An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma

Zaid W El-Husseini; Dmitry Khalenkow; Andy Lan; Thys van der Molen; Chris Brightling; Alberto Papi; Klaus F Rabe; Salman Siddiqui; Dave Singh; Monica Kraft; Bianca Beghe; Maarten van den Berge; Djoke van Gosliga; Martijn C Nawijn; Stefan Rose-John; Gerard H Koppelman; Reinoud Gosens

doi:10.1186/s12931-023-02617-w

An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma

Zaid W El-Husseini, Dmitry Khalenkow, Andy Lan, Thys van der Molen, Chris Brightling, Alberto Papi, Klaus F Rabe, Salman Siddiqui, Dave Singh, Monica Kraft, Bianca Beghe, Maarten van den Berge, Djoke van Gosliga, Martijn C Nawijn, Stefan Rose-John, Gerard H Koppelman, Reinoud Gosens^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

BACKGROUND: Asthma is stratified into type 2-high and type 2-low inflammatory phenotypes. Limited success has been achieved in developing drugs that target type 2-low inflammation. Previous studies have linked IL-6 signaling to severe asthma. IL-6 cooperates with soluble-IL-6Rα to activate cell signaling in airway epithelium.

OBJECTIVE: We sought to study the role of sIL-6Rα amplified IL-6 signaling in airway epithelium and to develop an IL-6+ sIL-6Rα gene signature that may be used to select asthma patients who potentially respond to anti-IL-6 therapy.

METHODS: Human airway epithelial cells were stimulated with combinations of IL-6, sIL-6Rα, and inhibitors, sgp130 (Olamkicept), and anti-IL-6R (Tocilizumab), to assess effects on pathway activation, epithelial barrier integrity, and gene expression. A gene signature was generated to identify IL-6 high patients using bronchial biopsies and nasal brushes.

RESULTS: Soluble-IL-6Rα amplified the activation of the IL-6 pathway, shown by the increase of STAT3 phosphorylation and stronger gene induction in airway epithelial cells compared to IL-6 alone. Olamkicept and Tocilizumab inhibited the effect of IL-6 + sIL-6Rα on gene expression. We developed an IL-6 + sIL-6Rα gene signature and observed enrichment of this signature in bronchial biopsies but not nasal brushes from asthma patients compared to healthy controls. An IL-6 + sIL-6Rα gene signature score was associated with lower levels of sputum eosinophils in asthma.

CONCLUSION: sIL-6Rα amplifies IL-6 signaling in bronchial epithelial cells. Higher local airway IL-6 + sIL-6Rα signaling is observed in asthma patients with low sputum eosinophils.

Original language	English
Article number	308
Number of pages	12
Journal	Respiratory Research
Volume	24
Issue number	1
DOIs	https://doi.org/10.1186/s12931-023-02617-w
Publication status	Published - 7-Dec-2023

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El-Husseini, Z. W., Khalenkow, D., Lan, A., van der Molen, T., Brightling, C., Papi, A., Rabe, K. F., Siddiqui, S., Singh, D., Kraft, M., Beghe, B., van den Berge, M., van Gosliga, D., Nawijn, M. C., Rose-John, S., Koppelman, G. H., & Gosens, R. (2023). An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma. Respiratory Research, 24(1), Article 308. https://doi.org/10.1186/s12931-023-02617-w

@article{42ce55eb965f47a1ad595d1b17799363,

title = "An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma",

abstract = "BACKGROUND: Asthma is stratified into type 2-high and type 2-low inflammatory phenotypes. Limited success has been achieved in developing drugs that target type 2-low inflammation. Previous studies have linked IL-6 signaling to severe asthma. IL-6 cooperates with soluble-IL-6Rα to activate cell signaling in airway epithelium.OBJECTIVE: We sought to study the role of sIL-6Rα amplified IL-6 signaling in airway epithelium and to develop an IL-6+ sIL-6Rα gene signature that may be used to select asthma patients who potentially respond to anti-IL-6 therapy.METHODS: Human airway epithelial cells were stimulated with combinations of IL-6, sIL-6Rα, and inhibitors, sgp130 (Olamkicept), and anti-IL-6R (Tocilizumab), to assess effects on pathway activation, epithelial barrier integrity, and gene expression. A gene signature was generated to identify IL-6 high patients using bronchial biopsies and nasal brushes.RESULTS: Soluble-IL-6Rα amplified the activation of the IL-6 pathway, shown by the increase of STAT3 phosphorylation and stronger gene induction in airway epithelial cells compared to IL-6 alone. Olamkicept and Tocilizumab inhibited the effect of IL-6 + sIL-6Rα on gene expression. We developed an IL-6 + sIL-6Rα gene signature and observed enrichment of this signature in bronchial biopsies but not nasal brushes from asthma patients compared to healthy controls. An IL-6 + sIL-6Rα gene signature score was associated with lower levels of sputum eosinophils in asthma.CONCLUSION: sIL-6Rα amplifies IL-6 signaling in bronchial epithelial cells. Higher local airway IL-6 + sIL-6Rα signaling is observed in asthma patients with low sputum eosinophils.",

author = "El-Husseini, {Zaid W} and Dmitry Khalenkow and Andy Lan and {van der Molen}, Thys and Chris Brightling and Alberto Papi and Rabe, {Klaus F} and Salman Siddiqui and Dave Singh and Monica Kraft and Bianca Beghe and {van den Berge}, Maarten and {van Gosliga}, Djoke and Nawijn, {Martijn C} and Stefan Rose-John and Koppelman, {Gerard H} and Reinoud Gosens",

