Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines
Abstract Background A growing body of evidence suggests that immune dysfunction and inflammation in the peripheral tissues as well as the central nervous system are associated with the neurodevelopmental deficits observed in autism spectrum disorder (ASD). Elevated expression of pro-inflammatory cyt...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Molecular Autism |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13229-024-00589-2 |
| _version_ | 1797274403127427072 |
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| author | Ryohei Takada Michihiro Toritsuka Takahira Yamauchi Rio Ishida Yoshinori Kayashima Yuki Nishi Mitsuru Ishikawa Kazuhiko Yamamuro Minobu Ikehara Takashi Komori Yuki Noriyama Kohei Kamikawa Yasuhiko Saito Hideyuki Okano Manabu Makinodan |
| author_facet | Ryohei Takada Michihiro Toritsuka Takahira Yamauchi Rio Ishida Yoshinori Kayashima Yuki Nishi Mitsuru Ishikawa Kazuhiko Yamamuro Minobu Ikehara Takashi Komori Yuki Noriyama Kohei Kamikawa Yasuhiko Saito Hideyuki Okano Manabu Makinodan |
| author_sort | Ryohei Takada |
| collection | DOAJ |
| description | Abstract Background A growing body of evidence suggests that immune dysfunction and inflammation in the peripheral tissues as well as the central nervous system are associated with the neurodevelopmental deficits observed in autism spectrum disorder (ASD). Elevated expression of pro-inflammatory cytokines in the plasma, serum, and peripheral blood mononuclear cells of ASD has been reported. These cytokine expression levels are associated with the severity of behavioral impairments and symptoms in ASD. In a prior study, our group reported that tumor necrosis factor-α (TNF-α) expression in granulocyte–macrophage colony-stimulating factor-induced macrophages (GM-CSF MΦ) and the TNF-α expression ratio in GM-CSF MΦ/M-CSF MΦ (macrophage colony-stimulating factor-induced macrophages) was markedly higher in individuals with ASD than in typically developed (TD) individuals. However, the mechanisms of how the macrophages and the highly expressed cytokines affect neurons remain to be addressed. Methods To elucidate the effect of macrophages on human neurons, we used a co-culture system of control human-induced pluripotent stem cell-derived neurons and differentiated macrophages obtained from the peripheral blood mononuclear cells of five TD individuals and five individuals with ASD. All participants were male and ethnically Japanese. Results Our results of co-culture experiments showed that GM-CSF MΦ affect the dendritic outgrowth of neurons through the secretion of pro-inflammatory cytokines, interleukin-1α and TNF-α. Macrophages derived from individuals with ASD exerted more severe effects than those derived from TD individuals. Limitations The main limitations of our study were the small sample size with a gender bias toward males, the use of artificially polarized macrophages, and the inability to directly observe the interaction between neurons and macrophages from the same individuals. Conclusions Our co-culture system revealed the non-cell autonomous adverse effects of GM-CSF MΦ in individuals with ASD on neurons, mediated by interleukin-1α and TNF-α. These results may support the immune dysfunction hypothesis of ASD, providing new insights into its pathology. |
| first_indexed | 2024-03-07T14:58:52Z |
| format | Article |
| id | doaj.art-d4371887269c4db7bf95d1b63ee05347 |
| institution | Directory Open Access Journal |
| issn | 2040-2392 |
| language | English |
| last_indexed | 2024-03-07T14:58:52Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Autism |
| spelling | doaj.art-d4371887269c4db7bf95d1b63ee053472024-03-05T19:19:06ZengBMCMolecular Autism2040-23922024-02-0115111610.1186/s13229-024-00589-2Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokinesRyohei Takada0Michihiro Toritsuka1Takahira Yamauchi2Rio Ishida3Yoshinori Kayashima4Yuki Nishi5Mitsuru Ishikawa6Kazuhiko Yamamuro7Minobu Ikehara8Takashi Komori9Yuki Noriyama10Kohei Kamikawa11Yasuhiko Saito12Hideyuki Okano13Manabu Makinodan14Department of Psychiatry, Nara Medical University School of MedicineDepartment of Psychiatry, Nara Medical University School of MedicineDepartment of Psychiatry, Nara Medical University School of