Background: Promotion of hematoma resolution in a timely manner reduces intracerebral hemorrhage (ICH) brain injury induced by toxic blood components and subsequent neuroinflammation. The meningeal lymphatic system is responsible for clearance of macromolecules and pathogenic substances from the central nervous system; however, its role in intraparenchymal hematoma clearance and ICH outcomes is unknown. In the present study, we aimed to understand the contribution of the meningeal lymphatic system to ICH pathologies and to test whether pharmacological enhancement of meningeal lymphatic function promotes hematoma resolution and brain recovery after ICH. Methods: Immunofluorescence of whole-mount meninges was used to measure complexity and coverage level of meningeal lymphatic vasculature following ICH induction. Fluorescent microbeads and PKH-26-labeled erythrocytes were used to evaluate drainage function of the meningeal lymphatic system. Visudyne treatment, deep cervical lymph node ligation, and VEGF (vascular endothelial growth factor)-C injection were performed to manipulate meningeal lymphatic function. Neurobehavioral performance and hematoma volume were assayed by the cylinder test and histological measurements. Iron deposition, residual erythrocytes, neuronal loss, and astrogliosis were assessed by immunohistochemistry and antibody-based fluorescence staining. Results: Meningeal lymphangiogenesis and enhanced lymphatic drainage occurred during the late phase of ICH. Ablation and blockage of meningeal lymphatic vessels impeded hematoma clearance, whereas pharmacological enhancement of their function reduced hematoma volume, improved behavioral performance, and reduced brain residual erythrocytes, iron deposition, neuronal loss, and astroglial activation. Conclusions: Early enhancement of meningeal lymphatic function is beneficial for ICH recovery. Targeting the meningeal lymphatic system is therefore a potential therapeutic approach for treating ICH.
Traumatic brain injury (TBI) affects millions worldwide with devastating long-term effects on health and cognition. Emerging data suggest that targeting the immune response may offer promising strategies to alleviate TBI outcomes; kahweol, an anti-inflammatory diterpene that remains in unfiltered coffee, has been shown to be beneficial in neuronal recovery. Here, we examined whether kahweol could alleviate brain trauma-induced injury in a mouse model of TBI and its underlying mechanisms. TBI was induced by controlled cortical impact (CCI) and various doses of kahweol were intraperitoneally administered following injury. Contusion volume, brain edema, neurobehavioral deficits, and protein expression and activity were evaluated in both short-term and long-term recovery. We found that kahweol treatments significantly reduced secondary brain injury and improved neurobehavioral outcomes in TBI mice. These changes were accompanied by the attenuation of proinflammatory cytokine secretion, decreased microglia/macrophage activation, and reduction of neutrophil and leukocyte infiltration. In addition, continuous kahweol treatment further improved short-term TBI outcomes compared to single-dosage. Collectively, our data showed that kahweol protects against TBI by reducing immune responses and may serve as a potential therapeutic intervention for TBI patients.
Background: Intracerebral hemorrhage (ICH) brain injury is induced by toxic blood components and subsequent neurologic deficits can be alleviated by promoting hematoma resolution. The meningeal lymphatic system has been shown to mediate substances clearance from the central nervous system, including macromolecules and pathogenic metabolites. However, it remains unclear whether this system plays a role in hematoma clearance and ICH outcomes. In this study, we investigated the correlation between meningeal lymphatic function and ICH pathologies. Pharmacological promotion of meningeal lymphatic function was also used to determine whether targeting meningeal lymphatic system can facilitate ICH recovery. Methods: Whole-mount meninges were used to evaluate the complexity and coverage rate of meningeal lymphatic vessels. Meningeal lymphatic drainage was evaluated by injecting fluorescent microbeads and PKH26-labeled erythrocytes into the cisterna magna and brain parenchyma, respectively. Hematoma volume was measured in fresh coronal brain sections. Neurobehavioral performance was evaluated by cylinder test. Pathological outcomes including iron deposition, residual erythrocytes, neuronal loss, and astrogliosis were detected by immunohistochemistry or immunofluorescence. Results: Meningeal lymphangiogenesis and increased lymphatic drainage occur during the late phase of ICH. Depriving the function of meningeal lymphatic vessels impeded hematoma clearance, whereas boosting meningeal lymphatic drainage and lymphangiogenesis improved hematoma clearance rate and behavioral function as well as reduced iron deposition, neuronal loss, and astrogliosis in the ICH brain. Conclusion: Early enhancement of meningeal lymphatic function is beneficial for ICH recovery, implicating the meningeal lymphatic system as a potential therapeutic target for treating ICH.
A high salt diet (HSD) is a top risk factor for human mortality. Beyond its heavily implicated role in hypertension, it is now linked to the development of inflammatory diseases before the onset of cardiovascular events. Even after salt reduction, HSD can induce prolonged tissue damage, yet the mechanisms by which HSD induces persistent negative effects on immune system are largely unexplored. While HSD is an established risk factor for stroke, its impact on long-term stroke recovery is unknown. Here, we model two major stroke types, intracerebral hemorrhage, and cerebral ischemia, to investigate how HSD induces unfavorable immune responses and subsequently impacts long-term tissue repair. We found HSD exclusively hampers alternative activation in monocytes-derived macrophages (MDMs) while sparing the major parenchymal macrophage—microglia—in the stroke brain. HSD induces innate immune memory in the hematopoietic stem and progenitor cells through downregulating mitochondrial oxidative phosphorylation and NR4a orphan nuclear receptors expression. This immunological memory was retained in the brain-infiltrating MDMs and restrained their reparative functions. Consequently lead to impaired tissue repair and neurobehavioral recovery during stroke recovery phase. Pharmacological treatment with NR4a1 activator and genetic overexpression of NR4a1 restored MDMs reparative phenotype suppressed by HSD and enabled stroke recovery. These findings establish a new mechanism linking HSD-induced maladaptive innate immune memory to a hindered macrophage alternative activation and delayed tissue recovery. Our data unveil innate immune memory and NR4a1 as potential therapeutic targets for treating HSD-associated diseases.
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