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Interleukin-17A stimulation induces alterations in Microglial microRNA expression profiles

Pediatric Research volume 95, pages 167–173 (2024)Cite this article

Abstract

Background

Increased maternal interleukin (IL)-17A and activated microglia are pivotal factors contributing to the pathological phenotypes of maternal immune activation (MIA), developing neurodevelopmental disorders in offspring. This study aimed to determine whether IL-17A affects the microglial microRNA (miRNA) profiles.

Methods

The miRNA expression profiles of primary cultured microglia stimulated with recombinant IL-17A were examined comprehensively using miRNA sequencing and validated through qRT-PCR. The expressions of miRNAs target genes identified using bioinformatics, were investigated in microglia transfected with mimic miRNA. The target gene’s expression was also examined in the fetal brains of the MIA mouse model induced by maternal lipopolysaccharide (LPS) administration.

Results

Primary cultured microglia expressed the IL-17A receptor and increased proinflammatory cytokines and nitric oxide synthase 2 upon treatment with IL-17A. Among the three miRNAs with |log2FC | >1, only mmu-miR-206-3p expression was significantly up-regulated by IL-17A. Transfection with the mmu-miR-206-3p mimic resulted in a significant decrease in the expression of Hdac4 and Igf1, target genes of mmu-miR-206-3p. Hdac4 expression also significantly decreased in the LPS-induced MIA model.

Conclusions

IL-17A affected microglial miRNA profiles with upregulated mmu-miR-206-3p. These findings suggest that targeting the IL-17A/mmu-miR-206-3p pathway may be a new strategy for predicting MIA-related neurodevelopmental deficits and providing preventive interventions.

Impact

  • Despite the growing evidence of interleukin (IL)-17A and microglia in the pathology of maternal immune activation (MIA), the downstream of IL-17A in microglia is not fully known.

  • IL-17A altered microRNA profiles and upregulated the mmu-miR-206-3p expression in microglia. The mmu-miR-206-3p reduced autism spectrum disorder (ASD) related gene expressions, Hdac4 and Igf1.

  • The Hdac4 expression was also reduced in the brain of MIA offspring.

  • The hsa-miR-206 sequence is consistent with that of mmu-miR-206-3p.

  • This study may provide clues to pathological mechanisms leading to predictions and interventions for ASD children born to mothers with IL-17A-related disorders.

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Fig. 1: The effect of IL-17A treatment on microglia.
Fig. 2: The effect of IL-17A on miRNA profiles in microglia.
Fig. 3: The differentially expressed miRNAs by IL-17A treatment in microglia.
Fig. 4: Transfection of mmu-miR-206-3p mimic in microglia.
Fig. 5: The effects of IL-17A on expressions of mmu-miR-206-3p related genes in microglia.

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Data availability

The datasets generated and analysed during the current study are available in the DDBJ Sequence Read Archive (DRA015999). All other relevant data are available within the article file from the authors upon reasonable request.

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Acknowledgements

We express our gratitude to the members of the Department of Obstetrics and Gynecology at the Nagoya University Graduate School of Medicine. We received technical support from the Division of Medical Research Engineering of Nagoya University Graduate School of Medicine. Funding: This work was financially supported by the Strategic Professional Development Program for Young Researchers (MEXT) and the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (Grant Numbers 17K11230 and 22K09638).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466‑8550, Japan

    Yukako Iitani, Kenji Imai, Kazuya Fuma, Takafumi Ushida, Sho Tano, Kosuke Yoshida, Akira Yokoi, Hiroaki Kajiyama & Tomomi Kotani

  2. Laboratory of Bell Research Center‑Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466‑8550, Japan

    Rika Miki

  3. Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Aichi, 466‑8560, Japan

    Takafumi Ushida & Tomomi Kotani

  4. Nagoya University Institute for Advanced Research, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan

    Kosuke Yoshida & Akira Yokoi

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Contributions

Conception and design; Y.I., T.U., K.I. and T.K., Acquisition of data; Y.I., R.M., K.F., S.T. and T.K., Analysis and interpretation of data; Y.I., T.U., K.I., R.M., K.Y., A.Y. and T.K., Drafting the article or revising it critically for important intellectual content; Y.I., T.U., K.I., A.Y., H.K., and T.K.. Final approval of the version to be published; all authors.

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Correspondence to Tomomi Kotani.

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Iitani, Y., Miki, R., Imai, K. et al. Interleukin-17A stimulation induces alterations in Microglial microRNA expression profiles. Pediatr Res 95, 167–173 (2024). https://doi.org/10.1038/s41390-023-02825-6

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