Neuroinflammatory reactive astrocyte formation correlates with adverse outcomes in perinatal white matter injury
Patricia Renz1,2,3, Marel Steinfort1,2,3, Valérie Haesler1,2
1Department of Obstetrics and Gynecology, Division of Feto-Maternal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Insights
Perinatal white matter injury (WMI) in preterm infants is linked to neuroinflammation. This study reveals that reactive astrocytes, driven by inflammatory molecules, worsen WMI outcomes, suggesting a new therapeutic target.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Perinatal white matter injury (WMI) is a primary cause of neurological disability in preterm infants.
- Neuroinflammation during early brain development is critical in WMI pathogenesis.
- The link between inflammation and the resulting failure of myelination in WMI is not fully understood.
Purpose of the Study:
- To investigate the role of astrocyte reactivity in perinatal white matter injury.
- To determine if targeting inflammatory pathways affecting astrocytes can improve WMI outcomes.
- To identify specific molecular signatures of reactive astrocytes in WMI.
Main Methods:
- Utilized an experimental mouse model of perinatal white matter injury.
- Generated mutant mice lacking key inflammatory molecules (TNF-α, IL-1α, C1q) to assess their impact on WMI.
- Analyzed astrocyte gene expression in both the mouse model and human WMI tissue.
Main Results:
- Mutant mice lacking TNF-α, IL-1α, and C1q showed improved WMI outcomes.
- Astrocytes in WMI models and human tissue exhibit a specific neuroinflammatory reactive state.
- This reactive astrocyte gene expression pattern was reduced in the injured mutant mice.
Conclusions:
- A neuroinflammatory reactive astrocyte substate is associated with adverse WMI outcomes.
- These reactive astrocytes may be causal players in WMI pathology.
- Targeting this astrocyte substate presents a potential therapeutic strategy for WMI.
Abstract:
Perinatal white matter injury (WMI) is the leading cause of long-term neurological morbidity in infants born preterm. Neuroinflammation during a critical window of early brain development plays a key role in WMI disease pathogenesis. The mechanisms linking inflammation with the long-term myelination failure that characterizes WMI, however, remain unknown. Here, we investigate the role of astrocyte reactivity in WMI. In an experimental mouse model of WMI, we demonstrate that WMI disease outcomes are improved in mutant mice lacking secretion of inflammatory molecules TNF-α, IL-1α, and C1q known, in addition to other roles, to induce the formation of a neuroinflammatory reactive astrocyte substate. We show that astrocytes express molecular signatures of the neuroinflammatory reactive astrocyte substate in both our WMI mouse model and human tissue affected by WMI, and that this gene expression pattern is dampened in injured mutant mice. Our data provide evidence that a neuroinflammatory reactive astrocyte substate correlates with adverse WMI disease outcomes, thus highlighting the need for further investigation of these cells as potential causal players in WMI pathology.
