IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury

Journal of Neuroinflammation

Research

Ning Qaun¹  Kelly N. Roberts²  Teresa Macheda²  Emma K. Higgins²  James B. Watson²  Lydia Sanders²  Ryan K. Shahidehpour³  Adam D. Bachstetter³  Colleen N. Garnett⁴  Jonathan C. Vincent⁵  Eric M. Blalock⁶ 

[1] Department of Biomedical Science, Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, FL, USA;Department of Neuroscience, University of Kentucky, 741 S. Limestone St., 40536, Lexington, KY, USA;Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA;Department of Neuroscience, University of Kentucky, 741 S. Limestone St., 40536, Lexington, KY, USA;Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA;Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA;Department of Neuroscience, University of Kentucky, 741 S. Limestone St., 40536, Lexington, KY, USA;Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA;Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA;Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA;Department of Neuroscience, University of Kentucky, 741 S. Limestone St., 40536, Lexington, KY, USA;Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA;Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA;MD/PhD Program, University of Kentucky, Lexington, KY, USA;Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA;

关键词: Neuroinflammation;    Interleukin-1;    Interleukin-1 receptor-1;    Astrocyte;    Microglia;    Traumatic brain injury;   

DOI  :  10.1186/s12974-023-02934-3

 received in 2023-05-02, accepted in 2023-10-17,  发布年份 2023

来源: Springer

【 摘 要 】

Neuroinflammation contributes to secondary injury cascades following traumatic brain injury (TBI), with alternating waves of inflammation and resolution. Interleukin-1 (IL-1), a critical neuroinflammatory mediator originating from brain endothelial cells, microglia, astrocytes, and peripheral immune cells, is acutely overexpressed after TBI, propagating secondary injury and tissue damage. IL-1 affects blood–brain barrier permeability, immune cell activation, and neural plasticity. Despite the complexity of cytokine signaling post-TBI, we hypothesize that IL-1 signaling specifically regulates neuroinflammatory response components. Using a closed-head injury (CHI) TBI model, we investigated IL-1's role in the neuroinflammatory cascade with a new global knock-out (gKO) mouse model of the IL-1 receptor (IL-1R1), which efficiently eliminates all IL-1 signaling. We found that IL-1R1 gKO attenuated behavioral impairments 14 weeks post-injury and reduced reactive microglia and astrocyte staining in the neocortex, corpus callosum, and hippocampus. We then examined whether IL-1R1 loss altered acute neuroinflammatory dynamics, measuring gene expression changes in the neocortex at 3, 9, 24, and 72 h post-CHI using the NanoString Neuroinflammatory panel. Of 757 analyzed genes, IL-1R1 signaling showed temporal specificity in neuroinflammatory gene regulation, with major effects at 9 h post-CHI. IL-1R1 signaling specifically affected astrocyte-related genes, selectively upregulating chemokines like Ccl2, Ccl3, and Ccl4, while having limited impact on cytokine regulation, such as Tnfα. This study provides further insight into IL-1R1 function in amplifying the neuroinflammatory cascade following CHI in mice and demonstrates that suppression of IL-1R1 signaling offers long-term protective effects on brain health.

【 授权许可】

CC BY   
© The Author(s) 2023

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