Ischemic stroke, caused by a blockage of blood flow to the brain, is a common cause of death and disability. Treatments are urgently needed to improve patient outcomes, because recovery currently depends largely on timely injections of a blood clot-dissolving drug. Treatment priorities include reducing inflammation at the site of ischemia and rebuilding nerve connections damaged by stroke. However, the molecule that can achieve these therapeutic effects has remained elusive.
In a study to be published in ApoplexyResearchers from Osaka University are offering patients new hope. They have identified two proteins, R-spondin 3 (RSPO3) and LGR4, that trigger a cascade of reactions in cells (that is, a signaling pathway) to reduce inflammation in the ischemic brain. RSPO3 and LGR4 also stimulate the outgrowth of extensions from neurons, a process called neurite outgrowth.
“Previous studies showed that RSPO3 was beneficial in lung injuries caused by inflammation. We also learned that RSPO3 stimulates a signaling pathway, called the ‘canonical Wnt pathway,’ that promotes neurite growth,” explains Munehisa Shimamura, lead author of the study. “We wondered if RSPO3 reduces inflammation and promotes neurite outgrowth after ischemic stroke.”
Previous studies showed that RSPO3 and LGR4 are present in the same brain structures, and that RSPO3 activates LGR4 to stimulate the canonical Wnt pathway. A team from Osaka University localized RSPO3 in endothelial cells and LGR4 in microglia/macrophages and neurons in the ischemic brain.
“Because of this close localization, RSPO3 can act on LGR4,” explains Hironori Nakagami, one of the study’s senior authors. “To test this hypothesis, we injected RSPO3 into the brains of mice 24 and 48 hours after the ischemic stroke.”
Remarkably, nine days after the stroke, mice injected with RSPO3 showed less sensory and motor deficits than mice injected with a control protein. The expression of pro-inflammatory factors was reduced, while markers of neurite outgrowth were increased. how? The researchers found that RSPO3/LGR4 reduced the expression of TLR4, which is one of the proteins necessary to trigger inflammation.
These results are particularly exciting because RPSO3 was administered to mice 1 day after stroke, indicating a potential benefit of treatments in later stages of stroke. Thus, targeting RSPO3/LGR4 signaling is a promising vanguard for developing novel stroke therapies and improving patient outcomes.
Shimamura, M.; et al. (2023) The R-spondin 3/LGR4 (Leucine-Rich repeat-containing G protein-Coupled Receptor 4) axis is a novel signaling system for inflammation and neuronal growth in the ischemic brain of mice. Apoplexy. doi.org/10.1161/STROKEAHA.122.041970.