Time-dependent cytokine and chemokine changes in mouse cerebral cortex following a mild traumatic brain injury
Abstract
Traumatic brain injury (TBI) is a serious global health concern, many individuals live with TBI-related neurological dysfunction. A lack of biomarkers of TBI has impeded medication development. To identify new potential biomarkers, we time-dependently evaluated mouse brain tissue and neuronally derived plasma extracellular vesicles proteins in a mild model of TBI with parallels to concussive head injury. Mice (CD-1, 30–40 g) received a sham procedure or 30 g weight-drop, and were euthanized 8, 24, 48, 72, 96 hours, 7, 14 and 30 days later. We quantified ipsilateral cortical proteins. Many of them differed from 8 hours onwards post mTBI compared to sham, 23 proteins changed in 4 or more of 8 different time points. Gene ontology pathways mapped from altered proteins over time related to pathological and physiological processes. Further validation of proteins identified in this study may provide utility as treatment response biomarkers.
Data availability
All data generated by US NIH funded research is available to the public, the data generated in this study is available to the public. The data used to generate the Figures in the manuscript are provided as source data files.
Article and author information
Author details
Funding
National Institutes of Health (AG000944)
- Nigel H Greig
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: AlI animal studies were conducted at the Intramural Research Program of the National Institute on Aging, Baltimore, MD, USA. Experimental animal protocols were approved by the Animal Care and Use Committee of the Intramural Research Program, National Institute on Aging (438-TGB-2022) and were in compliance with the guidelines for animal experimentation of the National Research Council (Committee for the Update of the Guide for the Care and Use of Laboratory Animals, 2011) and the National Institutes of Health (DHEW publication 85-23, revised, 1995).
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Metrics
-
- 2,658
- views
-
- 350
- downloads
-
- 28
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Genetics and Genomics
- Immunology and Inflammation
Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, NRTKs regulate activation, migration, and proliferation of immune cells. We found that the patients’ ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced pluripotent stem cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.
-
- Immunology and Inflammation
The adaptive T cell response is accompanied by continuous rewiring of the T cell’s electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report in mice that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency in mice causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.