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T2 cytokine-driven alarmin and antiviral responses in asthma: insights into immune modulation and the role of IL-4Ra targeting

Pesic, Jelena LU ; Nieto Fontarigo, Juan José LU ; Pardali, Katerina ; Delaney, Stephen ; Olsson, Henric and Uller, Lena LU (2025) In Frontiers in Allergy 6. p.01-09
Abstract
Introduction: Severe asthma is a heterogeneous condition characterized by distinct phenotypes and endotypes based on clinical or biological characteristics. Interleukin (IL) 4 and IL-13 are central cytokines in the type 2 (T2) immune response, crucial for T2 inflammation. Biologic therapies targeting the IL-4/IL-13 pathway, such as anti-IL-4Rα monoclonal antibodies (mAbs), have shown improvements in lung function and reductions in exacerbation rates for severe asthma. However, the precise role of early innate immune responses in mediating these therapeutic benefits remains unclear. This study investigates the acute and chronic effects of T2 cytokines on healthy and asthmatic bronchial epithelial cells (BECs), addressing the mechanisms... (More)
Introduction: Severe asthma is a heterogeneous condition characterized by distinct phenotypes and endotypes based on clinical or biological characteristics. Interleukin (IL) 4 and IL-13 are central cytokines in the type 2 (T2) immune response, crucial for T2 inflammation. Biologic therapies targeting the IL-4/IL-13 pathway, such as anti-IL-4Rα monoclonal antibodies (mAbs), have shown improvements in lung function and reductions in exacerbation rates for severe asthma. However, the precise role of early innate immune responses in mediating these therapeutic benefits remains unclear. This study investigates the acute and chronic effects of T2 cytokines on healthy and asthmatic bronchial epithelial cells (BECs), addressing the mechanisms underlying IL-4Rα mAb therapy in acute T2-driven inflammatory conditions and rhinoviral infection in asthma BECs.

Methods: Human BECs from healthy and asthma donors were cultured at the air–liquid interface (ALI) and stimulated with IL-4 and IL-13, acutely or chronically, with or without IL-4Rα mAb, followed by rhinovirus (RV) infection. Cells were harvested 24 h post-infection. Expression levels of chemokines, alarmins, and antiviral mediators were quantified using RT-qPCR and multiplex ELISA.

Results: CCL26 expression increased in response to IL-4 or IL-13 in healthy and asthmatic BECs, and this effect was significantly more pronounced in asthmatic BECs. IL-4Rα mAb treatment effectively inhibited CCL26 production in BECs from asthma patients. IL-4 and RV infection induced a significant increase in thymic stromal lymphopoietin (TSLP) levels in BECs from asthma compared with healthy, which was normalized by IL-4Rα mAb. No significant effects of T2 cytokines on alarmins were observed in healthy BECs. Chronic exposure to T2 cytokines following RV infection significantly decreased TSLP and IFNλ1 but increased IFNβ, specifically in asthmatic BECs.

