CoChat
Sign Up
Cited by 18Neuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and TreatmentsAcute Ischemic Stroke Management

Activation of Swell1 in microglia suppresses neuroinflammation and reduces brain damage in ischemic stroke

Open access
Chen, Baoyi, Xie, Cong, Shi, Tengrui, Yue, Shiqin, Li, Weiping, Huang, Guodong, Zhang, Yuan, Liu, Wenlan·2023·Neurobiology of Disease
DOI 10.1016/j.nbd.2022.105936
Open this paper in CoChat — free account

Abstract

Abstract Background Neuroinflammation and immune responses mediated by microglia are associated with brain injury after ischemic stroke, and it is novel that Cl− movement and Cl-sensitive signal pathways have been shown to be implicated in the survival and switch of inflammation patterns of immune cells. Swell1, one of the components of Volume-regulated Cl− currents (VRAC) is considered to be the main channels mediating Cl− efflux from nerves cells. However, the role of Swell11 in ischemia-induced inflammation and the effect of Swell1 on the inflammation patterns switch of microglia remain unknown. Methods Whole-cell patch clamp recordings was used to examine Swell1-mediated VRAC in BV2 cells. In vivo and vitro studies comparing EGFP and Swell1 conditional knock-in mice were performed to determine the role of microglia Swell1 on inflammation and brain injury after ischemic stroke. In vitro experiments to further explored the mechanism of microglia Swell1 in regulating neuroinflammation. Results Our data showed that knockdown or overexpression of Swell1 in cultured BV2 cells inhibited or increased hypotonic-activated Cl− currents, respectively, and these changes were completely blocked by the VRAC inhibitor DCPIB. Swell1 conditional knock-in mice promoted microglial survival in the lesion region, leading to reductions in neural cell apoptosis, infarction size 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 microglial survival and M2 polarization, thereby attenuating inflammation and ischemic brain injury. Conclusion Our results demonstrated that Swell1 is an essential component of microglia VRAC and its activation protects against ischemic brain injury through promoting microglial survival and M2 polarization, which provides new a new orientation for the treatment of ischemic stroke and other neurological diseases associated with inflammation.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.nbd.2022.105936

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • SGK1 facilitates M2 microglial polarization and aids in reducing post-ischemic microglial proliferation, diminishing neuroinflammation by activating SGK1-CREB-FOXO3a pathway.

    “SGK1 facilitates M2 microglial polarization and aids in reducing post-ischemic microglial proliferation, diminishing neuroinflammation by activating the SGK1-CREB-FOXO3a pathway”

    From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Chen et al., 2023

    The Results (p. 11) report that Swell1 overexpression promotes M2 microglial polarization and reduces inflammatory factors after ischemic stroke. But the Discussion (p. 16) says Swell1 promotes—not reduces—resident microglial proliferation through the SGK1–CREB–FOXO3a pathway. The claim reverses that proliferation finding and attributes the broader effects to SGK1 alone rather than Swell1 activation. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 49

