The blood–cerebrospinal fluid barrier (BCB) is important in maintaining brain manganese (Mn) homeostasis. This barrier consists of a single layer of epithelial cells, connected by tight junctions, that restrict the passage of nutrients to only allow molecules to be carried through the membrane by a transporter. These epithelial cells are polarized with asymmetrical blood-facing and cerebrospinal fluid-facing sides. Here, we have established a polarized model of a human choroid plexus papilloma cell line, HIBCPP. For the first time, Mn importers ZIP14 and ZIP8 were identified in HIBCPP cells and were found to be enriched at the basolateral and apical sides of the cell monolayer, respectively. The localization of each ZIP protein adds to the understanding of Mn transport across the HIBCPP BCB model to help understand the mechanism of Mn homeostasis within the brain.

Manganese (Mn) is an essential trace mineral for brain function, but excessive accumulation can cause irreversible nervous system damage, highlighting the need for proper Mn balance. ZIP14, ZnT10, and ZIP8 are key transporters involved in maintaining Mn homeostasis, particularly in the absorption and excretion of Mn in the intestine and liver. However, their roles in the brain are less understood. The blood–cerebrospinal fluid barrier and the blood–brain barrier, formed by the choroid plexus and brain blood vessels, respectively, are critical for brain protection and brain metal homeostasis. This study identified ZIP14 on the choroid plexus epithelium, and ZIP8 and ZnT10 in brain microvascular tissue. We show that despite significant Mn accumulation in the CSF of Znt10 knockout mice, ZIP14 expression levels in the blood–cerebrospinal fluid barrier remain unchanged, indicating that ZIP14 does not have a compensatory mechanism for regulating Mn uptake in the brain in vivo. Additionally, Mn still enters the CSF without ZIP14 when systemic levels rise. This indicates that alternative transport mechanisms or compensatory pathways ensure Mn balance in the CSF, shedding light on potential strategies for managing Mn-related disorders.

Macrophage-mediated phagocytosis of tumor cells elicits potent antitumor immunity. Nonetheless, sole-blockade of the anti-phagocytosis molecule CD47 has yielded insufficient therapeutic outcomes. Here, we report that glioblastoma (GBM) cells expressed abundant levels of phagocytosis checkpoint CD24. We further show that dual blockade of CD24 and CD47 synergistically enhances the pro-phagocytic activity of macrophages, thereby improving tumor antigen cross-presentation and activating the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway. This innate immune activation facilitates T cell infiltration into tumors and sensitizes tumors to anti-PD1 therapy, improving survival outcomes in murine GBM models, including immunosuppressive tumors reflecting human GBM-like features. Thus, our results indicate that dual-phagocytosis checkpoint blockade offers a promising therapeutic avenue to potentiate cancer immunotherapy.

Background/Objectives: Manganese is an essential nutrient involved in various biological processes, including reproductive health, yet the mechanisms regulating its homeostasis in the testis remain poorly understood. Methods and Results: In this study, we investigated the expression and regulation of key manganese transporters—ZIP8, ZIP14, and ZnT10—in mouse testes. Immunoblotting analyses revealed that ZIP8 is expressed in the testes, while ZIP14 and ZnT10 were undetectable. Using Zip14 knockout (Zip14^-/-) mice, which exhibit systemic manganese overload, we discovered a significant increase in manganese levels in the testis, accompanied by an upregulation of ZIP8. Importantly, the levels of other essential metals, such as iron, zinc, and copper, remained unchanged. Conclusions: Our findings suggest that ZIP8 plays a critical role in manganese transport in the testis, and its increased expression may contribute to manganese accumulation in the absence of ZIP14. This study advances our understanding of manganese homeostasis in the testis and its potential impact on male reproductive health.