Conclusions: Our study on T2 cytokines' effects on BECs reveals that asthma BECs have an increased inflammatory response to IL-4 and IL-13. These responses, marked by increased CCL26 and TSLP, were effectively mitigated by IL-4Rα mAb. Importantly, this treatment maintained essential antiviral defenses, such as IFNβ, even post-rhinoviral infection. Our results suggest a novel mechanism by which IL-4Rα mAb controls exacerbations and improves lung function. (Less)
Abstract (Swedish)
Introduction: Severe asthma is a heterogeneous condition characterized by
distinct phenotypes and endotypes based on clinical or biological
characteristics. Interleukin (IL) 4 and IL-13 are central cytokines in the type 2
(T2) immune response, crucial for T2 inflammation. Biologic therapies
targeting the IL-4/IL-13 pathway, such as anti-IL-4Rα monoclonal antibodies
(mAbs), have shown improvements in lung function and reductions in
exacerbation rates for severe asthma. However, the precise role of early innate
immune responses in mediating these therapeutic benefits remains unclear.
This study investigates the acute and chronic effects of T2 cytokines on
healthy and asthmatic bronchial epithelial cells... (More)
Introduction: Severe asthma is a heterogeneous condition characterized by
distinct phenotypes and endotypes based on clinical or biological
characteristics. Interleukin (IL) 4 and IL-13 are central cytokines in the type 2
(T2) immune response, crucial for T2 inflammation. Biologic therapies
targeting the IL-4/IL-13 pathway, such as anti-IL-4Rα monoclonal antibodies
(mAbs), have shown improvements in lung function and reductions in
exacerbation rates for severe asthma. However, the precise role of early innate
immune responses in mediating these therapeutic benefits remains unclear.
This study investigates the acute and chronic effects of T2 cytokines on
healthy and asthmatic bronchial epithelial cells (BECs), addressing the
mechanisms underlying IL-4Rα mAb therapy in acute T2-driven inflammatory
conditions and rhinoviral infection in asthma BECs.
Methods: Human BECs from healthy and asthma donors were cultured at the air–
liquid interface (ALI) and stimulated with IL-4 and IL-13, acutely or chronically, with
or without IL-4Rα mAb, followed by rhinovirus (RV) infection. Cells were harvested
24 h post-infection. Expression levels of chemokines, alarmins, and antiviral
mediators were quantified using RT-qPCR and multiplex ELISA.
Results: CCL26 expression increased in response to IL-4 or IL-13 in healthy and
asthmatic BECs, and this effect was significantly more pronounced in asthmatic
BECs. IL-4Rα mAb treatment effectively inhibited CCL26 production in BECs
from asthma patients. IL-4 and RV infection induced a significant increase in
thymic stromal lymphopoietin (TSLP) levels in BECs from asthma compared
with healthy, which was normalized by IL-4Rα mAb. No significant effects of
T2 cytokines on alarmins were observed in healthy BECs. Chronic exposure to
T2 cytokines following RV infection significantly decreased TSLP and IFNL1 but
increased IFNβ, specifically in asthmatic BECs.
Conclusions: Our study on T2 cytokines’ effects on BECs reveals that asthma
BECs have an increased inflammatory response to IL-4 and IL-13. These
responses, marked by increased CCL26 and TSLP, were effectively mitigated
by IL-4Rα mAb. Importantly, this treatment maintained essential antiviral
defenses, such as IFNβ, even post-rhinoviral infection. Our results suggest a
novel mechanism by which IL-4Rα mAb controls exacerbations and improves
lung function. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Frontiers in Allergy
volume
6
article number
1576816
pages
01 - 09
publisher
Frontiers Media S. A.
external identifiers
  • pmid:40370530
  • scopus:105005091299
ISSN
2673-6101
DOI
10.3389/falgy.2025.1576816
language
English
LU publication?
yes
id
93d185a5-1c33-498e-abb6-40c189592f6f
date added to LUP
2025-05-21 17:02:15
date last changed
2025-05-23 04:01:15
@article{93d185a5-1c33-498e-abb6-40c189592f6f,
  abstract     = {{Introduction: Severe asthma is a heterogeneous condition characterized by distinct phenotypes and endotypes based on clinical or biological characteristics. Interleukin (IL) 4 and IL-13 are central cytokines in the type 2 (T2) immune response, crucial for T2 inflammation. Biologic therapies targeting the IL-4/IL-13 pathway, such as anti-IL-4Rα monoclonal antibodies (mAbs), have shown improvements in lung function and reductions in exacerbation rates for severe asthma. However, the precise role of early innate immune responses in mediating these therapeutic benefits remains unclear. This study investigates the acute and chronic effects of T2 cytokines on healthy and asthmatic bronchial epithelial cells (BECs), addressing the mechanisms underlying IL-4Rα mAb therapy in acute T2-driven inflammatory conditions and rhinoviral infection in asthma BECs.<br/><br/>Methods: Human BECs from healthy and asthma donors were cultured at the air–liquid interface (ALI) and stimulated with IL-4 and IL-13, acutely or chronically, with or without IL-4Rα mAb, followed by rhinovirus (RV) infection. Cells were harvested 24 h post-infection. Expression levels of chemokines, alarmins, and antiviral mediators were quantified using RT-qPCR and multiplex ELISA.<br/><br/>Results: CCL26 expression increased in response to IL-4 or IL-13 in healthy and asthmatic BECs, and this effect was significantly more pronounced in asthmatic BECs. IL-4Rα mAb treatment effectively inhibited CCL26 production in BECs from asthma patients. IL-4 and RV infection induced a significant increase in thymic stromal lymphopoietin (TSLP) levels in BECs from asthma compared with healthy, which was normalized by IL-4Rα mAb. No significant effects of T2 cytokines on alarmins were observed in healthy BECs. Chronic exposure to T2 cytokines following RV infection significantly decreased TSLP and IFNλ1 but increased IFNβ, specifically in asthmatic BECs.<br/><br/>Conclusions: Our study on T2 cytokines' effects on BECs reveals that asthma BECs have an increased inflammatory response to IL-4 and IL-13. These responses, marked by increased CCL26 and TSLP, were effectively mitigated by IL-4Rα mAb. Importantly, this treatment maintained essential antiviral defenses, such as IFNβ, even post-rhinoviral infection. Our results suggest a novel mechanism by which IL-4Rα mAb controls exacerbations and improves lung function.}},
  author       = {{Pesic, Jelena and Nieto Fontarigo, Juan José and Pardali, Katerina and Delaney, Stephen and Olsson, Henric and Uller, Lena}},
  issn         = {{2673-6101}},
  language     = {{eng}},
  month        = {{04}},
  pages        = {{01--09}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Allergy}},
  title        = {{T2 cytokine-driven alarmin and antiviral responses in asthma: insights into immune modulation and the role of IL-4Ra targeting}},
  url          = {{http://dx.doi.org/10.3389/falgy.2025.1576816}},
  doi          = {{10.3389/falgy.2025.1576816}},
  volume       = {{6}},
  year         = {{2025}},
}