Frontiers in Cellular Neuroscience (Aug 2019)
Time-Dependent Changes in Microglia Transcriptional Networks Following Traumatic Brain Injury
- Saef Izzy,
- Saef Izzy,
- Saef Izzy,
- Saef Izzy,
- Qiong Liu,
- Qiong Liu,
- Zhou Fang,
- Zhou Fang,
- Zhou Fang,
- Zhou Fang,
- Sevda Lule,
- Sevda Lule,
- Limin Wu,
- Limin Wu,
- Joon Yong Chung,
- Joon Yong Chung,
- Aliyah Sarro-Schwartz,
- Aliyah Sarro-Schwartz,
- Alexander Brown-Whalen,
- Alexander Brown-Whalen,
- Caroline Perner,
- Caroline Perner,
- Caroline Perner,
- Suzanne E. Hickman,
- Suzanne E. Hickman,
- Suzanne E. Hickman,
- David L. Kaplan,
- Nikolaos A. Patsopoulos,
- Nikolaos A. Patsopoulos,
- Nikolaos A. Patsopoulos,
- Nikolaos A. Patsopoulos,
- Joseph El Khoury,
- Joseph El Khoury,
- Joseph El Khoury,
- Michael J. Whalen,
- Michael J. Whalen,
- Michael J. Whalen
Affiliations
- Saef Izzy
- Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Saef Izzy
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Saef Izzy
- Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
- Saef Izzy
- Harvard Medical School, Boston, MA, United States
- Qiong Liu
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China
- Qiong Liu
- Shanghai Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention, Shanghai, China
- Zhou Fang
- Harvard Medical School, Boston, MA, United States
- Zhou Fang
- Systems Biology and Computer Science Program, Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham and Women’s Hospital, Boston, MA, United States
- Zhou Fang
- Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Zhou Fang
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, United States
- Sevda Lule
- Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
- Sevda Lule
- 0Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Limin Wu
- Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
- Limin Wu
- 0Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Joon Yong Chung
- Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
- Joon Yong Chung
- 0Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Aliyah Sarro-Schwartz
- Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Aliyah Sarro-Schwartz
- Harvard Medical School, Boston, MA, United States
- Alexander Brown-Whalen
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Alexander Brown-Whalen
- Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
- Caroline Perner
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Caroline Perner
- Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
- Caroline Perner
- Harvard Medical School, Boston, MA, United States
- Suzanne E. Hickman
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Suzanne E. Hickman
- Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
- Suzanne E. Hickman
- Harvard Medical School, Boston, MA, United States
- David L. Kaplan
- 1Department of Biomedical Engineering, Tufts University, Medford, MA, United States
- Nikolaos A. Patsopoulos
- Harvard Medical School, Boston, MA, United States
- Nikolaos A. Patsopoulos
- Systems Biology and Computer Science Program, Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham and Women’s Hospital, Boston, MA, United States
- Nikolaos A. Patsopoulos
- Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Nikolaos A. Patsopoulos
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, United States
- Joseph El Khoury
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Joseph El Khoury
- Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
- Joseph El Khoury
- Harvard Medical School, Boston, MA, United States
- Michael J. Whalen
- Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
- Michael J. Whalen
- Harvard Medical School, Boston, MA, United States
- Michael J. Whalen
- 0Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- DOI
- https://doi.org/10.3389/fncel.2019.00307
- Journal volume & issue
-
Vol. 13
Abstract
The neuroinflammatory response to traumatic brain injury (TBI) is critical to both neurotoxicity and neuroprotection, and has been proposed as a potentially modifiable driver of secondary injury in animal and human studies. Attempts to broadly target immune activation have been unsuccessful in improving outcomes, in part because the precise cellular and molecular mechanisms driving injury and outcome at acute, subacute, and chronic time points after TBI remain poorly defined. Microglia play a critical role in neuroinflammation and their persistent activation may contribute to long-term functional deficits. Activated microglia are characterized by morphological transformation and transcriptomic changes associated with specific inflammatory states. We analyzed the temporal course of changes in inflammatory genes of microglia isolated from injured brains at 2, 14, and 60 days after controlled cortical impact (CCI) in mice, a well-established model of focal cerebral contusion. We identified a time dependent, injury-associated change in the microglial gene expression profile toward a reduced ability to sense tissue damage, perform housekeeping, and maintain homeostasis in the early stages following CCI, with recovery and transition to a specialized inflammatory state over time. This later state starts at 14 days post-injury and is characterized by a biphasic pattern of IFNγ, IL-4, and IL-10 gene expression changes, with concurrent proinflammatory and anti-inflammatory gene changes. Our transcriptomic data sets are an important step to understand microglial role in TBI pathogenesis at the molecular level and identify common pathways that affect outcome. More studies to evaluate gene expression at the single cell level and focusing on subacute and chronic timepoint are warranted.
Keywords
