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An Inhibitory Role for Sema4A in Antigen-Specific Allergic Asthma

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Abstract

Purpose

The class IV semaphorin Sema4A is critical for efficient TH1 differentiation and Sema4a −/− mice exhibit impaired TH1 immune responses. However, the role of Sema4A in TH2 cell-mediated allergic diseases has not been fully studied. The aim of this study was to clarify the regulatory role possessed by Sema4A in mouse models of allergic diseases, particularly allergic asthma.

Methods

Sema4a −/− mice on a BALB/c background were examined for the development of allergic diseases. To induce experimental asthma, mice were sensitized with ovalbumin (OVA) followed by intranasal challenges with OVA. After challenge, airway hyperreactivity (AHR) and airway inflammation were evaluated. The role of Sema4A in asthma was examined using Sema4a −/− mice and Sema4A-Fc fusion proteins. The direct effects of Sema4A-Fc on antigen-specific effector CD4+ T cells were also examined.

Results

A fraction of Sema4a −/− BALB/c mice spontaneously developed skin lesions that resembled atopic dermatitis (AD) in humans. Furthermore, AHR, airway inflammation, and TH2-type immune responses were enhanced in Sema4a −/− mice compared to wild type (WT) mice when immunized and challenged with OVA. In vivo systemic administration of Sema4A-Fc during the challenge period ameliorated AHR and lung inflammation and reduced the production of TH2-type cytokines in WT mice. The inhibitory effects of Sema4A on airway inflammation were also observed in mice deficient in Tim-2, a Sema4A receptor. Finally, we showed that Sema4A-Fc directly inhibited IL-4-producing OVA-specific CD4+ T cells.

Conclusion

These results demonstrate that Sema4A plays an inhibitory role in TH2-type allergic diseases, such as allergic asthma.

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Acknowledgments

We thank Ms. K. Kubota for excellent secretarial assistance. We also thank T. Sugimoto, T. Shiozaki, T. Yazawa, M. Ishiguro and M. Morihana for technical support.

Conflict of interest

The authors declare that they have no conflict of interest.

All sources of funding

This research was supported by a Grant-in-Aid for Scientific Research (S) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author information

Author notes

  1. Sho Goya

    Present address: Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Osaka, Japan

  2. Masayuki Mizui

    Present address: Division of Rheumatology, Department of medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

  3. Durubaka V. R. Prasad

    Present address: Department of Microbiology, Yogi Vemana University, Kadapa, India

Authors and Affiliations

  1. Department of Molecular Immunology, Research Institute for Microbial Diseases, WPI Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Tetsuo Morihana, Masayuki Mizui, Teruhito Yasui, Durubaka V. R. Prasad & Hitoshi Kikutani

  2. Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine, Osaka University, Osaka, Japan

    Sho Goya & Atsushi Kumanogoh

  3. Osaka Home Care Clinic, Osaka, Japan

    Manabu Tamura

  4. Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan

    Tetsuo Morihana, Takashi Shikina, Yohei Maeda, Yoriko Iwamoto & Hidenori Inohara

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  1. Tetsuo Morihana
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Correspondence to Hitoshi Kikutani.

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Morihana, T., Goya, S., Mizui, M. et al. An Inhibitory Role for Sema4A in Antigen-Specific Allergic Asthma. J Clin Immunol 33, 200–209 (2013). https://doi.org/10.1007/s10875-012-9798-5

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  • DOI: https://doi.org/10.1007/s10875-012-9798-5

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