Lipoxin A₄ Receptor Stimulation Attenuates Neuroinflammation in a Mouse Model of Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is caused by the rupture of blood vessels in the brain. The excessive activation of glial cells and the infiltration of numerous inflammatory cells are observed during bleeding. Thrombin is a key molecule that triggers neuroinflammation in the ICH brain. In this study, we focused on lipoxin A₄ (LXA₄), an arachidonic acid metabolite that has been reported to suppress inflammation and cell migration. LXA₄ and BML-111, an agonist of the LXA₄ receptor/formyl peptide receptor 2 (ALX/FPR2), suppressed microglial activation; LXA₄ strongly inhibited the migration of neutrophil-like cells in vitro. ALX/FPR2 was expressed on neutrophils in the ICH mouse brain and the daily administration of BML-111 attenuated the motor coordination dysfunction and suppressed the production of proinflammatory cytokines in the ICH mouse brain. On the other hand, BML-111 did not show a significant reduction in the number of microglia and neutrophils. These results suggest that systemic administration of ALX/FPR2 agonists may suppress the neuroinflammatory response of microglia and neutrophils without a change in cell numbers. Additionally, their combination with molecules that reduce cell numbers, such as modulators of leukotriene B₄ signaling, may be required in future studies.