Lipocalin-2 induces macrophage/microglia pro-inflammatory phenotype after intracerebral hemorrhage via Nrf2 signaling inhibition in young and aged mice

Microglia and macrophages (M/M) play significant roles in intracerebral hemorrhage (ICH) injury, but the underlying mechanism is complicated and remains largely unknown. Lipocalin-2 (LCN2) expression elevates in M/M after ICH, yet its role in M/M-induced inflammation after ICH has not been fully elucidated. In the current study, a mouse ICH model was established in LCN2^{fl/fl,CX3CR1-Cre} male (LCN2 cKO) mice and LCN2^fl/fl male mice. We then aimed to inject LCN2 protein or the Nrf2 inhibitor brusatol groups for mechanism study, and the BV2 and Raw264.7 cell lines were used for in vitro study. LCN2 induces pro-inflammatory phenotype and promotes pro-inflammatory secretion in M/M after blood injury, and M/M LCN2 knockout reduced the pro-inflammatory phenotype after ICH. The Nrf2 protein is activated and nuclear-translocated by LCN2 knockout/downregulation, and the Nrf2 inhibition abrogates the anti-inflammatory effect induced by LCN2 knockout/downregulation. LCN2 knockout/downregulation boosts M/M phagocytosis after ICH, which is partially reversed by Nrf2 inhibition. The LCN2 expression also increases in aged mouse brains and participates in pro-inflammation induction and phagocytosis inhibition after ICH. Our study demonstrates that post-ICH LCN2 expression in M/M induces pro-inflammatory phenotype via inhibiting Nrf2 signaling pathway.