Microglia through MFG-E8 signaling decrease the density of degenerating neurons and protect the brain from the development of cortical infarction after stroke

Eric Yuhsiang Wang; Hank Szuhan Chen; Meng-Chih Wu; Ya Lan Yang; Hwai-Lee Wang; Che-Wei Liu; Ted Weita Lai

doi:10.1371/journal.pone.0308464

Microglia through MFG-E8 signaling decrease the density of degenerating neurons and protect the brain from the development of cortical infarction after stroke

PLoS One. 2024 Aug 7;19(8):e0308464. doi: 10.1371/journal.pone.0308464. eCollection 2024.

Authors

Eric Yuhsiang Wang^{1

2}, Hank Szuhan Chen², Meng-Chih Wu^{1

3}, Ya Lan Yang¹, Hwai-Lee Wang⁴, Che-Wei Liu^{1

2

5}, Ted Weita Lai^{1

2

4

6

7

8}

Affiliations

¹ Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
² School of Medicine, China Medical University, Taichung, Taiwan.
³ School of Chinese Medicine, China Medical University, Taichung, Taiwan.
⁴ Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
⁵ Department of Plastic and Reconstructive Surgery, China Medical University Hospital, Taichung, Taiwan.
⁶ Neuroscience and Brain Disease Center, China Medical University, Taichung, Taiwan.
⁷ Drug Development Center, China Medical University, Taichung, Taiwan.
⁸ Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.

Abstract

Neuronal loss is a hallmark of stroke and other neurodegenerative diseases, and as such, neuronal loss caused by microglia has been thought to be a contributing factor to disease progression. Here, we show that microglia indeed contribute significantly to neuronal loss in a mouse model of stroke, but this microglial-dependent process of neuronal clearance specifically targets stressed and degenerating neurons in the ischemic cortical region and not healthy non-ischemic neurons. Nonspecific stimulation of microglia decreased the density of neurons in the ischemic cortical region, whereas specific inhibition of MFG-E8 signaling, which is required for microglial phagocytosis of neurons, had the opposite effect. In both scenarios, the effects were microglia specific, as the same treatments had no effect in mice whose microglia were depleted prior to stroke. Finally, even though the inhibition of MFG-E8 signaling increased neuronal density in the ischemic brain region, it substantially exacerbated the development of cortical infarction. In conclusion, microglia through MFG-E8 signaling contribute to the loss of ischemic neurons and, in doing so, minimize the development of cortical infarction after stroke.

Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

MeSH terms

Animals
Antigens, Surface* / metabolism
Brain / metabolism
Brain / pathology
Cerebral Cortex / metabolism
Cerebral Cortex / pathology
Cerebral Infarction / etiology
Cerebral Infarction / metabolism
Cerebral Infarction / pathology
Disease Models, Animal
Male
Mice
Mice, Inbred C57BL
Microglia* / metabolism
Microglia* / pathology
Milk Proteins* / metabolism
Neurons* / metabolism
Neurons* / pathology
Phagocytosis
Signal Transduction*
Stroke* / complications
Stroke* / metabolism
Stroke* / pathology

Substances

Mfge8 protein, mouse
Milk Proteins
Antigens, Surface

Grants and funding

This study was supported by research grants from the Healthy Longevity Global Grand Challenge (AS-HLGC-110-05), the China Medical University (CMU102-NSC-S1), the National Science and Technology Council (NSTC113-2320-B-039-015-MY3), the National Health Research Institutes (NHRI-EX112-10803NI), and the ‘Drug Development Center, China Medical University’ from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education in Taiwan. EYW, HSC, MCW, and CWL were supported by undergraduate student research awards from the Ministry of Science and Technology (110-2813-C-039-027-B and 112-2813- C-039-068-B to EYW; 112-2813-C-039-069-B to HSC; 108-2813-C-039-127-B, 109-2813- C-039-115-B, 110-2813-C-039-026-B, and 111-2813-C-039-070-B to MCW; 105-2815-C039-046-B, 106-2813-C-039-066-B, and 108-2813-C-039-125-B to CWL) and by a LongTerm Scholarship for Gifted Students from the Hsing Tian Kung Culture and Education Development Foundation (to EYW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.