TLR2/caspase-5/Panx1 pathway mediates necrosis-induced NLRP3 inflammasome activation in macrophages during acute kidney injury
Abstract Acute kidney injury (AKI) is characterized by necroinflammation formed by necrotic tubular epithelial cells (TECs) and interstitial inflammation. In necroinflammation, macrophages are key inflammatory cells and can be activated and polarized into proinflammatory macrophages. Membranous Toll...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-022-01032-2 |
| _version_ | 1828366730859118592 |
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| author | Chongbin Liu Yanting Shen Liuwei Huang Jun Wang |
| author_facet | Chongbin Liu Yanting Shen Liuwei Huang Jun Wang |
| author_sort | Chongbin Liu |
| collection | DOAJ |
| description | Abstract Acute kidney injury (AKI) is characterized by necroinflammation formed by necrotic tubular epithelial cells (TECs) and interstitial inflammation. In necroinflammation, macrophages are key inflammatory cells and can be activated and polarized into proinflammatory macrophages. Membranous Toll-like receptors (TLRs) can cooperate with intracellular NOD-like receptor protein 3 (NLRP3) to recognize danger signals from necrotic TECs and activate proinflammatory macrophages by assembling NLRP3 inflammasome. However, the cooperation between TLRs and NLRP3 is still unclear. Using conditioned medium from necrotic TECs, we confirmed that necrotic TECs could release danger signals to activate NLRP3 inflammasome in macrophages. We further identified that necrotic TECs-induced NLRP3 inflammasome activation was dependent on ATP secretion via Pannexin-1 (Panx1) channel in macrophages. Next, we verified that TLR2 was required for the activation of Panx1 and NLRP3 in macrophages. Mechanistically, we indicated that caspase-5 mediated TLR2-induced Panx1 activation. In addition, we showed that necrotic TECs-induced activation of TLR2/caspase-5/Panx1 axis could be decreased in macrophages when TECs was protected by N-acetylcysteine (NAC). Overall, we demonstrate that danger signals from necrotic TECs could activate NLRP3 inflammasome in macrophages via TLR2/caspase-5/Panx1 axis during AKI. |
| first_indexed | 2024-04-14T05:48:57Z |
| format | Article |
| id | doaj.art-c0b5778d01e84daeae69780e49854080 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-14T05:48:57Z |
| publishDate | 2022-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-c0b5778d01e84daeae69780e498540802022-12-22T02:09:11ZengNature Publishing GroupCell Death Discovery2058-77162022-04-018111310.1038/s41420-022-01032-2TLR2/caspase-5/Panx1 pathway mediates necrosis-induced NLRP3 inflammasome activation in macrophages during acute kidney injuryChongbin Liu0Yanting Shen1Liuwei Huang2Jun Wang3Clinical Research Center of Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical UniversityClinical Research Center of Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical UniversityClinical Research Center of Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical UniversityClinical Research Center of Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical UniversityAbstract Acute kidney injury (AKI) is characterized by necroinflammation formed by necrotic tubular epithelial cells (TECs) and interstitial inflammation. In necroinflammation, macrophages are key inflammatory cells and can be activated and polarized into proinflammatory macrophages. Membranous Toll-like receptors (TLRs) can cooperate with intracellular NOD-like receptor protein 3 (NLRP3) to recognize danger signals from necrotic TECs and activate proinflammatory macrophages by assembling NLRP3 inflammasome. However, the cooperation between TLRs and NLRP3 is still unclear. Using conditioned medium from necrotic TECs, we confirmed that necrotic TECs could release danger signals to activate NLRP3 inflammasome in macrophages. We further identified that necrotic TECs-induced NLRP3 inflammasome activation was dependent on ATP secretion via Pannexin-1 (Panx1) channel in macrophages. Next, we verified that TLR2 was required for the activation of Panx1 and NLRP3 in macrophages. Mechanistically, we indicated that caspase-5 mediated TLR2-induced Panx1 activation. In addition, we showed that necrotic TECs-induced activation of TLR2/caspase-5/Panx1 axis could be decreased in macrophages when TECs was protected by N-acetylcysteine (NAC). Overall, we demonstrate that danger signals from necrotic TECs could activate NLRP3 inflammasome in macrophages via TLR2/caspase-5/Panx1 axis during AKI.https://doi.org/10.1038/s41420-022-01032-2 |
| spellingShingle | Chongbin Liu Yanting Shen Liuwei Huang Jun Wang TLR2/caspase-5/Panx1 pathway mediates necrosis-induced NLRP3 inflammasome activation in macrophages during acute kidney injury Cell Death Discovery |
| title | TLR2/caspase-5/Panx1 pathway mediates necrosis-induced NLRP3 inflammasome activation in macrophages during acute kidney injury |
| title_full | TLR2/caspase-5/Panx1 pathway mediates necrosis-induced NLRP3 inflammasome activation in macrophages during acute kidney injury |
| title_fullStr | TLR2/caspase-5/Panx1 pathway mediates necrosis-induced NLRP3 inflammasome activation in macrophages during acute kidney injury |
| title_full_unstemmed | TLR2/caspase-5/Panx1 pathway mediates necrosis-induced NLRP3 inflammasome activation in macrophages during acute kidney injury |
| title_short | TLR2/caspase-5/Panx1 pathway mediates necrosis-induced NLRP3 inflammasome activation in macrophages during acute kidney injury |
| title_sort | tlr2 caspase 5 panx1 pathway mediates necrosis induced nlrp3 inflammasome activation in macrophages during acute kidney injury |
| url | https://doi.org/10.1038/s41420-022-01032-2 |
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