note = "{\textcopyright} 2023. The Author(s).",

year = "2023",

month = dec,

day = "7",

doi = "10.1186/s12931-023-02617-w",

language = "English",

volume = "24",

journal = "Respiratory Research",

issn = "1465-9921",

publisher = "BioMed Central Ltd.",

number = "1",

}

El-Husseini, ZW, Khalenkow, D, Lan, A, van der Molen, T, Brightling, C, Papi, A, Rabe, KF, Siddiqui, S, Singh, D, Kraft, M, Beghe, B, van den Berge, M , van Gosliga, D , Nawijn, MC, Rose-John, S, Koppelman, GH & Gosens, R 2023, 'An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma', Respiratory Research, vol. 24, no. 1, 308. https://doi.org/10.1186/s12931-023-02617-w

TY - JOUR

T1 - An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma

AU - El-Husseini, Zaid W

AU - Khalenkow, Dmitry

AU - Lan, Andy

AU - van der Molen, Thys

AU - Brightling, Chris

AU - Papi, Alberto

AU - Rabe, Klaus F

AU - Siddiqui, Salman

AU - Singh, Dave

AU - Kraft, Monica

AU - Beghe, Bianca

AU - van den Berge, Maarten

AU - van Gosliga, Djoke

AU - Nawijn, Martijn C

AU - Rose-John, Stefan

AU - Koppelman, Gerard H

AU - Gosens, Reinoud

PY - 2023/12/7

Y1 - 2023/12/7

N2 - BACKGROUND: Asthma is stratified into type 2-high and type 2-low inflammatory phenotypes. Limited success has been achieved in developing drugs that target type 2-low inflammation. Previous studies have linked IL-6 signaling to severe asthma. IL-6 cooperates with soluble-IL-6Rα to activate cell signaling in airway epithelium.OBJECTIVE: We sought to study the role of sIL-6Rα amplified IL-6 signaling in airway epithelium and to develop an IL-6+ sIL-6Rα gene signature that may be used to select asthma patients who potentially respond to anti-IL-6 therapy.METHODS: Human airway epithelial cells were stimulated with combinations of IL-6, sIL-6Rα, and inhibitors, sgp130 (Olamkicept), and anti-IL-6R (Tocilizumab), to assess effects on pathway activation, epithelial barrier integrity, and gene expression. A gene signature was generated to identify IL-6 high patients using bronchial biopsies and nasal brushes.RESULTS: Soluble-IL-6Rα amplified the activation of the IL-6 pathway, shown by the increase of STAT3 phosphorylation and stronger gene induction in airway epithelial cells compared to IL-6 alone. Olamkicept and Tocilizumab inhibited the effect of IL-6 + sIL-6Rα on gene expression. We developed an IL-6 + sIL-6Rα gene signature and observed enrichment of this signature in bronchial biopsies but not nasal brushes from asthma patients compared to healthy controls. An IL-6 + sIL-6Rα gene signature score was associated with lower levels of sputum eosinophils in asthma.CONCLUSION: sIL-6Rα amplifies IL-6 signaling in bronchial epithelial cells. Higher local airway IL-6 + sIL-6Rα signaling is observed in asthma patients with low sputum eosinophils.

AB - BACKGROUND: Asthma is stratified into type 2-high and type 2-low inflammatory phenotypes. Limited success has been achieved in developing drugs that target type 2-low inflammation. Previous studies have linked IL-6 signaling to severe asthma. IL-6 cooperates with soluble-IL-6Rα to activate cell signaling in airway epithelium.OBJECTIVE: We sought to study the role of sIL-6Rα amplified IL-6 signaling in airway epithelium and to develop an IL-6+ sIL-6Rα gene signature that may be used to select asthma patients who potentially respond to anti-IL-6 therapy.METHODS: Human airway epithelial cells were stimulated with combinations of IL-6, sIL-6Rα, and inhibitors, sgp130 (Olamkicept), and anti-IL-6R (Tocilizumab), to assess effects on pathway activation, epithelial barrier integrity, and gene expression. A gene signature was generated to identify IL-6 high patients using bronchial biopsies and nasal brushes.RESULTS: Soluble-IL-6Rα amplified the activation of the IL-6 pathway, shown by the increase of STAT3 phosphorylation and stronger gene induction in airway epithelial cells compared to IL-6 alone. Olamkicept and Tocilizumab inhibited the effect of IL-6 + sIL-6Rα on gene expression. We developed an IL-6 + sIL-6Rα gene signature and observed enrichment of this signature in bronchial biopsies but not nasal brushes from asthma patients compared to healthy controls. An IL-6 + sIL-6Rα gene signature score was associated with lower levels of sputum eosinophils in asthma.CONCLUSION: sIL-6Rα amplifies IL-6 signaling in bronchial epithelial cells. Higher local airway IL-6 + sIL-6Rα signaling is observed in asthma patients with low sputum eosinophils.

U2 - 10.1186/s12931-023-02617-w

DO - 10.1186/s12931-023-02617-w

M3 - Article

C2 - 38062491

SN - 1465-9921

VL - 24

JO - Respiratory Research

JF - Respiratory Research

IS - 1

M1 - 308

ER -

An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma

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