  1. [1]1. Campbell, B. C. V.et al. Ischaemic stroke. Nat Rev Dis Primers 5, 70, doi:10.1038/s41572-019-0118-8 (2019). · DOI
  2. [2]2. Lipton, P . Ischemic cell death in brain neurons. Physiol Rev 79, 1431-1568, doi:10.1152/physrev.1999.79.4.1431 (1999). · DOI · Paper page
  3. [3]3. Iadecola, C. & Anrather, J. The immunology of stroke: from mechanisms to translation. Nat Med 17, 796-808, doi:10.1038/nm.2399 (2011). · DOI · Paper page
  4. [4]4. Fu, Y., Liu, Q., Anrather, J. & Shi, F. D. Immune interventions in stroke. Nat Rev Neurol 11, 524-535, doi:10.1038/nrneurol.2015.144 (2015). · DOI
  5. [5]5. Kim, E. & Cho, S. Microglia and Monocyte-Derived Macrophages in Stroke. Neurotherapeutics 13, 702-718, doi:10.1007/s13311-016-0463-1 (2016). · DOI
  6. [6]6. Petrovic-Djergovic, D., Goonewardena, S. N. & Pinsky, D. J. Inflammatory Disequilibrium in Stroke. Circ Res 119, 142-158, doi:10.1161/CIRCRESAHA.116.308022 (2016). · DOI
  7. [7]7. Ma, Y., Wang, J., Wang, Y. & Yang, G. Y. The biphasic function of microglia in ischemic stroke. Prog Neurobiol 157, 247-272, doi:10.1016/j.pneurobio.2016.01.005 (2017). · DOI
  8. [8]8. Hu, X.et al. Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol 11, 56-64, doi:10.1038/nrneurol.2014.207 (2015). · DOI
  9. [9]9. Lyu, J.et al. Microglial/Macrophage polarization and function in brain injury and repair after stroke. CNS Neurosci Ther 27, 515-527, doi:10.1111/cns.13620 (2021). · DOI
  10. [10]10. Lalancette-Hebert, M., Gowing, G., Simard, A., Weng, Y. C. & Kriz, J. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 27, 2596-2605, doi:10.1523/JNEUROSCI.5360-06.2007 (2007). · DOI · Paper page
  11. [11]11. Rudolph, M.et al. Microglia-mediated phagocytosis of apoptotic nuclei is impaired in the adult murine hippocampus after stroke. Glia 69, 2006-2022, doi:10.1002/glia.24009 (2021). · DOI
  12. [12]12. Salter, M. W. & Stevens, B. Microglia emerge as central players in brain disease. Nat Med 23, 10181027, doi:10.1038/nm.4397 (2017). · DOI · Paper page
  13. [13]13. Arandjelovic, S. & Ravichandran, K. S. Phagocytosis of apoptotic cells in homeostasis. Nat Immunol 16, 907-917, doi:10.1038/ni.3253 (2015). · DOI · Paper page
  14. [14]14. Rungta, R. L.et al. The cellular mechanisms of neuronal swelling underlying cytotoxic edema. Cell 161, 610-621, doi:10.1016/j.cell.2015.03.029 (2015). · DOI
  15. [15]15. Hoffmann, E. K., Lambert, I. H. & Pedersen, S. F. Physiology of cell volume regulation in vertebrates. Physiol Rev 89, 193-277, doi:10.1152/physrev.00037.2007 (2009). · DOI · Paper page
  16. [16]16. Lahey, L. J.et al. LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters of cGAMP . Mol Cell 80, 578-591 e575, doi:10.1016/j.molcel.2020.10.021 (2020). · DOI
  17. [17]17. Qiu, Z.et al. SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel. Cell 157, 447-458, doi:10.1016/j.cell.2014.03.024 (2014). · DOI · Paper page
  18. [18]18. Green, J. P .et al. LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation. Elife 9, doi:10.7554/eLife.59704 (2020). · DOI
  19. [19]19. Voss, F. K.et al. Identification of LRRC8 heteromers as an essential component of the volumeregulated anion channel VRAC. Science 344, 634-638, doi:10.1126/science.1252826 (2014). · DOI
  20. [20]20. Zhou, J. J.et al. LRRC8A-dependent volume-regulated anion channels contribute to ischemia-induced brain injury and glutamatergic input to hippocampal neurons. Exp Neurol 332, 113391, - doi:10.1016/j.expneurol.2020.113391 (2020). · DOI
