Spred1, a Suppressor of the Ras-ERK Pathway, Negatively Regulates Expansion and Function of Group 2 Innate Lymphoid Cells

Mayu Suzuki; Rimpei Morita; Yasuko Hirata; Takashi Shichita; Akihiko Yoshimura

doi:10.4049/jimmunol.1500531

Spred1, a Suppressor of the Ras-ERK Pathway, Negatively Regulates Expansion and Function of Group 2 Innate Lymphoid Cells

J Immunol. 2015 Aug 1;195(3):1273-81. doi: 10.4049/jimmunol.1500531. Epub 2015 Jun 26.

Authors

Mayu Suzuki¹, Rimpei Morita¹, Yasuko Hirata¹, Takashi Shichita², Akihiko Yoshimura³

Affiliations

¹ Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo 102-0075, Japan; and.
² Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Precursory Research for Embryonic Science and Technology, Chiyoda-ku, Tokyo 102-0075, Japan.
³ Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo 102-0075, Japan; and yoshimura@a6.keio.jp.

PMID: 26116510
DOI: 10.4049/jimmunol.1500531

Abstract

Cytokines from group 2 innate lymphoid cells (ILC2s) have been implicated in acute allergic responses, such as papain-induced lung inflammation. However, the means of homeostatic regulation of ILC2s have not been established. In this study, we demonstrated that Spred1, a negative regulator of the Ras-ERK pathway, plays an important role in the proliferation and apoptosis of ILC2s and in cytokine secretion from ILC2s. Intranasal administration of papain stimulated IL-5 and IL-13 production in the lung, which was enhanced when Spred1 was deleted. In vitro, Spred1(-/-) ILC2s proliferated faster than wild type ILC2s did and produced higher levels of cytokines in response to IL-33. On the contrary, a MEK inhibitor suppressed ILC2 proliferation and cytokine production. Spred1 deficiency resulted in stabilization of GATA3, which has been shown to play essential roles in the maintenance and cytokine production of ILC2. These data suggest that Spred1 negatively regulates ILC2 development and functions through the suppression of the Ras-ERK pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Apoptosis / genetics
Asthma / genetics
Asthma / immunology*
Cell Line
Cell Proliferation / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism
GATA3 Transcription Factor / metabolism
HEK293 Cells
Humans
Interleukin-13 / biosynthesis
Interleukin-33
Interleukin-5 / biosynthesis
Interleukins
Lung / cytology
Lung / immunology*
Lung / pathology
Lymphocytes / cytology
Lymphocytes / immunology*
MAP Kinase Kinase 1 / antagonists & inhibitors
MAP Kinase Signaling System / immunology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Oncogene Protein p21(ras) / metabolism
Papain / adverse effects*
Pneumonia / chemically induced
Pneumonia / genetics
Pneumonia / immunology
Repressor Proteins / genetics*

Substances

Adaptor Proteins, Signal Transducing
GATA3 Transcription Factor
Gata3 protein, mouse
Il33 protein, mouse
Interleukin-13
Interleukin-33
Interleukin-5
Interleukins
Repressor Proteins
Spred1 protein, mouse
Extracellular Signal-Regulated MAP Kinases
MAP Kinase Kinase 1
Papain
Oncogene Protein p21(ras)