9 January 2019
Ischemic stroke occurs when a blockage or blood clot forms in one of the brain’s arteries. The resulting cerebral inﬂammation could be targeted by therapies to reduce its debilitating impact. Now, researchers in Japan have revealed how the body naturally resolves cerebral inﬂammation and hope to create a therapy that promotes this recovery process.
Scientists know that a set of proteins released from dead cells known as ‘damage-associated molecular patterns’ (DAMPs) disrupt the blood-brain barrier after an ischemic stroke, triggering inﬂammation. However, it had not been clear how the body resolves such inﬂammation over the following days.
“Strong anti-inﬂammatory agents like steroids do not improve the pathology of ischemic stroke,” explains Takashi Shichita, from Keio University in Tokyo, who worked on the project with a colleague, Akihiko Yoshimura, and others across Japan. “In fact, such agents may even inhibit the repair process after tissue injury. We wanted to clarify how the body resolves cerebral inﬂammation, and develop a therapeutic method to promote the repair process.”
The team isolated cells taken from mice brains three days after ischemic stroke was induced. They found that DAMPs were taken up by two groups of phagocytes — immune system cells that consume and destroy dangerous or dead cells. They showed that one of these phagocyte types, MSR1, is a key mediator of DAMP destruction in mice brains. They identified three genes that play vital roles in the process, and showed that deﬁciencies in one or more of these genes resulted in severe inﬂammation and exacerbated brain injury.
Further analysis showed that MSR1 is controlled by a transcription factor called Mafb, and that levels of MSR1 increased in the days following stroke in response to rising Mafb expression.
“If we can enhance MSR1 levels, we might be able to resolve inﬂammation,” says Shichita. “We conducted a trial using an existing neuroprotective agent called Am80, which has been used to treat acute leukaemia and is undergoing clinical trials against Crohn’s and Alzheimer’s disease.”
By targeting the Mafb/MSR1 pathway, Am80 increased Mafb expression and enhanced MSR1 levels as the researchers hoped. However, there was a drawback, as Shichita explains: “We had to use a relatively high dose of Am80 (2 mg per day) to suﬃciently enhance the MSR1 expression and associated phagocyte behaviour. We decided not to conduct clinical trials with Am80 and are instead focusing on ﬁnding novel agents that will target the Mafb/MSR1 pathway.”
- Shichita, T., Ito, M., Morita, R., Komai, K., Noguchi, Y. et al. MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1. Nature Medicine (2017).| article