MedicineDepartment of Psychiatry, Nara Medical University School of MedicineDepartment of Psychiatry, Nara Medical University School of MedicineDepartment of Psychiatry, Nara Medical University School of MedicineDepartment of Physiology, Keio University School of MedicineDepartment of Psychiatry, Nara Medical University School of MedicineDepartment of Psychiatry, Nara Medical University School of MedicineDepartment of Psychiatry, Nara Medical University School of MedicineDepartment of Psychiatry, Nara Medical University School of MedicineDepartment of Psychiatry, Nara Medical University School of MedicineDepartment of Neurophysiology, Nara Medical University School of MedicineDepartment of Physiology, Keio University School of MedicineDepartment of Psychiatry, Nara Medical University School of MedicineAbstract Background A growing body of evidence suggests that immune dysfunction and inflammation in the peripheral tissues as well as the central nervous system are associated with the neurodevelopmental deficits observed in autism spectrum disorder (ASD). Elevated expression of pro-inflammatory cytokines in the plasma, serum, and peripheral blood mononuclear cells of ASD has been reported. These cytokine expression levels are associated with the severity of behavioral impairments and symptoms in ASD. In a prior study, our group reported that tumor necrosis factor-α (TNF-α) expression in granulocyte–macrophage colony-stimulating factor-induced macrophages (GM-CSF MΦ) and the TNF-α expression ratio in GM-CSF MΦ/M-CSF MΦ (macrophage colony-stimulating factor-induced macrophages) was markedly higher in individuals with ASD than in typically developed (TD) individuals. However, the mechanisms of how the macrophages and the highly expressed cytokines affect neurons remain to be addressed. Methods To elucidate the effect of macrophages on human neurons, we used a co-culture system of control human-induced pluripotent stem cell-derived neurons and differentiated macrophages obtained from the peripheral blood mononuclear cells of five TD individuals and five individuals with ASD. All participants were male and ethnically Japanese. Results Our results of co-culture experiments showed that GM-CSF MΦ affect the dendritic outgrowth of neurons through the secretion of pro-inflammatory cytokines, interleukin-1α and TNF-α. Macrophages derived from individuals with ASD exerted more severe effects than those derived from TD individuals. Limitations The main limitations of our study were the small sample size with a gender bias toward males, the use of artificially polarized macrophages, and the inability to directly observe the interaction between neurons and macrophages from the same individuals. Conclusions Our co-culture system revealed the non-cell autonomous adverse effects of GM-CSF MΦ in individuals with ASD on neurons, mediated by interleukin-1α and TNF-α. These results may support the immune dysfunction hypothesis of ASD, providing new insights into its pathology.https://doi.org/10.1186/s13229-024-00589-2Autism spectrum disorderHuman iPS cellMacrophageInterleukin-1αTumor necrosis factor-αDendrite |
| spellingShingle | Ryohei Takada Michihiro Toritsuka Takahira Yamauchi Rio Ishida Yoshinori Kayashima Yuki Nishi Mitsuru Ishikawa Kazuhiko Yamamuro Minobu Ikehara Takashi Komori Yuki Noriyama Kohei Kamikawa Yasuhiko Saito Hideyuki Okano Manabu Makinodan Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines Molecular Autism Autism spectrum disorder Human iPS cell Macrophage Interleukin-1α Tumor necrosis factor-α Dendrite |
| title | Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines |
| title_full | Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines |
| title_fullStr | Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines |
| title_full_unstemmed | Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines |
| title_short | Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines |
| title_sort | granulocyte macrophage colony stimulating factor induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro inflammatory cytokines |
| topic | Autism spectrum disorder Human iPS cell Macrophage Interleukin-1α Tumor necrosis factor-α Dendrite |
| url | https://doi.org/10.1186/s13229-024-00589-2 |
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