ILC2s Are Responsible for RSV-induced Pulmonary Eosinophilic Infiltration by Response to IL-4/IL-13 via STAT6 Signaling

Abstract Group 2 innate lymphoid cells (ILC2s) play an important role in respiratory syncytial virus (RSV)-induced lung inflammation, including eosinophilic infiltration. However, the underlying signals are still not fully understood. Therefore, we aimed to explore the potential mechanism(s) of ILC2s contributes to the RSV-induced eosinophilic infiltration. RSV-induced mouse airway inflammation model was established. The mice were treated with or without recombinant human IL-4 to block signal transducer and activator of transcription 6 (STAT6). The proportions of different leukocyte subtypes, numbers of eosinophils and ILC2s, and mRNAs levels of IL-4Rα and IL-13Rα1 in ILC2s were assessed. Moreover, ILC2s or recombinant human IL-4 pre-treated-ILC2s were administrated to the mice, and then histologic analysis of lung tissues and the number of eosinophils were analyzed. Furthermore, after treatment with IL-4 + IL-13, the migration of ILC2s was investigated. Block of STAT6 significantly decreased RSV-induced eosinophilic infiltration and the number of ILC2s, and also statistically reduced the mRNAs levels of IL-4Rα and IL-13Rα1 in ILC2s. Adoptive transfer of recombinant human IL-4 pre-treated ILC2 did not augment RSV-induced eosinophilic infifiltration, including less mucous and infiltrated cells in the airways. Furthermore, the lung ILC2s were responded to IL-4/IL-13-induced production of STAT6 and STAT6-mediated signals regulated ILC2s proliferation and migration during the RSV-induced pulmonary eosinophilia recruitment. However, STAT6 did not regulate the transcriptional levels of IL-4 and IL-13 in ILC2s. In conclusion, ILC2s are responsible for RSV-induced pulmonary eosinophilic infiltration by response to IL-4/IL-13 via STAT6 signaling.

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Faculty Opinions recommendation of Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718304528.793492827 ◽

2014 ◽

Author(s):

Marc Daëron ◽

Anne Tsicopoulos ◽

Renaud Lesourne

Keyword(s):

Lung Inflammation ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

T Helper ◽

T Helper 2 ◽

Allergic Lung Inflammation ◽

Group 2

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NK Cells Alleviate Lung Inflammation by Negatively Regulating Group 2 Innate Lymphoid Cells

The Journal of Immunology ◽

10.4049/jimmunol.1601830 ◽

2017 ◽

Vol 198 (8) ◽

pp. 3336-3344 ◽

Cited By ~ 31

Author(s):

Jiacheng Bi ◽

Lulu Cui ◽

Guang Yu ◽

Xiaolu Yang ◽

Youhai Chen ◽

...

Keyword(s):

Nk Cells ◽

Lung Inflammation ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Group 2

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Androgen signaling negatively controls group 2 innate lymphoid cells

Journal of Experimental Medicine ◽

10.1084/jem.20161807 ◽

2017 ◽

Vol 214 (6) ◽

pp. 1581-1592 ◽

Cited By ~ 95

Author(s):

Sophie Laffont ◽

Eve Blanquart ◽

Magali Savignac ◽

Claire Cénac ◽

Gilles Laverny ◽

...

Keyword(s):

Airway Inflammation ◽

Lung Inflammation ◽

Inflammatory Responses ◽

Allergic Airway Inflammation ◽

Innate Lymphoid Cells ◽

Protective Role ◽

Lymphoid Cells ◽

Peripheral Tissues ◽

Group 2

Prevalence of asthma is higher in women than in men, but the mechanisms underlying this sex bias are unknown. Group 2 innate lymphoid cells (ILC2s) are key regulators of type 2 inflammatory responses. Here, we show that ILC2 development is greatly influenced by male sex hormones. Male mice have reduced numbers of ILC2 progenitors (ILC2Ps) and mature ILC2s in peripheral tissues compared with females. In consequence, males exhibit reduced susceptibility to allergic airway inflammation in response to environmental allergens and less severe IL-33–driven lung inflammation, correlating with an impaired expansion of lung ILC2s. Importantly, orchiectomy, but not ovariectomy, abolishes the sex differences in ILC2 development and restores IL-33–mediated lung inflammation. ILC2Ps express the androgen receptor (AR), and AR signaling inhibits their differentiation into mature ILC2s. Finally, we show that hematopoietic AR expression limits IL-33–driven lung inflammation through a cell-intrinsic inhibition of ILC2 expansion. Thus, androgens play a crucial protective role in type 2 airway inflammation by negatively regulating ILC2 homeostasis, thereby limiting their capacity to expand locally in response to IL-33.

