Brain–cervical lymph node crosstalk contributes to brain injury induced by subarachnoid hemorrhage in mice

Cross-talk between the brain and cervical lymph nodes (CLNs) is crucial in brain pathologies. However, the precise roles and the mechanisms of CLNs in brain damage during subarachnoid hemorrhage (SAH) remain unclear. In this study, mandibular lymph node (part of CLNs) removal attenuates brain damage in SAH mouse models. Notably, the extravasated erythrocytes following SAH are significantly engulfed by lymphatic endothelial cells (LECs) in CLNs. Single-cell RNA sequencing reveals that the differentially expressed genes in medullary LECs are enriched in lysosomes after SAH, with a notable upregulation of Ctss (which encodes cathepsin S). Importantly, the deficiency of cathepsin S specifically in LECs, achieved through transgenic mice, or the use of a cathepsin S inhibitor, significantly reduces neuroinflammation and neurological deficits induced by SAH. These findings elucidate mechanisms of how CLNs participate in brain injury following SAH in mice. Targeting this process may offer effective therapeutic strategies to alleviate SAH-related pathologies. Crosstalk between the brain and CLNs is critical in brain pathologies. Here, the authors show in a mouse model that extravasated erythrocytes following SAH are degraded by cathepsin S of medullary LECs in CLNs, which plays an important role in SAH pathology.