Silencing the lncRNA <i>Maclpil</i> in pro-inflammatory macrophages attenuates acute experimental ischemic stroke via LCP1 in mice

Abstract

Long noncoding RNAs (lncRNA) expression profiles change in the ischemic brain after stroke, but their roles in specific cell types after stroke have not been studied. We tested the hypothesis that lncRNA modulates brain injury by altering macrophage functions. Using RNA deep sequencing, we identified 73 lncRNAs that were differentially expressed in monocyte-derived macrophages (MoDMs) and microglia-derived macrophages (MiDMs) isolated in the ischemic brain three days after stroke. Among these, the lncRNA, GM15628, is highly expressed in pro-inflammatory MoDMs but not in MiDMs, and are functionally related to its neighbor gene, lymphocyte cytosolic protein 1 (LCP1), which plays a role in maintaining cell shape and cell migration. We termed this lncRNA as <u>Ma</u>crophage <u>c</u>ontained <u>L</u>CP1 related <u>p</u>ro-<u>i</u>nflammatory <u>l</u>ncRNA, <i>Maclpil</i>. Using cultured macrophages polarized by LPS, M(LPS), we found that downregulation of <i>Maclpil</i> in M(LPS) decreased pro-inflammatory gene expression while promoting anti-inflammatory gene expression. <i>Maclpil</i> inhibition also reduced the migration and phagocytosis ability of MoDMs by inhibiting <i>LCP1</i>. Furthermore, adoptive transfer of <i>Maclpil</i> silenced M(LPS), reduced ischemic brain infarction, improved behavioral performance and attenuated penetration of MoDMs in the ischemic hemisphere. We conclude that by blocking macrophage, <i>Maclpil</i> protects against acute ischemic stroke by inhibiting neuroinflammation.