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Follistatin-Like 1 Induces the Activation of Type 2 Innate Lymphoid Cells to Promote Airway Inflammation in Asthma

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Abstract

Asthma is a chronic disease closely related to airway inflammation. It has been proven that type 2 innate lymphoid cells (ILC2s) play an essential role in airway inflammation in asthma. Furthermore, there is growing evidence that Follistatin-like 1 (FSTL1) can participate in various inflammatory reactions mediated by the JAK/STAT signaling pathway, among others. Therefore, we put forward a new hypothesis: FSTL1 promotes asthmatic airway inflammation by activating ILC2. This study generated an ovalbumin-sensitized asthma model in C57BL/6 and Fstl1+/− mice. The results showed that the absolute number and the proportion of ILC2 in the ovalbumin-challenged Fstl1+/− group were lower than in the ovalbumin-challenged wild-type group. We also measured the levels of Th2-type cytokines in the serum and bronchoalveolar lavage fluid (BALF) of mice and found that the corresponding cytokines in the Fstl1+/− were lower than in the wild-type groups. Finally, we tested whether MEK-JAK-STAT-GATA3 is the specific pathway for FSTL1 to activate ILC2, and further tested our working hypothesis by adding various inhibitors of proteins from this pathway. Overall, these findings reveal that FSTL1 can activate ILC2 through MEK-JAK-STAT-GATA3 to promote airway inflammation and participate in the pathogenesis of asthma.

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Data Availability

All data and materials are available from the corresponding author upon request.

Abbreviations

ILC2s:

Type 2 innate lymphoid cells

FSTL1:

Follistatin-like 1

JAK:

Janus kinase

STAT:

Signal transducer and activator of transcription

OVA:

Ovalbumin

WT:

Wild-type

BALF:

Bronchoalveolar lavage fluid

MEK:

Mitogen-activated protein kinase kinase

GATA3:

GATA binding protein 3

DCs:

Dendritic cells

IL-4:

Interleukin-4

SCA1:

Spinocerebellar ataxia type 1

KLRG1:

Killer cell lectin-like receptor G1

TSC-36:

TGF-β1-stimulated clone 36

SPARC:

Secreted protein acidic and rich in cysteine

SADs:

Systemic autoimmune diseases

IFN-γ:

Interferon-γ

TNF-α:

Tumor necrosis factor-α

NLRP3:

The nod-like receptor family, pyrin domain-containing 3

TSLP:

Thymic stromal lymphopoietin

PBS:

Phosphate-buffered saline

TBST:

Tris-buffered saline containing 0.05% (v/v) Tween 20

qRT-PCR:

Quantitative real-time polymerase chain reaction

ELISA:

Enzyme-linked immunosorbent assay

MAPK:

Mitogen-activated protein kinase

NF-κB:

Nuclear factor kappa B

FO:

FSTL1+/− OVA

WO:

WT OVA

FC:

FSTL1+/− CONTROL

WC:

WT CONTROL

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Acknowledgements

We would like to thank Prof. Xu Zhang and Xiang Gao for generous help with the FSTL1 knockout mice.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81770029).

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Authors and Affiliations

  1. Department of Respiratory, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China

    Siyuan Huang, Rong Zeng, Jing Wang, Xinrui Qiao, Dong Zhang & Jiawei Xu

  2. Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Science, Jinan, China

    Shuo Li

  3. Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong University, The First Affiliated Hospital of Shandong First Medical University, Shandong Institute of Respiratory Diseases, Jinan, China

    Liang Dong

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  1. Siyuan Huang
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Contributions

Siyuan Huang designed the experiments, analyzed the results, designed the images, and wrote the manuscript. Siyuan Huang performed the experiments with the assistance of Rong Zeng and Xinrui Qiao. Shuo Li and Dong Zhang reviewed the results and the manuscript. Jing Wang and Rong Zeng assisted in solving the problem during the revision process. Liang Dong approved final version of manuscript.

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All mouse experiments were approved by the Institutional Animal Care and Use Committee of Shandong University.

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Huang, S., Zeng, R., Wang, J. et al. Follistatin-Like 1 Induces the Activation of Type 2 Innate Lymphoid Cells to Promote Airway Inflammation in Asthma. Inflammation 45, 904–918 (2022). https://doi.org/10.1007/s10753-021-01594-w

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