Institute for Advanced Medical Sciences, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan.
Department of Therapeutic Progress in Brain Diseases, Hyogo Medical University, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan.
Cells. 2024 Oct 20;13(20):1737. doi: 10.3390/cells13201737.
Brain injuries, such as ischemic stroke, cause cell death. Although phagocytosis of cellular debris is mainly performed by microglia/macrophages (MGs/MΦs), excessive accumulation beyond their phagocytic capacities results in waste product buildup, delaying brain cell regeneration. Therefore, it is essential to increase the potential for waste product removal from damaged brains. Lipocalin-type prostaglandin D synthase (L-PGDS) is the primary synthase for prostaglandin D2 (PGD2) and has been reported as a scavenger of waste products. However, the mechanism by which the L-PGDS-PGD2 axis exerts such an effect remains unelucidated. In this study, using a mouse model of ischemic stroke, we found that L-PGDS and its downstream signaling pathway components, including PGD2 and PGD2 receptor DP1 (but not DP2), were significantly upregulated in ischemic areas. Immunohistochemistry revealed the predominant expression of L-PGDS in the leptomeninges of ischemic areas and high expression levels of DP1 in CD36 MGs/MΦs that were specifically present within ischemic areas. Furthermore, PGD2 treatment promoted the conversion of MGs/MΦs into CD36 scavenger types and increased phagocytic activities of CD36 MGs/MΦs. Because CD36 MGs/MΦs specifically appeared within ischemic areas after stroke, our findings suggest that the L-PGDS-PGD2-DP1 axis plays an important role in brain tissue repair by regulating phagocytic activities of CD36 MGs/MΦs.
脑损伤，如缺血性中风，会导致细胞死亡。虽然细胞碎片的吞噬主要由小胶质细胞/巨噬细胞（MGs/MΦs）完成，但超过其吞噬能力的过度积累会导致废物堆积，从而延迟脑细胞再生。因此，增加从受损大脑中清除废物的潜力至关重要。脂联素型前列腺素 D 合酶（L-PGDS）是前列腺素 D2（PGD2）的主要合成酶，已被报道为废物的清除剂。然而，L-PGDS-PGD2 轴发挥这种作用的机制仍不清楚。在本研究中，我们使用缺血性中风的小鼠模型发现，L-PGDS 及其下游信号通路成分，包括 PGD2 和 PGD2 受体 DP1（但不是 DP2），在缺血区域显著上调。免疫组织化学显示 L-PGDS 在缺血区域的软脑膜中表达丰富，DP1 在 CD36 MGs/MΦs 中表达水平较高，而 CD36 MGs/MΦs 特异性存在于缺血区域。此外，PGD2 处理促进了 MGs/MΦs 向 CD36 吞噬型的转化，并增加了 CD36 MGs/MΦs 的吞噬活性。因为 CD36 MGs/MΦs 在中风后特异性出现在缺血区域，我们的发现表明 L-PGDS-PGD2-DP1 轴通过调节 CD36 MGs/MΦs 的吞噬活性在脑组织修复中发挥重要作用。
