KCNJ2 is Required for NLRP3 Inflammasome Activation That Drives Allergic Airway Inflammation and Remodeling
Source abstract
Abstract
ABSTRACT Airway inflammation and remodeling are cardinal features of asthma pathogenesis. Genome‐wide association studies have shown that several SNPs of KCNJ2 , a member of the inwardly rectifying potassium channel family, are associated with asthma in patients. However, the role of KCNJ2 in airway inflammation and remodeling in asthma remains unknown. Here, we demonstrate that the Kcnj2 serves as a critical regulator of airway epithelial inflammation and remodeling. KCNJ2 expression is significantly reduced in the airway epithelium of asthmatic patients, which is associated with goblet cell metaplasia and mucus overproduction. Epithelial cell depletion of Kcnj2 attenuates airway inflammation, Th2 inflammatory response, goblet cell metaplasia, and mucus overproduction in the airways of asthmatic mice. In cultured primary airway epithelial cells of asthmatic patients, KCNJ2 inhibition also hampers goblet cell metaplasia, mucus production, and lung epithelial cell‐derived alarmins expression. This process appears to be mediated, at least in part, through inhibition of NLRP3 by restricting Ca 2+ influx and K + efflux, as pharmacological activation of NLRP3 diminishes the KCNJ2 inhibition‐ameliorated airway phenotypes. These results provide insight into the role of Kcnj2 in airway inflammation and remodeling in asthmatic conditions.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Ion Channels and Receptors · Ion channel regulation and function · Asthma and respiratory diseases
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease National Center for Respiratory Medicine Joint International Research Laboratory of Respiratory Health Guangdong Basic Research Center of Excellence for Respiratory Medicine Guangzhou Institute of Respiratory Health Guangzhou National Laboratory China‐Portugal Artificial Intelligence and Public Health Technologies Joint Laboratory the First Affiliated Hospital of Guangzhou Medical University ...
Guangzhou National Laboratory Guangzhou International Bio Island Guangzhou Guangdong P. R. China
China‐Portugal Artificial Intelligence and Public Health Technologies Joint Laboratory Guangdong‐Hong Kong‐Macao Joint Laboratory of Respiratory Infectious Diseases Guangdong Provincial Key Laboratory of Respiratory Disease Research Guangzhou Medical University Guangzhou Guangdong P. R. China
Key Laboratory of Biological Targeting Diagnosis Therapy and Rehabilitation of Guangdong Higher Education Institutes the Fifth Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong P. R. China
Funding
National Natural Science Foundation of China
References (74)
Show source-provided references
1. 10.1016/j.eclinm.2023.10193610.1016/j.eclinm.2023.101936 ↗
2. 10.3109/02770903.2012.73826810.3109/02770903.2012.738268 ↗
3. 10.1038/nrdp.2015.2510.1038/nrdp.2015.25 ↗
4. 10.1164/ajrccm.164.supplement_2.210606610.1164/ajrccm.164.supplement_2.2106066 ↗
5. 10.1016/j.immuni.2019.03.01810.1016/j.immuni.2019.03.018 ↗
6. SPDEF Is Required for Mouse Pulmonary Goblet Cell Differentiation and Regulates a Network of Genes Associated With Mucus Production
7. 10.1164/rccm.200811‐1768OC10.1164/rccm.200811‐1768OC ↗
8. 10.1172/JCI7942210.1172/JCI79422 ↗
9. 10.1128/MCB.00934‐1210.1128/MCB.00934‐12 ↗
10. 10.1096/fj.201600954r10.1096/fj.201600954r ↗
11. 10.1164/rccm.201101-0106OC10.1164/rccm.201101-0106OC ↗
