Fibroblast activation protein protects the ischemic brain through regulation of post-ischemic inflammation

Low circulating levels of soluble fibroblast activation protein (sFAP) are associated with poor outcomes in patients with ischemic stroke, while its function in the ischemic brain remains unclear. This study investigated the role of FAP in ischemic stroke. BALB/c mice were subjected to transient middle cerebral artery occlusion and treated with recombinant FAP (rFAP) or CPD60, a selective FAP inhibitor. Temporal and spatial patterns of FAP expression in brain were analyzed. sFAP showed a greater decrease in CSF than in serum after ischemic stroke. Astrocytes expressed FAP but did not secrete it. Meningeal fibroblasts constitutively released FAP, and this release decreased after exposure to Toll-like receptor (TLR) 4 ligands. In cultured microglial and macrophages, rFAP suppressed TLR2/4-induced cytokine production. rFAP protected neurons and decreased tumor necrosis factor-α and interleukin-1β levels in neuron-glia cultures. Systemic or intracerebroventricular administration of rFAP reduced post-ischemic inflammation and infarct volume, whereas CPD60 worsened tissue injury. FAP also inhibited monocyte migration and inflammation induced by C-C motif chemokine ligand 2 and complement C1q tumor necrosis factor-related protein 6, suggesting that these chemokines are potential substrates. Overall, FAP regulates post-ischemic inflammation and protects neurons after ischemic stroke, indicating its therapeutic potential in ischemic stroke.