See the published version of this preprint at BMC Immunology.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
A new preprint design is coming!
We have improved readability, clarity, accessibility, and opportunities for engagement.
Research Article
Sorif Uddin
GlaxoSmithKline (United Kingdom)
Corresponding Author
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Phosphoinositide-3-kinase-delta (PI3Kδ) inhibition is a promising therapeutic approach for inflammatory conditions due to its role in leucocyte proliferation, migration and activation. However, the effect of PI3Kδ inhibition on group-2-innate lymphoid cells (ILC2s) and inflammatory eosinophils remains unknown. Using a murine model exhibiting persistent airway inflammation we sought to understand the effect of PI3Kδ inhibition, montelukast and anti-IL5 antibody treatment on IL33 expression, group-2-innate lymphoid cells, inflammatory eosinophils, and goblet cell metaplasia.
Results: Mice were sensitised to house dust mite and after allowing inflammation to resolve, were re-challenged with house dust mite to re-initiate airway inflammation. ILC2s were found to persist in the airways following house dust mite sensitisation and after re-challenge their numbers increased further along with accumulation of inflammatory eosinophils. In contrast to montelukast or anti-IL5 antibody treatment, PI3Kδ inhibition ablated IL33 expression and prevented group-2-innate lymphoid cell accumulation. Only PI3Kδ inhibition and IL5 neutralization reduced the infiltration of inflammatory eosinophils. Moreover, PI3Kδ inhibition reduced goblet cell metaplasia.
Conclusions: Hence, we show that PI3Kδ inhibition dampens allergic inflammatory responses by ablating key cell types and cytokines involved in T-helper-2-driven inflammatory responses.
Keywords
PI3Kδ, IL33, ILC2, goblet cell metaplasia, Siglec-Fhi inflammatory eosinophils
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
No competing interests reported.
This is a list of supplementary files associated with this preprint. Click to download.
Loading...
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at BMC Immunology.
Version 1
Posted 19 Feb, 2021
No community comments so far
Editorial decision: Major revision
On 09 Mar, 2021
Reviews received
Received 26 Feb, 2021
Reviewers agreed
On 18 Feb, 2021
Reviewers agreed
On 16 Feb, 2021
Reviewers invited
Invitations sent on 16 Feb, 2021
Editor assigned
On 15 Feb, 2021
Editor invited
On 15 Feb, 2021
Submission checks complete
On 15 Feb, 2021
First submitted
On 05 Feb, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Immunology
Learn more about our company.
A new preprint design is coming!
We have improved readability, clarity, accessibility, and opportunities for engagement.
See the published version of this preprint at BMC Immunology.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Sorif Uddin
GlaxoSmithKline (United Kingdom)
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at BMC Immunology.
Version 1
Posted 19 Feb, 2021
No community comments so far
Editorial decision: Major revision
On 09 Mar, 2021
Reviews received
Received 26 Feb, 2021
Reviewers agreed
On 18 Feb, 2021
Reviewers agreed
On 16 Feb, 2021
Reviewers invited
Invitations sent on 16 Feb, 2021
Editor assigned
On 15 Feb, 2021
Editor invited
On 15 Feb, 2021
Submission checks complete
On 15 Feb, 2021
First submitted
On 05 Feb, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Immunology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at BMC Immunology.
Background: Phosphoinositide-3-kinase-delta (PI3Kδ) inhibition is a promising therapeutic approach for inflammatory conditions due to its role in leucocyte proliferation, migration and activation. However, the effect of PI3Kδ inhibition on group-2-innate lymphoid cells (ILC2s) and inflammatory eosinophils remains unknown. Using a murine model exhibiting persistent airway inflammation we sought to understand the effect of PI3Kδ inhibition, montelukast and anti-IL5 antibody treatment on IL33 expression, group-2-innate lymphoid cells, inflammatory eosinophils, and goblet cell metaplasia.
Results: Mice were sensitised to house dust mite and after allowing inflammation to resolve, were re-challenged with house dust mite to re-initiate airway inflammation. ILC2s were found to persist in the airways following house dust mite sensitisation and after re-challenge their numbers increased further along with accumulation of inflammatory eosinophils. In contrast to montelukast or anti-IL5 antibody treatment, PI3Kδ inhibition ablated IL33 expression and prevented group-2-innate lymphoid cell accumulation. Only PI3Kδ inhibition and IL5 neutralization reduced the infiltration of inflammatory eosinophils. Moreover, PI3Kδ inhibition reduced goblet cell metaplasia.
Conclusions: Hence, we show that PI3Kδ inhibition dampens allergic inflammatory responses by ablating key cell types and cytokines involved in T-helper-2-driven inflammatory responses.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
No competing interests reported.
This is a list of supplementary files associated with this preprint. Click to download.
Loading...