biostudies-literatureNakamura KMitsubishi FoundationSENSHIN Medical Research FoundationTakeda Science FoundationJapan Agency for Medical Research and DevelopmentToray Science and Technology GrantOno Medical Research FoundationMSD Life Science Foundation, Public Interest Incorporated FoundationMinistry of Education, Culture, Sports, Science and Technology of JapanSenri Life Science FoundationJapan Society for the Promotion of Sciencee3000939https://www.ebi.ac.uk/biostudies/studies/S-EPMC8136727biostudies-literatureUnknown19(5)Inflammation is implicated in the onset and progression of various diseases, including cerebral pathologies. Here, we report that DJ-1, which plays a role within cells as an antioxidant protein, functions as a damage-associated molecular pattern (DAMP) and triggers inflammation if released from dead cells into the extracellular space. We first found that recombinant DJ-1 protein induces the production of various inflammatory cytokines in bone marrow-derived macrophages (BMMs) and dendritic cells (BMDCs). We further identified a unique peptide sequence in the αG and αH helices of DJ-1 that activates Toll-like receptor 2 (TLR2) and TLR4. In the ischemic brain, DJ-1 is released into the extracellular space from necrotic neurons within 24 h after stroke onset and makes direct contact with TLR2PLoS biologyExtracellular DJ-1 induces sterile inflammation in the ischemic brain.PMC813672720H0495718K1483119H04765JP20gm591002317K15204JP20J21472JP20gm121001017H05096Yogiashi YSakai STsuyama JNakamura KMasai HShichita TOtani KNakamura AKurabayashi KfalseExtracellular DJ-1 induces sterile inflammation in the ischemic brain.Inflammation is implicated in the onset and progression of various diseases, including cerebral pathologies. Here, we report that DJ-1, which plays a role within cells as an antioxidant protein, functions as a damage-associated molecular pattern (DAMP) and triggers inflammation if released from dead cells into the extracellular space. We first found that recombinant DJ-1 protein induces the production of various inflammatory cytokines in bone marrow-derived macrophages (BMMs) and dendritic cells (BMDCs). We further identified a unique peptide sequence in the αG and αH helices of DJ-1 that activates Toll-like receptor 2 (TLR2) and TLR4. In the ischemic brain, DJ-1 is released into the extracellular space from necrotic neurons within 24 h after stroke onset and makes direct contact with TLR22021-01-01T00:00:00Z2021 May2026-05-08T23:01:57.568Z2022-02-10T13:23:32.811ZS-EPMC81367273401492110.1371/journal.pbio.3000939