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.

The brain maintains homeostasis partially by scavenging waste products. Failure of this function is closely associated with the onset and pathogenesis of various brain diseases, such as Alzheimer’s disease, sleep disorder, and the delay of the reparative process after brain injuries. We recently demonstrated that brain pericytes (BPCs) are sources of lipocalin-type prostaglandin D synthase (L-PGDS), a waste scavenger, in the brain. Based on the above, chemical compounds which promote L-PGDS production could have potential against brain diseases, such as dementia, sleep disorders, and brain injuries. However, the specific chemical compounds that may enhance L-PGDS production in BPCs have not yet been identified. In this study, we explored 158 chemical compounds from FDA-approved drug libraries with these activities. qPCR analysis showed that mirtazapine (MTZ), a noradrenergic and specific serotonergic antidepressant, can increase L-PGDS expression in BPCs as well as in mouse- (m-BPCs) and human-derived BPCs (h-BPCs) in a dose-dependent manner. Since L-PGDS is a secretory protein, m-BPCs and h-BPCs were treated with various MTZ doses and L-PGDS levels in the culture supernatant were investigated. Western blot analysis showed that L-PGDS levels were significantly increased in a dose-dependent manner in both cell types, indicating that MTZ promoted L-PGDS secretion from m-BPCs and h-BPCs. Thus, MTZ may have the potential to be applied as drug repositioning for various brain diseases other than depression by activating L-PGDS production in BPCs, highlighting the importance of BPCs as the source to maintain brain homeostasis.