Matrilin-3 supports neuroprotection in ischemic stroke by suppressing astrocyte-mediated neuroinflammation.

In the brain, the role of matrilin-3, an extracellular matrix component in cartilage, is unknown. Here, we identify that matrilin-3 decreased in reactive astrocytes but was unchanged in neurons after ischemic stroke in animals. Importantly, it declined in serum of patients with acute ischemic stroke. Genetic or pharmacological inhibition or supplementation of matrilin-3 aggravates or reduces brain injury, astrocytic cell death, and glial scar, respectively, but has no direct effect on neuronal cell death. RNA sequencing demonstrates that Matn3-/- mice display an increased inflammatory response profile in the ischemic brain, including the nuclear factor κB (NF-κB) signaling pathway. Both endogenous and exogenous matrilin-3 reduce inflammatory mediators. Mechanistically, extracellular matrilin-3 enters astrocytes via caveolin-1-mediated endocytosis. Cytoplasmic matrilin-3 translocates into the nucleus by binding to NF-κB p65, suppressing inflammatory cytokine transcription. Extracellular matrilin-3 binds to BMP-2, blocking the BMP-2/Smads pathway. Thus, matrilin-3 is required for astrocytes to exert neuroprotection, at least partially, by suppressing astrocyte-mediated neuroinflammation.

The association between serum phosphorus and common carotid artery intima-media thickness in ischemic stroke patients.

Purpose: An elevated concentration of phosphorus is associated with an increased risk of atherosclerosis and cardiovascular diseases. Common carotid artery intima-media thickness (cIMT) is an imaging marker of atherosclerosis. However, data on the relationship between phosphorus and cIMT in ischemic stroke are scarce. We aimed to evaluate the association between serum phosphorus levels and cIMT in patients who had experienced ischemic stroke. Patients and methods: A total of 1,450 ischemic stroke patients were enrolled. Participants were divided into four groups (quartiles) according to baseline serum phosphorus level. Carotid atherosclerosis was identified by measurement of cIMT; abnormal cIMT was defined as a maximum cIMT or mean cIMT ≥ 1 mm. Multivariable logistic regression models were used to assess the association between serum phosphorus level and the presence of abnormal cIMT. Results: In the multivariable adjusted analysis, falling into the highest quartile for serum phosphorus (Q4) was associated with a 2.00-fold increased risk of having abnormal maximum cIMT [adjusted odds ratio (OR) 2.00; 95% confidence interval (CI) 1.44-2.79] and a 1.76-fold increased risk of having abnormal mean cIMT (adjusted OR 1.76; 95% CI 1.22-2.53) in comparison to Q1. Furthermore, the association between serum phosphorus and abnormal cIMT was confirmed in analyses treating serum phosphorus as a continuous variable and in subgroup analyses. Conclusion: In acute ischemic stroke patients, baseline elevated serum phosphorus level was found to be independently associated with carotid atherosclerosis, as measured by cIMT.