The TREM1-AQP4 Axis Mediates Neuroinflammatory Injury and Brain Edema after Experimental Subarachnoid Hemorrhage

Objective: Secondary brain injury following subarachnoid hemorrhage (SAH) is a major factor contributing to poor patient outcomes, with neuroinflammation and cerebral edema representing core pathological mechanisms. Triggering receptor expressed on myeloid cells-1 (TREM1), a major inflammatory amplifier in innate immunity, remains poorly understood in SAH regarding its specific role, cellular targets, and association with aquaporin-4 (AQP4), a key cerebral edema molecule. To elucidate the regulatory role of TREM1 in neuroinflammatory injury following experimental SAH and to investigate whether it functions by driving microglial activation and modulating AQP4 expression. Methods: An SAH model was established in rats via internal carotid artery puncture. TREM1 expression was specifically upregulated or downregulated in vivo through lateral ventricle injection of adeno-associated virus (AAV). Animals were randomly assigned to sham surgery, SAH empty vector control, SAH TREM1 overexpression, and SAH TREM1 knockdown groups. Twenty-four hours post-SAH, neurological function was assessed using the modified Garcia score and balance beam test; brain water content was measured by dry-wet weight method; HE staining was used to observe neuronal morphology; Western Blot and real-time quantitative PCR (qRT-PCR) were employed to detect TREM1, Iba1, GFAP, AQP4, NeuN, Cleaved Caspase-3, IL-6, and IL-13 expression; Immunofluorescence staining was performed for localization and semi-quantitative analysis. Results: Following subarachnoid hemorrhage (SAH), TREM1 expression is significantly upregulated in brain tissue, with its levels negatively correlated with neurological deficits. Functional and molecular studies demonstrate that TREM1 inhibition improves neurological function, reduces cerebral edema, and mitigates neuronal apoptosis, whereas overexpression exacerbates injury. Mechanistic studies reveal that TREM1 exacerbates secondary brain injury by promoting microglial hyperactivation and inflammatory responses, while simultaneously upregulating astrocytic AQP4 expression. Conclusion: This study first reveals the TREM1-AQP4 axis as a critical bridge linking neuroinflammation and cerebral edema after SAH. TREM1 exacerbates brain injury by driving microglia-mediated neuroinflammation and upregulating astrocytic AQP4 expression. Targeting TREM1 inhibition holds promise as a novel therapeutic strategy to improve SAH prognosis by simultaneously alleviating inflammation and reducing edema.