Monocytechemotactic protein-induced protein 1 (MCPIP1), a newly recognized mRNA endonuclease, can be induced by lipopolysaccharide (LPS) and ischemic attack, then exerts a negative feedback loop against neuroinflammatory injury, but the specific underlying signaling pathway of the induction is unclear. Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE) signaling pathways are involved in LPS/ischemia-evoked inflammation. This study aims to explore which receptor signaling is mainly involved in the induction of MCPIP1 by LPS and ischemic attack. BV2 cells and mice were subjected to LPS stimulation or transient middle cerebral artery occlusion (MCAO) to examine the modulation of MCPIP1. Specific inhibitors for TLR4, TLR2 or RAGE were preadministered to explore the mechanisms of MCPIP1 expression. Results showed that MCPIP1 was significantly increased by LPS and ischemic stress both in vitro and in vivo in time and dose dependent manners. Inhibition of TLR4, rather than TLR2 or RAGE, downregulated the LPS/ischemia-induced expression of MCPIP1 and reduced the levels of TLR4, MyD88, phosphorylated-MAPK (p-P38), phosphorylated-IκBα (p-IκBα), as well as the translocation of NF-κB (p65). In conclusion, we firstly demonstrate that TLR4 signaling pathway, not TLR2 or RAGE, predominantly mediates the LPS/ischemia-induced expression of MCPIP1 in microglia. Copyright © 2018 Elsevier B.V. All rights reserved.