12. 10.1126/scisignal.aai858310.1126/scisignal.aai8583 ↗
13. 10.1038/s41423‐019‐0210‐810.1038/s41423‐019‐0210‐8 ↗
14. 10.1016/j.cell.2021.02.01610.1016/j.cell.2021.02.016 ↗
15. 10.1242/dev.07859210.1242/dev.078592 ↗
16. 10.1016/j.ydbio.2018.02.01210.1016/j.ydbio.2018.02.012 ↗
17. 10.1038/s41467‐018‐05043‐510.1038/s41467‐018‐05043‐5 ↗
18. 10.1371/journal.pgen.100309810.1371/journal.pgen.1003098 ↗
19. 10.1038/ng.301110.1038/ng.3011 ↗
20. 10.1183/13993003.02693‐202010.1183/13993003.02693‐2020 ↗
21. 10.1038/s41421‐020‐0167‐x10.1038/s41421‐020‐0167‐x ↗
22. 10.1038/s41577‐019‐0165‐010.1038/s41577‐019‐0165‐0 ↗
23. 10.1038/nrd.2018.9710.1038/nrd.2018.97 ↗
24. 10.1183/09031936.0010501310.1183/09031936.00105013 ↗
25. 10.1016/j.jaci.2018.04.03710.1016/j.jaci.2018.04.037 ↗
26. 10.1111/j.1398‐9995.2011.02586.x10.1111/j.1398‐9995.2011.02586.x ↗
27. 10.4049/jimmunol.160003510.4049/jimmunol.1600035 ↗
28. 10.1164/rccm.201609‐1830OC10.1164/rccm.201609‐1830OC ↗
29. 10.1038/s41385‐019‐0181‐110.1038/s41385‐019‐0181‐1 ↗
30. 10.1016/j.jaci.2019.05.00610.1016/j.jaci.2019.05.006 ↗
31. 10.1016/j.immuni.2013.05.01610.1016/j.immuni.2013.05.016 ↗
32. 10.1016/j.immuni.2018.04.03210.1016/j.immuni.2018.04.032 ↗
33. 10.1002/glia.2417410.1002/glia.24174 ↗
34. 10.7554/eLife.8384210.7554/eLife.83842 ↗
35. 10.1038/nature1158810.1038/nature11588 ↗
36. 10.1126/sciadv.abf446810.1126/sciadv.abf4468 ↗
37. 10.3389/fcell.2021.79613610.3389/fcell.2021.796136 ↗
38. 10.1016/j.stem.2024.03.00410.1016/j.stem.2024.03.004 ↗
39. 10.1152/ajpcell.00901.202410.1152/ajpcell.00901.2024 ↗
40. 10.1038/s41467‐022‐31149‐y10.1038/s41467‐022‐31149‐y ↗
41. 10.1242/dev.19980410.1242/dev.199804 ↗
42. 10.1038/s41577‐018‐0006‐610.1038/s41577‐018‐0006‐6 ↗
43. 10.1016/j.jaci.2014.06.03610.1016/j.jaci.2014.06.036 ↗
44. 10.1016/j.chom.2020.02.00610.1016/j.chom.2020.02.006 ↗
45. 10.1371/journal.pone.013146110.1371/journal.pone.0131461 ↗
46. 10.1038/ncomms728110.1038/ncomms7281 ↗
47. 10.1016/j.neuron.2017.12.00210.1016/j.neuron.2017.12.002 ↗
48. 10.1021/cb200146a10.1021/cb200146a ↗
49. 10.1186/s12985-024-02575-910.1186/s12985-024-02575-9 ↗
50. 10.1128/JVI.75.14.6615‐6624.200110.1128/JVI.75.14.6615‐6624.2001 ↗
51. 10.1111/all.1220210.1111/all.12202 ↗
52. 10.1016/j.molimm.2022.11.01110.1016/j.molimm.2022.11.011 ↗
53. 10.1038/sj.cdd.440219510.1038/sj.cdd.4402195 ↗
54. 10.1165/rcmb.2011‐0031OC10.1165/rcmb.2011‐0031OC ↗
55. 10.1038/nmat435710.1038/nmat4357 ↗
56. 10.1038/nm.380610.1038/nm.3806 ↗
57. 10.31083/j.fbl290205810.31083/j.fbl2902058 ↗
58. 10.1111/all.1527910.1111/all.15279 ↗
59. 10.1165/rcmb.2006‐0180OC10.1165/rcmb.2006‐0180OC ↗
60. 10.1165/rcmb.2015‐0227OC10.1165/rcmb.2015‐0227OC ↗
61. 10.1016/j.celrep.2020.10787210.1016/j.celrep.2020.107872 ↗
62. 10.1111/j.1476‐5381.2009.00362.x10.1111/j.1476‐5381.2009.00362.x ↗
63. 10.1165/rcmb.2012‐0103OC10.1165/rcmb.2012‐0103OC ↗
64. 10.1074/jbc.M113.51703710.1074/jbc.M113.517037 ↗
65. 10.1016/j.jaci.2009.11.01810.1016/j.jaci.2009.11.018 ↗
66. 10.1038/tpj.2015.6510.1038/tpj.2015.65 ↗
67. 10.1152/ajplung.90525.200810.1152/ajplung.90525.2008 ↗
68. 10.1038/s41564‐021‐01049‐w10.1038/s41564‐021‐01049‐w ↗
69. 10.1074/jbc.273.35.2280710.1074/jbc.273.35.22807 ↗
70. 10.1161/CIRCRESAHA.107.16829410.1161/CIRCRESAHA.107.168294 ↗
71. 10.1093/cvr/cvt10310.1093/cvr/cvt103 ↗
72. 10.1002/cne.2152910.1002/cne.21529 ↗
73. 10.1038/s41423‐023‐01079‐w10.1038/s41423‐023‐01079‐w ↗
74. 10.1186/1465‐9921‐10‐6110.1186/1465‐9921‐10‐61 ↗