Activation of Both TLR and NOD Signaling Confers Host Innate Immunity-Mediated Protection Against Microbial Infection
The detection of microbial pathogens relies on the recognition of highly conserved microbial structures by the membrane sensor Toll-like receptors (TLRs) and cytosolic sensor NOD-like receptors (NLRs). Upon detection, these sensors trigger innate immune responses to eradicate the invaded microbial p...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.03082/full |
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| author | Huiting Zhou Andrew P. Coveney Ming Wu Jie Huang Siobhan Blankson He Zhao D. Peter O'Leary Zhenjiang Bai Yiping Li H. Paul Redmond Jiang Huai Wang Jian Wang Jian Wang |
| author_facet | Huiting Zhou Andrew P. Coveney Ming Wu Jie Huang Siobhan Blankson He Zhao D. Peter O'Leary Zhenjiang Bai Yiping Li H. Paul Redmond Jiang Huai Wang Jian Wang Jian Wang |
| author_sort | Huiting Zhou |
| collection | DOAJ |
| description | The detection of microbial pathogens relies on the recognition of highly conserved microbial structures by the membrane sensor Toll-like receptors (TLRs) and cytosolic sensor NOD-like receptors (NLRs). Upon detection, these sensors trigger innate immune responses to eradicate the invaded microbial pathogens. However, it is unclear whether TLR and NOD signaling are both critical for innate immunity to initiate inflammatory and antimicrobial responses against microbial infection. Here we report that activation of both TLR and NOD signaling resulted in an augmented inflammatory response and the crosstalk between TLR and NOD led to an amplified downstream NF-κB activation with increased nuclear transactivation of p65 at both TNF-α and IL-6 promoters. Furthermore, co-stimulation of macrophages with TLR and NOD agonists maximized antimicrobial activity with accelerated phagosome maturation. Importantly, administration of both TLR and NOD agonists protected mice against polymicrobial sepsis-associated lethality with increased serum levels of inflammatory cytokines and accelerated clearance of bacteria from the circulation and visceral organs. These results demonstrate that activation of both TLR and NOD signaling synergizes to induce efficient inflammatory and antimicrobial responses, thus conferring protection against microbial infection. |
| first_indexed | 2024-12-10T21:32:40Z |
| format | Article |
| id | doaj.art-e912dba1da5d4e21bf02c492fa845a11 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-10T21:32:40Z |
| publishDate | 2019-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-e912dba1da5d4e21bf02c492fa845a112022-12-22T01:32:45ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-01-01910.3389/fimmu.2018.03082425267Activation of Both TLR and NOD Signaling Confers Host Innate Immunity-Mediated Protection Against Microbial InfectionHuiting Zhou0Andrew P. Coveney1Ming Wu2Jie Huang3Siobhan Blankson4He Zhao5D. Peter O'Leary6Zhenjiang Bai7Yiping Li8H. Paul Redmond9Jiang Huai Wang10Jian Wang11Jian Wang12Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, ChinaDepartment of Academic Surgery, University College Cork, Cork University Hospital, Cork, IrelandInstitute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, ChinaInstitute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, ChinaDepartment of Academic Surgery, University College Cork, Cork University Hospital, Cork, IrelandInstitute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, ChinaDepartment of Academic Surgery, University College Cork, Cork University Hospital, Cork, IrelandInstitute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, ChinaInstitute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, ChinaDepartment of Academic Surgery, University College Cork, Cork University Hospital, Cork, IrelandDepartment of Academic Surgery, University College Cork, Cork University Hospital, Cork, IrelandInstitute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, ChinaDepartment of Pediatric Surgery, Children's Hospital of Soochow University, Suzhou, ChinaThe detection of microbial pathogens relies on the recognition of highly conserved microbial structures by the membrane sensor Toll-like receptors (TLRs) and cytosolic sensor NOD-like receptors (NLRs). Upon detection, these sensors trigger innate immune responses to eradicate the invaded microbial pathogens. However, it is unclear whether TLR and NOD signaling are both critical for innate immunity to initiate inflammatory and antimicrobial responses against microbial infection. Here we report that activation of both TLR and NOD signaling resulted in an augmented inflammatory response and the crosstalk between TLR and NOD led to an amplified downstream NF-κB activation with increased nuclear transactivation of p65 at both TNF-α and IL-6 promoters. Furthermore, co-stimulation of macrophages with TLR and NOD agonists maximized antimicrobial activity with accelerated phagosome maturation. Importantly, administration of both TLR and NOD agonists protected mice against polymicrobial sepsis-associated lethality with increased serum levels of inflammatory cytokines and accelerated clearance of bacteria from the circulation and visceral organs. These results demonstrate that activation of both TLR and NOD signaling synergizes to induce efficient inflammatory and antimicrobial responses, thus conferring protection against microbial infection.https://www.frontiersin.org/article/10.3389/fimmu.2018.03082/fullTLR signalingNOD signalinginflammatory responseantimicrobial activityNF-κB pathwayphagosome maturation |
| spellingShingle | Huiting Zhou Andrew P. Coveney Ming Wu Jie Huang Siobhan Blankson He Zhao D. Peter O'Leary Zhenjiang Bai Yiping Li H. Paul Redmond Jiang Huai Wang Jian Wang Jian Wang Activation of Both TLR and NOD Signaling Confers Host Innate Immunity-Mediated Protection Against Microbial Infection Frontiers in Immunology TLR signaling NOD signaling inflammatory response antimicrobial activity NF-κB pathway phagosome maturation |
| title | Activation of Both TLR and NOD Signaling Confers Host Innate Immunity-Mediated Protection Against Microbial Infection |
| title_full | Activation of Both TLR and NOD Signaling Confers Host Innate Immunity-Mediated Protection Against Microbial Infection |
| title_fullStr | Activation of Both TLR and NOD Signaling Confers Host Innate Immunity-Mediated Protection Against Microbial Infection |
| title_full_unstemmed | Activation of Both TLR and NOD Signaling Confers Host Innate Immunity-Mediated Protection Against Microbial Infection |
| title_short | Activation of Both TLR and NOD Signaling Confers Host Innate Immunity-Mediated Protection Against Microbial Infection |
| title_sort | activation of both tlr and nod signaling confers host innate immunity mediated protection against microbial infection |
| topic | TLR signaling NOD signaling inflammatory response antimicrobial activity NF-κB pathway phagosome maturation |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.03082/full |
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