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Cerebral inflammation is a promising therapeutic target for ischaemic stroke. After ischaemic stroke, inflammatogenic self-molecules, which originate from damaged brain tissue due to ischaemia, activate infiltrating immune cells (neutrophils, macrophages and lymphocytes) and thereby trigger sterile inflammation. Innate immunity plays the central role in sterile inflammation at the acute phase of brain ischaemia, although immune response by T lymphocytes (innate or acquired immunity) is also implicated in inflammation at the subacute phase, which sustains ischaemic brain damage. In the recovery phase, infiltrating macrophages remove the damage-associated molecular patterns (DAMPs) from the ischaemic brain. These pro-resolving myeloid cells also produce neurotrophic factors involved in neural repair. Through a series of inflammatory mechanisms activated by ischaemic stroke, various immune cells change their functions from inflammation to repair in a precise process. In order to establish therapeutic strategies for the improvement of neurological deficits after ischaemic stroke, it is necessary to clarify the detailed molecular and cellular mechanisms of sterile inflammation after ischaemic brain injury.

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 TLR2 and TLR4 in infiltrating myeloid cells. Although DJ-1 deficiency in a murine model of middle cerebral artery occlusion did not attenuate neuronal injury, the inflammatory cytokine expression in infiltrating immune cells was significantly decreased. Next, we found that the administration of an antibody to neutralize extracellular DJ-1 suppressed cerebral post-ischemic inflammation and attenuated ischemic neuronal damage. Our results demonstrate a previously unknown function of DJ-1 as a DAMP and suggest that extracellular DJ-1 could be a therapeutic target to prevent inflammation in tissue injuries and neurodegenerative diseases., Intracellular expression of the antioxidant protein DJ-1 has previously been shown to be neuroprotective. This study reveals that extracellularly released DJ-1 from necrotic neurons is a trigger of sterile inflammation that promotes neuronal injury and neurological deficits after ischemic stroke.