B cells mediate lung ischemia/reperfusion injury by recruiting classical monocytes via synergistic B cell receptor/TLR4 signaling
Ischemia/reperfusion injury-mediated (IRI-mediated) primary graft dysfunction (PGD) adversely affects both short- and long-term outcomes after lung transplantation, a procedure that remains the only treatment option for patients suffering from end-stage respiratory failure. While B cells are known to regulate adaptive immune responses, their role in lung IRI is not well understood. Here, we demonstrated by intravital imaging that B cells are rapidly recruited to injured lungs, where they extravasate into the parenchyma. Using hilar clamping and transplant models, we observed that lung-infiltrating B cells produce the monocyte chemokine CCL7 in a TLR4-TRIF-dependent fashion, a critical step contributing to classical monocyte (CM) recruitment and subsequent neutrophil extravasation, resulting in worse lung function. We found that synergistic BCR-TLR4 activation on B cells is required for the recruitment of CMs to the injured lung. Finally, we corroborated our findings in reperfused human lungs, in which we observed a correlation between B cell infiltration and CM recruitment after transplantation. This study describes a role for B cells as critical orchestrators of lung IRI. As B cells can be depleted with currently available agents, our study provides a rationale for clinical trials investigating B cell-targeting therapies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:134 |
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| Enthalten in: |
The Journal of clinical investigation - 134(2024), 6 vom: 23. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Farahnak, Khashayar [VerfasserIn] |
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| Links: |
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| Themen: |
Chemokines |
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| Anmerkungen: |
Date Completed 18.03.2024 Date Revised 18.03.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/JCI170118 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369776968 |
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| 100 | 1 | |a Farahnak, Khashayar |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a B cells mediate lung ischemia/reperfusion injury by recruiting classical monocytes via synergistic B cell receptor/TLR4 signaling |
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| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Ischemia/reperfusion injury-mediated (IRI-mediated) primary graft dysfunction (PGD) adversely affects both short- and long-term outcomes after lung transplantation, a procedure that remains the only treatment option for patients suffering from end-stage respiratory failure. While B cells are known to regulate adaptive immune responses, their role in lung IRI is not well understood. Here, we demonstrated by intravital imaging that B cells are rapidly recruited to injured lungs, where they extravasate into the parenchyma. Using hilar clamping and transplant models, we observed that lung-infiltrating B cells produce the monocyte chemokine CCL7 in a TLR4-TRIF-dependent fashion, a critical step contributing to classical monocyte (CM) recruitment and subsequent neutrophil extravasation, resulting in worse lung function. We found that synergistic BCR-TLR4 activation on B cells is required for the recruitment of CMs to the injured lung. Finally, we corroborated our findings in reperfused human lungs, in which we observed a correlation between B cell infiltration and CM recruitment after transplantation. This study describes a role for B cells as critical orchestrators of lung IRI. As B cells can be depleted with currently available agents, our study provides a rationale for clinical trials investigating B cell-targeting therapies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Chemokines | |
| 650 | 4 | |a Immunology | |
| 650 | 4 | |a Monocytes | |
| 650 | 4 | |a Organ transplantation | |
| 650 | 4 | |a Transplantation | |
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| 650 | 7 | |a Receptors, Antigen, B-Cell |2 NLM | |
| 650 | 7 | |a TLR4 protein, human |2 NLM | |
| 700 | 1 | |a Bai, Yun Zhu |e verfasserin |4 aut | |
| 700 | 1 | |a Yokoyama, Yuhei |e verfasserin |4 aut | |
| 700 | 1 | |a Morkan, Deniz B |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhiyi |e verfasserin |4 aut | |
| 700 | 1 | |a Amrute, Junedh M |e verfasserin |4 aut | |
| 700 | 1 | |a De Filippis Falcon, Alejandro |e verfasserin |4 aut | |
| 700 | 1 | |a Terada, Yuriko |e verfasserin |4 aut | |
| 700 | 1 | |a Liao, Fuyi |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Wenjun |e verfasserin |4 aut | |
| 700 | 1 | |a Shepherd, Hailey M |e verfasserin |4 aut | |
| 700 | 1 | |a Hachem, Ramsey R |e verfasserin |4 aut | |
| 700 | 1 | |a Puri, Varun |e verfasserin |4 aut | |
| 700 | 1 | |a Lavine, Kory J |e verfasserin |4 aut | |
| 700 | 1 | |a Gelman, Andrew E |e verfasserin |4 aut | |
| 700 | 1 | |a Bharat, Ankit |e verfasserin |4 aut | |
| 700 | 1 | |a Kreisel, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Nava, Ruben G |e verfasserin |4 aut | |
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