  21. [21]21. Yang, J.et al. Glutamate-Releasing SWELL1 Channel in Astrocytes Modulates Synaptic Transmission and Promotes Brain Damage in Stroke. Neuron 102, 813-827 e816, doi:10.1016/j.neuron.2019.03.029 (2019). · DOI
  22. [22]22. Li, P .et al. LRRC8 family proteins within lysosomes regulate cellular osmoregulation and enhance cell survival to multiple physiological stresses. Proc Natl Acad Sci U S A 117, 29155-29165, doi:10.1073/pnas.2016539117 (2020). · DOI
  23. [23]23. Serra, S. A.et al. LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions. Proc Natl Acad Sci U S A 118, doi:10.1073/pnas.2025013118 (2021). · DOI
  24. [25]25. Zhang, Y. J.et al. WNK1 is required for proliferation induced by hypotonic challenge in rat vascular smooth muscle cells. Acta Pharmacol Sin 39, 35-47, doi:10.1038/aps.2017.56 (2018). · DOI
  25. [26]26. Perry, J. S. A.et al. Interpreting an apoptotic corpse as anti-inflammatory involves a chloride sensing pathway. Nat Cell Biol 21, 1532-1543, doi:10.1038/s41556-019-0431-1 (2019). · DOI
  26. [27]27. Longa, E. Z., Weinstein, P . R., Carlson, S. & Cummins, R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20, 84-91, doi:10.1161/01.str.20.1.84 (1989). · DOI · Paper page
  27. [28]28. Jin, X.et al. Spatiotemporal evolution of blood brain barrier damage and tissue infarction within the first 3h after ischemia onset. Neurobiol Dis 48, 309-316, doi:10.1016/j.nbd.2012.07.007 (2012). · DOI
  28. [29]29. Sumida, T.et al. Activated beta-catenin in Foxp3(+) regulatory T cells links inflammatory environments to autoimmunity. Nat Immunol 19, 1391-1402, doi:10.1038/s41590-018-0236-6 (2018). · DOI
  29. [30]30. Zhang, Q.et al. Cell cycle inhibition attenuates microglial proliferation and production of IL-1beta, MIP-1alpha, and NO after focal cerebral ischemia in the rat. Glia 57, 908-920, doi:10.1002/glia.20816 (2009). · DOI
  30. [33]33. David, S. & Kalb, R. G. Serum/glucocorticoid-inducible kinase can phosphorylate the cyclic AMP response element binding protein, CREB. FEBS Lett 579, 1534-1538, doi:10.1016/j.febslet.2005.01.040 (2005). · DOI
  31. [34]34. Alessi, D. R.et al. The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters. Sci Signal 7, re3, doi:10.1126/scisignal.2005365 (2014). · DOI
  32. [35]35. Moriguchi, T.et al. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. J Biol Chem 280, 42685-42693, - doi:10.1074/jbc.M510042200 (2005). · DOI
  33. [36]36. Huang, H.et al. The WNK-SPAK/OSR1 Kinases and the Cation-Chloride Cotransporters as Therapeutic Targets for Neurological Diseases. Aging Dis 10, 626-636, doi:10.14336/AD.2018.0928 (2019). · DOI
  34. [37]37. Clauzure, M.et al. NLR family pyrin domain containing 3 (NLRP3) and caspase 1 (CASP1) modulation by intracellular Cl(-) concentration. Immunology 163, 493-511, doi:10.1111/imm.13336 (2021). · DOI
  35. [38]38. Mayes-Hopfinger, L.et al. Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis. Nat Commun 12, 4546, doi:10.1038/s41467-021-24784-4 (2021). · DOI
  36. [39]39. Gagnon, K. B., England, R. & Delpire, E. Characterization of SPAK and OSR1, regulatory kinases of the Na-K-2Cl cotransporter. Mol Cell Biol 26, 689-698, doi:10.1128/MCB.26.2.689-698.2006 (2006). · DOI
  37. [40]40. Hebert, S. C., Mount, D. B. & Gamba, G. Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family. Pflugers Arch 447, 580-593, doi:10.1007/s00424-003-1066-3 (2004). · DOI
  38. [41]41. Lutter, D., Ullrich, F., Lueck, J. C., Kempa, S. & Jentsch, T. J. Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels. J Cell Sci 130, 1122-1133, doi:10.1242/jcs.196253 (2017). · DOI
