, its role in airway inflammation in
asthma is less known.3 By analysing single nucleotide
polymorphisms in different asthma clusters, Li et al . identified
that the Notch4 receptor gene was significantly associated with lung
function in asthma.4 Furthermore, Xia et al .
explored cellular and molecular mechanisms of allergic airway
inflammation. They found that the presence of pollutant ultrafine
particles (UFPs) increased inflammation by promoting a
Jag1-Notch4-dependent interaction between alveolar macrophages (AMs) and
allergen-specific CD4 T cells, thus increasing Th cell
differentiation.5
Harb et al . focused on identifying Notch4-mediated immune
tolerance disruption mechanisms that cause tissue inflammation in
allergic asthma.2 They studied the impact of Notch4
dysregulation on immune tolerance in the context of allergic airway
inflammation. First, they found that Notch4 is expressed on Treg cells
in allergic airway inflammation. They discovered that the deletion of
Notch4 in Treg cells in mice suppressed ovalbumin-specific IgE
production along with lung tissue Th2 and Th17 cell responses. Further,
the infiltration of T cells and eosinophils into the lung tissues was
attenuated. They also observed that the Hippo and the Wnt pathway
promoted Th17 and Th2 responses, respectively, in an in vitromodel. Additionally, to analyse the role of each of the Hippo and Wnt
pathways in Treg cells, they performed a combined deletion ofYap1 , Wntr1 (Hippo pathway) and Ctnnb1 (Wnt
pathway) genes. In this case, they observed a suppression of Th2 and
Th17 cell responses. Of note, this effect did not occur when the
deletion was performed individually, demonstrating that the disruption
of immune tolerance is dependent upon both pathways being affected
concurrently.2 This may be construed as the reason why
therapies targeting only Th17 pathway in asthma have not been clinically
relevant.6
Notch4 expression also reduced the capacity of lung Treg cells to
supress type 2 innate lymphoid cells (ILC2s) and activated the
Wnt–cytokine growth and differentiation factor 15 (GDF15) axis,
demonstrating an important role of the latter in promoting airway
inflammation. These results support the critical role of Notch
regulating ILC2 cell secretion of Th2 cytokines. Interestingly, Notch4
expression analysis in peripheral blood mononuclear cells of asthmatics
revealed a differential increased expression in the Treg population,
that was associated with clinical severity.2 The role
of Tregs cells is perhaps more clinically relevant in immune tolerance
and autoimmune responses in severe allergic asthma than in patients with
mild allergic asthma. Indeed, dysregulation of Tregs in eosinophilic
airways may underlie susceptibility and progression into
autoinflammatory pathology, as observed in one-third of eosinophilic
asthmatics.7 Moreover, autoantibodies against
eosinophil cationic proteins, such as eosinophil peroxidase, can induce
ILC2 to release Th2 cytokines via activation of death
receptors.8 Taken together, the Notch4-GDF15 axis may
be the transcriptional switch for this mechanism, warranting further
investigation. Indeed, this signalling axis may be more clinically
relevant in the severe patients in whom ILC2 cell biology may play a
prominent role.
The authors also identified IL-6 as an inducer of Notch4 expression in
the inducible Treg cells in the lung tissue, during allergen-specific
differentiation (Figure 1 ). Interestingly, treatment with an
anti-IL-6 receptor (IL-6R) monoclonal antibody suppressed Notch4
expression in a patient with severe asthma. This is consistent with
anecdotal evidence from Etsy et al. where treatment with
tocilizumab, a humanized anti-IL-6R monoclonal antibody, showed clinical
improvement in two patients with severe asthma.9 The
activation of cell types with no or low expression of membrane IL-6R
depend on IL-6 trans-signalling.10 In this regard,
increased IL-6R trans-signalling may increase airway eosinophilia by
inducing IL-33 expression, which is a potent activator of mature
eosinophils.10 These data suggest that IL-6 targeting
might be effective in selected patients with IL-4R polymorphism and a
pleotropic airway cellular response.
With their findings, Harb et al . uncover the activation of the
Notch4–Wnt–GDF15 axis in Treg cells, demonstrating that this axis acts
by dysregulating its immunomodulatory function and promoting
inflammation in allergic asthma.2 In brief, once the
UFPs enter the airway, they are absorbed by the AMs causing IL-6
release, which ultimately promotes Notch4-receptor expression on Treg
cells. Notch4 signalling activates the Hippo and Wnt pathways which can
modify Treg cells leading into the activation of the Th2 and Th17
pathways. Furthermore, the Wnt pathway permits the release of GDF15
which promotes IL-13 production by ILC2, thus contributing to the
inflammatory response (Figure 1 ).3 Harbet al . provide novel insights about the Notch4–Wnt–GDF15 axis
in Treg cells functioning for the understanding of the pathogenesis of
airway tissue inflammation, particularly the mechanisms involved in
severe asthma. This may lead to new therapeutic strategies being
explored that target Notch4 to restore immune tolerance in allergic
asthma.
Conflict of interest : The authors declare that they have no
conflicts of interest in relation to this manuscript.
Financial support : The authors received no specific funding for
this work.
Authorship : All authors contributed to the manuscript, revised
and edited.
References :
1. Amsen D, Helbig C, Backer RA. Notch in T Cell Differentiation: All
Things Considered. Trends Immunol. 2015;36(12):802-814.
2. Harb H, Stephen-Victor E, Crestani E, et al. A regulatory T cell
Notch4-GDF15 axis licenses tissue inflammation in asthma. Nat
Immunol. 2020;21(11):1359-1370.
3. Hammad H, Lambrecht BN. Wnt and Hippo pathways in regulatory T cells:
a NOTCH above in asthma. Nat Immunol. 2020;21(11):1313-1314.
4. Li X, Howard TD, Moore WC, et al. Importance of hedgehog interacting
protein and other lung function genes in asthma. J Allergy Clin
Immunol. 2011;127(6):1457-1465.
5. Xia M, Harb H, Saffari A, Sioutas C, Chatila TA. A Jagged 1-Notch 4
molecular switch mediates airway inflammation induced by ultrafine
particles. J Allergy Clin Immunol. 2018;142(4):1243-1256 e1217.
6. Busse WW, Holgate S, Kerwin E, et al. Randomized, double-blind,
placebo-controlled study of brodalumab, a human anti-IL-17 receptor
monoclonal antibody, in moderate to severe asthma. Am J Respir
Crit Care Med. 2013;188(11):1294-1302.
7. Mukherjee M, Bulir DC, Radford K, et al. Sputum autoantibodies in
patients with severe eosinophilic asthma. J Allergy Clin Immunol.2018;141(4):1269-1279.
8. Machida K, Aw M, Salter BMA, et al. The Role of the TL1A/DR3 Axis in
the Activation of Group 2 Innate Lymphoid Cells in Subjects with
Eosinophilic Asthma. Am J Respir Crit Care Med.2020;202(8):1105-1114.
9. Esty B, Harb H, Bartnikas LM, et al. Treatment of severe persistent
asthma with IL-6 receptor blockade. J Allergy Clin Immunol Pract.2019;7(5):1639-1642 e1634.
10. Jevnikar Z, Ostling J, Ax E, et al. Epithelial IL-6 trans-signaling
defines a new asthma phenotype with increased airway inflammation.J Allergy Clin Immunol. 2019;143(2):577-590.