DHA plays a protective role in cerebral ischemia–reperfusion injury by affecting macrophage/microglia type polarization

•DHA can alleviate cerebral ischemia–reperfusion injury.•DHA reverses the polarization of macrophages/microglia to M1 phenotype and promotes their transformation to M2 phenotype.•NALP3 inflammasome is activated in the brain tissue after ischemia and reperfusion.•DHA can regulate the M1 and M2 polarization of cells by inhibiting the activation of NALP3. A close correlation exists between the macrophage/microglia(MΦ/MG) polarization states and the development of cerebral ischemia and reperfusion (I/R). Therefore it is of great significance to research on how to modulate the MΦ/MG states for improved patient outcomes. In particular, regulatory mechanisms involved in this process remain to be identified. Hereby, we aim to shed light on how docosahexaenoic acid (DHA) actively modulates the switch between M1 and M2 macrophage states by restraining the NACHT-LRR-PYD-containing protein three inflammasome (NALP3). We found that NALP3-positive cells were detected in clinical human cerebral infarction tissue samples and the mouse tMCAO model. In mice after DHA treatment, the number of NALP3-positive cells was significantly reduced, significantly decreasing infarct volume and improving the postoperative physical status of mice. NALP3-positive cells were found to be MΦ/MG after co-staining with CD11b. By extracting peritoneal macrophages, it was verified that DHA inhibited the activation of NALP3 and regulated the transformation of M1 and M2 cells, thereby reducing I/R injury.