  39. [42]42. Osei-Owusu, J., Yang, J., Vitery, M. D. C. & Qiu, Z. Molecular Biology and Physiology of VolumeRegulated Anion Channel (VRAC). Curr Top Membr 81, 177-203, doi:10.1016/bs.ctm.2018.07.005 (2018). · DOI
  40. [43]43. Kang, C.et al. SWELL1 is a glucose sensor regulating beta-cell excitability and systemic glycaemia. Nat Commun 9, 367, doi:10.1038/s41467-017-02664-0 (2018). · DOI
  41. [44]44. Kumar, A.et al. SWELL1 regulates skeletal muscle cell size, intracellular signaling, adiposity and glucose metabolism. Elife 9, doi:10.7554/eLife.58941 (2020). · DOI
  42. [45]45. Alghanem, A. F.et al. The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function. Elife 10, doi:10.7554/eLife.61313 (2021). · DOI
  43. [46]46. Barros, L. F., Hermosilla, T. & Castro, J. Necrotic volume increase and the early physiology of necrosis. Comp Biochem Physiol A Mol Integr Physiol 130, 401-409, doi:10.1016/s1095-6433(01)00438-x (2001). · DOI
  44. [47]47. Schilling, M., Strecker, J. K., Ringelstein, E. B., Schabitz, W. R. & Kiefer, R. The role of CC chemokine receptor 2 on microglia activation and blood-borne cell recruitment after transient focal cerebral ischemia in mice. Brain Res 1289, 79-84, doi:10.1016/j.brainres.2009.06.054 (2009). · DOI
  45. [48]48. Priller, J.et al. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med 7, 1356-1361, doi:10.1038/nm1201-1356 (2001). · DOI · Paper page
  46. [49]49. Stoll, G. & Jander, S. The role of microglia and macrophages in the pathophysiology of the CNS. Prog Neurobiol 58, 233-247, doi:10.1016/s0301-0082(98)00083-5 (1999). · DOI
  47. [50]50. Xiong, X. Y., Liu, L. & Yang, Q. W. Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. Prog Neurobiol 142, 23-44, - doi:10.1016/j.pneurobio.2016.05.001 (2016). · DOI
  48. [51]51. Kim, D. H.et al. Early immature neuronal death initiates cerebral ischemia-induced neurogenesis in the dentate gyrus. Neuroscience 284, 42-54, doi:10.1016/j.neuroscience.2014.09.074 (2015). · DOI
  49. [52]52. Chen, B. Y.et al. SGK1 mediates hypotonic challenge-induced proliferation in basilar artery smooth muscle cells via promoting CREB signaling pathway. Eur J Pharmacol 898, 173997, doi:10.1016/j.ejphar.2021.173997 (2021). · DOI

Cited by

Sorted by citations

Authors
Chen, B., Xie, C., Shi, T., Yue, S., Li, W., Huang, G., Zhang, Y., & Liu, W.
Affiliations
Shenzhen University (CN)
Corresponding author
  • Zhang, Yuan
  • Liu, Wenlan
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2023-01
Volume
176
Pages
105936
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2022.105936
OpenAlex
W4310255074
Cited by
18
References
4
Citations by year
2026: 6 · 2025: 4 · 2024: 6 · 2023: 2
FWCI
1.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81760227, 81873747)
  • Natural Science Foundation of Guangdong Province (2019A1515010311)
  • Science, Technology and Innovation Commission of Shenzhen Municipality (GJHZ20190820115001765, JCYJ20210324115601005)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
Keywords
microglia, ischemic stroke, neuroinflammation, chloride currents, volume-regulated anion channel, DCPIB, SGK1, WNK1, CCC, microglial survival, transient middle cerebral artery occlusion, infarct size, neurological deficit
MeSH terms
Ischemic Stroke, Neuroinflammatory Diseases, Animals, Brain, Brain Injuries, Brain Ischemia, Microglia, Infarction, Middle Cerebral Artery, Stroke, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review