LCN2+ Astrocytes Mark a Pro-inflammatory Astrocyte State Associated with Secondary Brain Injury After Cerebral Venous Thrombosis

A recent study has shed light on a specific state of reactive astrocytes following cerebral venous thrombosis (CVT), a cerebrovascular disorder. Despite overall astrocyte numbers remaining unchanged, a subset of these cells exhibited an elevated expression of the protein Lcn2, which was predominantly found in the later stages of the CVT process. This Lcn2+ astrocyte state was identified by single-cell RNA sequencing of brain tissue samples from murine CVT models.

The Lcn2+ astrocytes demonstrated heightened inflammatory and stress response characteristics, as well as alterations in the vascular-immune microenvironment, suggesting that this particular astrocyte state is primarily responsible for secondary brain injury after CVT. Pseudotime trajectory analysis further corroborated the role of these cells in a late-stage reactive state, characterized by sustained upregulation of inflammation- and stress-associated genes.

Additionally, the study revealed extensive predicted cell-cell communication between the Lcn2+ astrocytes and various cell types, including myeloid cells, vascular-associated cells, and neuronal/synaptic populations. This suggests a potential role in the dynamic remodeling of the lesion microenvironment following CVT. The presence of Lcn2-high astrocytes was also observed in the MCAO model, albeit with weaker expression compared to CVT.

Interestingly, genetic deletion of LCN2 in mice led to a reduction in CVT-induced brain tissue injury, providing functional evidence of the detrimental role played by the LCN2-associated pathological state. The findings of this study offer new cellular insights into the mechanisms underlying secondary brain injury after CVT, and highlight potential targets for therapeutic intervention in managing this condition.