Maresin-1 Ameliorates Sepsis-Induced Microglial Activation Through Modulation of the P38 MAPK Pathway

Sepsis is a life-threatening disease characterized by a dysregulated immune response to infection, often leading to neuroinflammation. As a known immunomodulator, Maresin-1 (MaR1) may have potential applications in the treatment of sepsis-induced neuroinflammation, but its effects in this context are unknown. We used a mouse cecum ligation and puncture (CLP)-induced sepsis model and an in vitro lipopolysaccharide (LPS)-induced neuroinflammatory model of BV2 microglia. Expression of microglial cell markers (IBA1, CD11B, CD68, CD86 and CD206) and pro-inflammatory markers (iNOS and COX2) was assessed. The role of MaR1 in regulating the P38 MAPK pathway was explored using the P38 MAPK inhibitor SB203580. In the CLP model, an increased proportion of M1-type microglia was observed, and MaR1 was able to reverse it. However, the combination of SB203580 and MaR1 did not enhance the therapeutic effect compared to SB20580 alone. In vitro experiments, MaR1 inhibited LPS-induced P38 MAPK nuclear translocation and decreased the expression of pro-inflammatory markers such as iNOS and COX2. As with the animal results, no stacking effect could be obtained with the co-administration of SB203580 and MaR1. Our findings suggest that MaR1 attenuates sepsis-induced neuroinflammation mainly by inhibiting phosphorylation of P38 MAPK in microglial cells. This suggests that MaR1 may have a potential therapeutic role in the treatment of sepsis neuroinflammation.Graphical AbstractUnder sepsis, the phosphorylation of P38 MAPK in the brain is increased, which may cause resting microglia in the brain in the transformation to M1-type microglia. At the same time, P38 MAPK in microglia translocates to the nucleus and increases its phosphorylation level, which may promote microglia to trigger neuroinflammation and further induce neuronal degeneration. MaR1 can inhibit the above process. This figure was created by Figdraw Maresin-1 reduces the proportion of M1-type microglia in sepsis mice.Maresin-1 reduces the expression levels of iNOS and COX2 in microglia in vitro.Maresin-1 affects nuclear translocation of p38 MAPK in microglia.