Postdoctoral Researcher Univ. of Texas Southwestern Med. Ctr., Texas, United States
Introduction/Rationale: Acute intracranial pressure (ICP) spikes are a common but understudied feature of brain injury. Using a novel cisterna magna infusion model that reproduces rapid ICP elevation without introducing blood, we reveal a pressure-sensitive immune cascade within the dura mater.
Methods: Mice were subjected to injection of blood or aCSF into the cisterna magna at rapid (30 μL/sec) or slow (30 μL/min) rates. Duras were collected at various time points from these mice and observed by flow cytometry, immunohistochemistry, live 2 photon microscopy, and RNA sequencing to characterize the immune changes of the dura following ICP spike. aCSF infusion challenge was performed to test pressure compensatory capacities of mice following ICP injury, and MRI was used to confirm hydrocephalus in ICP spike injured animals.
Results: Rapid infusion of blood or aCSF (30 μL/sec) causes depletion of resident macrophages followed by infiltration of Ly6G+CD11c+CD206+ immature granulocytes originating from skull marrow. These spikes lead to TGF-β pathway activation and profibrotic transcriptional programs. Histologic and second-harmonic imaging demonstrate peri-sinus and peri-venous collagen accumulation coinciding with loss of pressure buffering and ventricular enlargement. In contrast, slow infusions (30 μL/min) of blood or aCSF do not trigger immune infiltration or fibrosis. Pharmacologic transcranial blockade of CXCR2 with SB225002 prevents "neutrophil primed" cell migration, reduces collagen deposition, and restores compensatory compliance.
Conclusion: Together, these data define a previously unrecognized dura-based immune mechanism linking transient ICP spikes to chronic CSF outflow failure. This work positions the dura as an active immune organ that senses mechanical stress and mounts maladaptive fibrotic responses, providing new insight into the pathogenesis of post-injury hydrocephalus and immune–mechanical crosstalk at the brain’s borders.