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Group 2 Innate Lymphoid Cells Are Critical for the Initiation of Adaptive T Helper 2 Cell-Mediated Allergic Lung Inflammation

Immunity ◽

10.1016/j.immuni.2014.01.011 ◽

2014 ◽

Vol 40 (3) ◽

pp. 425-435 ◽

Cited By ~ 535

Author(s):

Timotheus Y.F. Halim ◽

Catherine A. Steer ◽

Laura Mathä ◽

Matthew J. Gold ◽

Itziar Martinez-Gonzalez ◽

...

Keyword(s):

Lung Inflammation ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

T Helper ◽

T Helper 2 ◽

Allergic Lung Inflammation ◽

Group 2

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c-Rel Is Required for IL-33-Dependent Activation of ILC2s

Frontiers in Immunology ◽

10.3389/fimmu.2021.667922 ◽

2021 ◽

Vol 12 ◽

Author(s):

Aidil Zaini ◽

Thomas S. Fulford ◽

Raelene J. Grumont ◽

Jessica Runting ◽

Grace Rodrigues ◽

...

Keyword(s):

Lung Inflammation ◽

Cytokine Production ◽

Control Point ◽

Cell Types ◽

Lymphoid Cells ◽

Central Control ◽

Critical Component ◽

Interleukin 33 ◽

Group 2 ◽

And Function

Group 2 innate lymphoid cells (ILC2s) are emerging as important cellular regulators of homeostatic and disease-associated immune processes. The cytokine interleukin-33 (IL-33) promotes ILC2-dependent inflammation and immunity, with IL-33 having been shown to activate NF-κB in a wide variety of cell types. However, it is currently unclear which NF-κB members play an important role in IL-33-dependent ILC2 biology. Here, we identify the NF-κB family member c-Rel as a critical component of the IL-33-dependent activation of ILC2s. Although c-Rel is dispensable for ILC2 development, it is critical for ILC2 function in the lung, with c-Rel-deficient (c-Rel–/–) mice present a significantly reduced response to papain- and IL-33-induced lung inflammation. We also show that the absence of c-Rel reduces the IL-33-dependent expansion of ILC2 precursors and lower levels of IL-5 and IL-13 cytokine production by mature ILC2s in the lung. Together, these results identify the IL-33-c-Rel axis as a central control point of ILC2 activation and function.

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IL-17–producing ST2+ group 2 innate lymphoid cells play a pathogenic role in lung inflammation

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2018.03.007 ◽

2019 ◽

Vol 143 (1) ◽

pp. 229-244.e9 ◽

Cited By ~ 35

Author(s):

Ting Cai ◽

Jinxin Qiu ◽

Yan Ji ◽

Wenjing Li ◽

Zhaoyun Ding ◽

...

Keyword(s):

Lung Inflammation ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Pathogenic Role ◽

Group 2

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Faculty Opinions recommendation of Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718304528.793493048 ◽

2014 ◽

Author(s):

Padraic Fallon

Keyword(s):

Lung Inflammation ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

T Helper ◽

T Helper 2 ◽

Allergic Lung Inflammation ◽

Group 2

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Essential role of CD4+ T cells for the activation of group 2 innate lymphoid cells during respiratory syncytial virus infection in mice

Immunotherapy ◽

10.2217/imt-2019-0084 ◽

2019 ◽

Vol 11 (15) ◽

pp. 1303-1313 ◽

Cited By ~ 5

Author(s):

Xu Han ◽

Song Bai ◽

Yulin Cui ◽

Wenwen Zhu ◽

Na Zhao ◽

...

Keyword(s):

T Cells ◽

Respiratory Syncytial Virus ◽

Lymphoid Cells ◽

Type 2 Cytokines ◽

Study Results ◽

Cellular Source ◽

Rsv Infection ◽

Group 2 ◽

Syncytial Virus

Aim: To investigate whether and how CD4+ T cells contribute to ILC2 activation during respiratory syncytial virus (RSV) infection. Methods: The methods of flow cytometry, quantitative PCR and ELISA were used in the present study. Results: Depletion of CD4+ T cells diminished the numbers of lung ILC2s as well as their ability to produce type 2 cytokines. CD4+ T cell-mediated ILC2 activation is related to IL-2. The main cellular source of IL-2 was CD4+ T cells. Depletion of CD4+ T cells decreased IL-2 levels in the lungs of RSV-infected mice. IL-2 can directly stimulate ILC2 proliferation and promote ILC2s to produce cytokines. Treatment of mice with neutralizing anti-IL-2 monoclonal antibodies diminished ILC2 activation. Conclusion: These results suggest that CD4+ T cells contribute to RSV-induced ILC2 activation partly via producing IL-2.

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