Proteins RSPO3 and LGR4 show promise for reducing inflammation and promoting neuron growth after ischemic stroke

Ischemic stroke is a leading cause of death and disability, caused by a blockage of blood flow to the brain. Current treatments rely heavily on the timely administration of a blood clot-dissolving drug, emphasizing the need for more effective therapies. One of the priorities for therapy is to reduce inflammation at the ischemic site and rebuild neuronal connections damaged by the stroke. However, identifying a molecule that can achieve these therapeutic effects has proven difficult.

In a forthcoming study in the journal Stroke, researchers from Osaka University may offer a glimmer of hope for patients. The researchers have pinpointed two proteins, R-spondin 3 (RSPO3) and LGR4, that trigger a series of reactions in cells, known as a signaling pathway, that can reduce inflammation in the ischemic brain. RSPO3 and LGR4 also promote the growth of extensions from neurons, a process called neurite outgrowth.

Munehisa Shimamura, lead author of the study, explains, “Previous studies showed that RSPO3 was beneficial in lung injuries caused by inflammation. We also knew that RSPO3 stimulates a signaling pathway, named the ‘canonical Wnt pathway,’ that promotes neurite outgrowth. We wondered whether RSPO3 reduces inflammation and promotes neurite outgrowth after ischemic stroke.”

Previous studies have demonstrated that RSPO3 and LGR4 are present in the same brain structures and that RSPO3 activates LGR4 to stimulate the canonical Wnt pathway. The Osaka University team localized RSPO3 in endothelial cells and LGR4 in microglia/macrophage cells and neurons in the ischemic brain.

(A) When recombinant RSPO3 was administered intracerebroventricularly one day after the stroke, the neurological deficit was reduced. (B) Neurite outgrowth was promoted in primary neuronal cells cultured in medium containing RSPO3. (C) RSPO3 suppressed the expression of inflammatory cytokines in LPS-stimulated microglia. Credit: Stroke (2023). DOI: 10.1161/STROKEAHA.122.041970

The close proximity of RSPO3 and LGR4 in the brain suggests that RSPO3 may be able to act on LGR4, says Hironori Nakagami, a senior author of the study. To test this theory, the team administered RSPO3 into the brains of mice 24 and 48 hours after an ischemic stroke.

Incredibly, mice that were given RSPO3 showed fewer sensory and motor deficits nine days after the stroke than those that were given a control protein. The expression of pro-inflammatory factors decreased, while indications of neurite outgrowth increased. The researchers discovered that RSPO3/LGR4 lowered the expression of TLR4, a protein that is essential for causing inflammation.

These findings are especially encouraging because RSPO3 was given to the mice one day after the stroke, implying that it may have a beneficial effect on later-stage treatments. Therefore, targeting the RSPO3/LGR4 signaling pathway could be a promising approach to developing new therapies for ischemic stroke and improving patient outcomes.

Source: Osaka University

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