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Cl− movement and Cl−-sensitive signal pathways contributes to the survival and switch of inflammatory phenotype of microglia and are believed to play a key role in the inflammatory brain injury after ischemic stroke. Here, we demonstrated an important role of Cl− transmembrane transporter Swell1, in the survival and M2-like polarization of microglia in ischemic stroke. Knockdown or overexpression of Swell1 in cultured microglia inhibited or increased hypotonic-activated Cl− currents, respectively, and these changes were completely blocked by the volume-regulated anion channels (VRACs) inhibitor DCPIB. Swell1 conditional knock-in mice promoted microglia survival in ischemic brain region and resulted in significant reductions in neural cell death, infarction volume and neurological deficits following transient middle cerebral artery occlusion (tMCAO). Using gene manipulating technique and pharmacological inhibitors, we further revealed that Swell1 opening led to SGK1 (a Cl−-sensitive kinase)-mediated activation of FOXO3a/CREB as well as WNK1 (another Cl−-sensitive kinase)-mediated SPAK/OSR1-CCCs activation, which promoted microglia survival and M2-like polarization, thereby attenuating neuroinflammation and ischemic brain injury. Taken together, our results demonstrated that Swell1 is an essential component of microglia VRACs and its activation protects against ischemic brain injury through promoting microglia survival and M2-like polarization.

Chondrocyte hypertrophy is a significant factor in cartilage development, yet the molecular mechanism for cell volume expand during the process is remains unclear. In the present study, the relationship between Swell1, a cell volume regulated anion channel, and chondrocyte hypertrophy was explored. The results reveal that the spatiotemporal expression of Swell1 was similar with the development process of hypertrophic chondrocytes in condyles. Through Col10a1 mediated knock out of Swell1 in hypertrophy chondrocytes, we found that there are less obvious boundary between different condylar cartilage layers in which increased hypertrophic chondrocytes were scattered in all three cartilage layers. The cortical bone mass and bone mineral density in the subchondral bone significantly increased. Additionally, knock out of Swell1 could increase the expression of OCN in the femur condyle. Based on the aforementioned findings, a conclusion could be drawn that Swell1 is a significant factor in chondrocyte hypertrophy during the condylar osteochondral development process, and there was some difference between the mandibular and femur condyles, which will provide some new clues for understanding the development of cartilage and related diseases., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)