Complement factor C5 inhibition reduces type 2 responses without affecting group 2 innate lymphoid cells in a house dust mite induced murine asthma model

Abstract 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.

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IL-10–producing innate lymphoid cells increased in patients with house dust mite allergic rhinitis following immunotherapy

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2020.10.029 ◽

2020 ◽

Author(s):

Tadech Boonpiyathad ◽

Pongsakokorn Tantilipikorn ◽

Kiat Ruxrungtham ◽

Panitan Pradubpongsa ◽

Wat Mitthamsiri ◽

...

Keyword(s):

Allergic Rhinitis ◽

House Dust ◽

House Dust Mite ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Dust Mite

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House Dust Mite Induces Bone Marrow IL-33-Responsive ILC2s and TH Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21113751 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3751

Author(s):

Emma Boberg ◽

Kristina Johansson ◽

Carina Malmhäll ◽

Julie Weidner ◽

Madeleine Rådinger

Keyword(s):

Bone Marrow ◽

House Dust ◽

House Dust Mite ◽

Allergic Diseases ◽

Lymphoid Cells ◽

Th2 Cells ◽

Initial Increase ◽

Th Cells ◽

Dust Mite

Type 2 innate lymphoid cells (ILC2s) and their adaptive counterpart type 2 T helper (TH2) cells respond to interleukin-33 (IL-33) by producing IL-5, which is a crucial cytokine for eosinophil development in the bone marrow. The aim of this study was to determine if bone marrow ILC2s, TH cells, and eosinophils are locally regulated by IL-33 in terms of number and activation upon exposure to the common aeroallergen house dust mite (HDM). Mice that were sensitized and challenged with HDM by intranasal exposures induced eosinophil development in the bone marrow with an initial increase of IL5Rα+ eosinophil progenitors, following elevated numbers of mature eosinophils and the induction of airway eosinophilia. Bone marrow ILC2s, TH2, and eosinophils all responded to HDM challenge by increased IL-33 receptor (ST2) expression. However, only ILC2s, but not TH cells, revealed increased ST2 expression at the onset of eosinophil development, which significantly correlated with the number of eosinophil progenitors. In summary, our findings suggest that airway allergen challenges with HDM activates IL-33-responsive ILC2s, TH cells, and eosinophils locally in the bone marrow. Targeting the IL-33/ST2 axis in allergic diseases including asthma may be beneficial by decreasing eosinophil production in the bone marrow.

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PI3Kδ inhibition prevents IL33, ILC2s and inflammatory eosinophils in persistent airway inflammation

BMC Immunology ◽

10.1186/s12865-021-00461-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Sorif Uddin ◽

Augustin Amour ◽

David J. Lewis ◽

Chris D. Edwards ◽

Matthew G. Williamson ◽

...

Keyword(s):

Airway Inflammation ◽

Goblet Cell ◽

House Dust ◽

House Dust Mite ◽

Inflammatory Responses ◽

Lymphoid Cells ◽

Antibody Treatment ◽

Dust Mite ◽

Group 2 ◽

Goblet Cell Metaplasia

Abstract 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.

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Kinetics of Lung Eosinophil and Neutrophil Distribution in a House Dust Mite (HDM)-Induced Murine Asthma Model

10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a7633 ◽

2020 ◽

Author(s):

E.F. Mateus ◽

C. Ujaldon ◽

R. Osuna ◽

V. Plaza ◽

D. Ramos

Keyword(s):

House Dust ◽

House Dust Mite ◽

Asthma Model ◽

Dust Mite ◽

Kinetics Of ◽

Murine Asthma Model

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Kininogen deficiency or depletion reduces enhanced pause independent of pulmonary inflammation in a house dust mite-induced murine asthma model

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00162.2018 ◽

2019 ◽

Vol 316 (1) ◽

pp. L187-L196 ◽

Cited By ~ 1

Author(s):

Jack Yang ◽

Cornelis van ’t Veer ◽

Joris J. T. H. Roelofs ◽

Jeroen W. J. van Heijst ◽

Alex F. de Vos ◽

...

Keyword(s):

House Dust ◽

House Dust Mite ◽

Lung Inflammation ◽

Lung Pathology ◽

Kinin System ◽

Mucus Production ◽

Asthma Model ◽

Allergic Lung Inflammation ◽

Dust Mite ◽

Murine Asthma Model

High-molecular-weight kininogen is an important substrate of the kallikrein-kinin system. Activation of this system has been associated with aggravation of hallmark features in asthma. We aimed to determine the role of kininogen in enhanced pause (Penh) measurements and lung inflammation in a house dust mite (HDM)-induced murine asthma model. Normal wild-type mice and mice with a genetic deficiency of kininogen were subjected to repeated HDM exposure (sensitization on days 0, 1, and 2; challenge on days 14, 15, 18, and 19) via the airways to induce allergic lung inflammation. Alternatively, kininogen was depleted after HDM sensitization by twice-weekly injections of a specific antisense oligonucleotide (kininogen ASO) starting at day 3. In kininogen-deficient mice HDM induced in Penh was completely prevented. Remarkably, kininogen deficiency did not modify HDM-induced eosinophil/neutrophil influx, T helper 2 responses, mucus production, or lung pathology. kininogen ASO treatment started after HDM sensitization reduced plasma kininogen levels by 75% and reproduced the phenotype of kininogen deficiency: kininogen ASO administration prevented the HDM-induced increase in Penh without influencing leukocyte influx, Th2 responses, mucus production, or lung pathology. This study suggests that kininogen could contribute to HDM-induced rise in Penh independently of allergic lung inflammation. Further research is warranted to confirm these data using invasive measurements of airway responsiveness.

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