Abstract Inflammation and autophagy are two highly intertwined cellular processes. The relationship between inflammation and autophagy is quite complex and reciprocal. There is evidence that autophagy inhibits inflammation. However, the mechanisms that relieve this autophagy-mediated inhibition to permit an inflammatory response remain poorly understood. Our recent studies define a mechanism by which inflammatory stimulus releases the brake exerted by autophagy in microglial cells to trigger a robust inflammatory response. Using LPS as a model agent, we showed that proinflammatory signal leads to a p38α MAPK-dependent phosphorylation of ULK1 in microglial cells, which inhibits ULK1 kinase activity, prevents it from binding to the downstream effector ATG13 in the initiation complex, and reduces autophagy in microglia. This appears to be required for LPS-induced morphological changes and the production of IL-1β by primary microglia in vitro and in the brain. Furthermore, inhibition of ULK1 alone was sufficient to promote an inflammatory response in the absence of overt inflammatory stimulation. Interestingly, this regulatory mechanism seems to operate robustly only in microglial but not peripheral microphage cells. Thus, p38 MAPK-ULK1 link is a functional switch that enables microglia to fully engage the inflammatory machinery following the initial stimulation.