Microglial identity and inflammatory responses are controlled by the combined effects of neurons and astrocytes
Paul S. Baxter,
Owen Dando,
Katie Emelianova,
Xin He,
Sean McKay,
Giles E. Hardingham,
Jing Qiu
Affiliations
Paul S. Baxter
UK Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School, Edinburgh EH16 4TJ, UK; Centre for Discovery Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK
Owen Dando
UK Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School, Edinburgh EH16 4TJ, UK; Centre for Discovery Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK
Katie Emelianova
UK Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School, Edinburgh EH16 4TJ, UK; Centre for Discovery Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK
Xin He
UK Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School, Edinburgh EH16 4TJ, UK; Centre for Discovery Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK
Sean McKay
UK Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School, Edinburgh EH16 4TJ, UK; Centre for Discovery Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK
Giles E. Hardingham
UK Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School, Edinburgh EH16 4TJ, UK; Centre for Discovery Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK; Corresponding author
Jing Qiu
UK Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School, Edinburgh EH16 4TJ, UK; Centre for Discovery Brain Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK; Corresponding author
Summary: Microglia, brain-resident macrophages, require instruction from the CNS microenvironment to maintain their identity and morphology and regulate inflammatory responses, although what mediates this is unclear. Here, we show that neurons and astrocytes cooperate to promote microglial ramification, induce expression of microglial signature genes ordinarily lost in vitro and in age and disease in vivo, and repress infection- and injury-associated gene sets. The influence of neurons and astrocytes separately on microglia is weak, indicative of synergies between these cell types, which exert their effects via a mechanism involving transforming growth factor β2 (TGF-β2) signaling. Neurons and astrocytes also combine to provide immunomodulatory cues, repressing primed microglial responses to weak inflammatory stimuli (without affecting maximal responses) and consequently limiting the feedback effects of inflammation on the neurons and astrocytes themselves. These findings explain why microglia isolated ex vivo undergo de-differentiation and inflammatory deregulation and point to how disease- and age-associated changes may be counteracted.
