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Progranulin (PGRN) is a secreted glycoprotein, the expression of which is linked to several neurodegenerative diseases. Although its specific function is still unclear, several studies have linked it with lysosomal functions and immune system regulation. Here, we have explored the role of PGRN in peripheral and central immune system homeostasis by investigating the consequences of PGRN deficiency on adaptive and innate immune cell populations. First, we used gene co-expression network analysis of published data to test the hypothesis that has a critical role in regulating the activation status of immune cell populations in both central and peripheral compartments. To investigate the extent to which PGRN-deficiency resulted in immune dysregulation, we performed deep immunophenotyping by flow cytometry of 19-24-month old male and female deficient mice (PGRN KO) and littermate -sufficient controls (WT). Male PGRN KO mice exhibited a lower abundance of microglial cells with higher MHC-II expression, increased CD44 expression on monocytes in the brain, and more CNS-associated CD8 T cells compared to WT mice. Furthermore, we observed an increase in CD44 on CD8 T cells in the peripheral blood. Female PGRN KO mice also had fewer microglia compared to WT mice, and we also observed reduced expression of MHC-II on brain monocytes. Additionally, we found an increase in Ly-6C monocyte frequency and decreased CD44 expression on CD8 and CD4 T cells in PGRN KO female blood. Given that , which encodes for the lysosomal protein Glycoprotein non-metastatic melanoma protein B, has been reported to be upregulated in PGRN KO mice, we investigated changes in GPNMB protein expression associated with PGRN deficits and found that GPNMB is modulated in myeloid cells in a sex-specific manner. Our data suggest that PGRN and GPNMB jointly regulate the peripheral and the central immune system in a sex-specific manner; thus, understanding their associated mechanisms could pave the way for developing new neuroprotective strategies to modulate central and peripheral inflammation to lower risk for neurodegenerative diseases and possibly delay or halt progression.

The notion that the central nervous system is an immunologically immune-exempt organ has changed over the past two decades, with increasing evidence of strong links and interactions between the central nervous system and the peripheral immune system, both in the healthy state and after ischemic and hemorrhagic stroke. Although primary injury after stroke is certainly important, the limited therapeutic efficacy, poor neurological prognosis and high mortality have led researchers to realize that secondary injury and damage may also play important roles in influencing long-term neurological prognosis and mortality and that the neuroinflammatory process in secondary injury is one of the most important influences on disease progression. Here, we summarize the interactions of the central nervous system with the peripheral immune system after ischemic and hemorrhagic stroke, in particular, how the central nervous system activates and recruits peripheral immune components, and we review recent advances in corresponding therapeutic approaches and clinical studies, emphasizing the importance of the role of the peripheral immune system in ischemic and hemorrhagic stroke.

Background Processes related to how the intracranial microvasculature initiates brain‒peripheral crosstalk for subsequent blood‒brain barrier (BBB) dysfunction at an early stage after subarachnoid hemorrhage (SAH) ictus are still unknown. This study elucidated the effect and potential mechanism of intracranial microvasculature-mediated T-cell infiltration on BBB function after SAH. Methods Publicly available single-cell RNA sequencing data related to SAH ( https://ngdc.cncb.ac.cn/omix ; Accession No. OMIX006611) were retrieved and analyzed. The dataset was derived from the white matter region of adult male C57BL/6J mice at 1 and 7 days after experimental SAH. The SAH model was induced by endovascular perforation, and experiments were subsequently conducted at 1, 3, 7, and 14 days after SAH to evaluate T-cell infiltration, BBB integrity, neuronal injury, and neurological function. Results After SAH, CXCL12 expression was increased in endothelial cells and pericytes, promoting CD8 + T-cell infiltration via the CXCR4 pathway. This immune infiltration appeared to exacerbate BBB disruption and contribute to worsened neurological function. Blocking CXCL12-CXCR4 signaling with a CXCL12 neutralizing antibody or the CXCR4-specific inhibitor AMD3100 significantly reduced CD8 + T-cell infiltration, attenuated BBB damage and improved the neurobehavioral outcomes of SAH mice. Conclusion This study suggests that, following SAH, both pericytes and endothelial cells may contribute to immune regulation by producing CXCL12, which promotes CD8⁺ T-cell infiltration into the brain. This mechanism may play a role in BBB disruption and neurological dysfunction. Targeting the CXCL12–CXCR4 axis could offer a potential approach for mitigating immune-mediated injury after SAH.

In a model of bilateral common carotid artery ligation,Gao et al.reports on the changes to microglia morphology, as well as changes to gene transcription, for various lengths of occlusion. Jing et al.reported that lncRNA GAS5 was higher in patients experiencing cardiac arrest and cardiopulmonary resuscitation. The work byYang et al.in ischemic stroke patients examined eosinophil counts before and after intravenous thrombolysis and observed that a drastic decrease in eosinophil count of greater than 75% was associated with a 2.5 times higher risk for poor outcome and more than a 13-fold increased risk of death. [...]an article byLi et al.suggests that co-administering a sphingosine 1-phosphate receptor antagonist with tPA can improve thrombolysis.