We found that stress-induced abnormal MKP-1 elevation in hippocampal neurons while MKP-1 knockdown reduced stressed-associated neuroinflammation and reversed stress-induced downregulation of ERK and p38 MAPK signaling pathways, suggesting that neuroinflammation increases depression risk by upregulating MKP-1 and leading to insufficient MAPK signaling, which is necessary for neuronal survival and adaptive plasticity under stress. Here, DUSP1 is linked to major depressive disorder.