Microglia-released leukotriene B 4 promotes neutrophil infiltration and microglial activation following intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) from blood vessel rupture results in parenchymal hematoma formation and neuroinflammation, ultimately leading to neurodegeneration. Several lines of evidence suggest that the severity of ICH-induced neural damage is exacerbated by infiltration of T-cells, monocytes, and especially neutrophils into the hematoma. Neutrophil migration is regulated by chemokines, formyl peptides, and leukotriene B ₄ (LTB ₄ ), a metabolite of arachidonic acid. In this study, we demonstrate that LTB ₄ is a key signaling factor promoting microglial activity and leukocyte infiltration into hematoma and thus a potentially critical determinant of ICH pathogenesis and clinical outcome. Lipidomic analysis revealed markedly increased LTB ₄ concentration in the hematoma-containing brain tissues 6-24 h after experimental ICH in mice. Expression of 5-lipoxygenase, a rate-limiting enzyme for LTB ₄ production, was upregulated in activated microglia and neutrophils within the hematoma following ICH. Treatment of cultured BV-2 microglia with thrombin, which is abundant in hematoma, promoted activation, proinflammatory cytokine expression, and LTB ₄ secretion. Further, conditioned medium from thrombin-stimulated BV-2 cells potentiated the transwell migration of neutrophil-like cells, a response blocked by a LTB ₄ receptor antagonist. These results suggest that arachidonic acid conversion to LTB ₄ following ICH contributes to neuroinflammation and ensuing neural tissue damage by inducing microglial activation and neutrophil recruitment.
Competing Interests: Declaration of Competing Interest None.
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