Diverse Injury Pathways Induce Alveolar Epithelial Cell CCL2/12, Which Promotes Lung Fibrosis
Accumulating evidence suggests that fibrosis is a multicellular process with contributions from alveolar epithelial cells (AECs), recruited monocytes/macrophages, and fibroblasts. We have previously shown that AEC injury is sufficient to induce fibrosis, but the precise mechanism remains unclear. Several cell types, including AECs, can produce CCL2 and CCL12, which can promote fibrosis through CCR2 activation. CCR2 signaling is critical for the initiation and progression of pulmonary fibrosis, in part through recruitment of profibrotic bone marrow-derived monocytes. Attempts at inhibiting CCL2 in patients with fibrosis demonstrated a marked upregulation of CCL2 production and no therapeutic response. To better understand the mechanisms involved in CCL2/CCR2 signaling, we generated mice with conditional deletion of CCL12, a murine homolog of human CCL2. Surprisingly, we found that mice with complete deletion of CCL12 had markedly increased concentrations of other CCR2 ligands and were not protected from fibrosis after bleomycin injury. In contrast, mice with lung epithelial cell-specific deletion of CCL12 were protected from bleomycin-induced fibrosis and had expression of CCL2 and CCL7 similar to that of control mice treated with bleomycin. Deletion of CCL12 within AECs led to decreased recruitment of exudate macrophages. Finally, injury to murine and human primary AECs resulted in increased production of CCL2 and CCL12, in part through activation of the mTOR pathway. In conclusion, these data suggest that targeting CCL2 may be a viable antifibrotic strategy once the pathways involved in the production and function of CCL2 and other CCR2 ligands are better defined.
| Errataetall: |
CommentIn: Am J Respir Cell Mol Biol. 2020 May;62(5):546-547. - PMID 31951476 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:62 |
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| Enthalten in: |
American journal of respiratory cell and molecular biology - 62(2020), 5 vom: 25. Mai, Seite 622-632 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Jibing [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.07.2020 Date Revised 16.07.2022 published: Print CommentIn: Am J Respir Cell Mol Biol. 2020 May;62(5):546-547. - PMID 31951476 Citation Status MEDLINE |
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| doi: |
10.1165/rcmb.2019-0297OC |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM305220993 |
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| 245 | 1 | 0 | |a Diverse Injury Pathways Induce Alveolar Epithelial Cell CCL2/12, Which Promotes Lung Fibrosis |
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| 500 | |a published: Print | ||
| 500 | |a CommentIn: Am J Respir Cell Mol Biol. 2020 May;62(5):546-547. - PMID 31951476 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Accumulating evidence suggests that fibrosis is a multicellular process with contributions from alveolar epithelial cells (AECs), recruited monocytes/macrophages, and fibroblasts. We have previously shown that AEC injury is sufficient to induce fibrosis, but the precise mechanism remains unclear. Several cell types, including AECs, can produce CCL2 and CCL12, which can promote fibrosis through CCR2 activation. CCR2 signaling is critical for the initiation and progression of pulmonary fibrosis, in part through recruitment of profibrotic bone marrow-derived monocytes. Attempts at inhibiting CCL2 in patients with fibrosis demonstrated a marked upregulation of CCL2 production and no therapeutic response. To better understand the mechanisms involved in CCL2/CCR2 signaling, we generated mice with conditional deletion of CCL12, a murine homolog of human CCL2. Surprisingly, we found that mice with complete deletion of CCL12 had markedly increased concentrations of other CCR2 ligands and were not protected from fibrosis after bleomycin injury. In contrast, mice with lung epithelial cell-specific deletion of CCL12 were protected from bleomycin-induced fibrosis and had expression of CCL2 and CCL7 similar to that of control mice treated with bleomycin. Deletion of CCL12 within AECs led to decreased recruitment of exudate macrophages. Finally, injury to murine and human primary AECs resulted in increased production of CCL2 and CCL12, in part through activation of the mTOR pathway. In conclusion, these data suggest that targeting CCL2 may be a viable antifibrotic strategy once the pathways involved in the production and function of CCL2 and other CCR2 ligands are better defined | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a CCL12 | |
| 650 | 4 | |a CCL2 | |
| 650 | 4 | |a alveolar epithelial cell | |
| 650 | 4 | |a fibrosis | |
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| 650 | 7 | |a TOR Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 700 | 1 | |a Agarwal, Manisha |e verfasserin |4 aut | |
| 700 | 1 | |a Ling, Song |e verfasserin |4 aut | |
| 700 | 1 | |a Teitz-Tennenbaum, Seagal |e verfasserin |4 aut | |
| 700 | 1 | |a Zemans, Rachel L |e verfasserin |4 aut | |
| 700 | 1 | |a Osterholzer, John J |e verfasserin |4 aut | |
| 700 | 1 | |a Sisson, Thomas H |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Kevin K |e verfasserin |4 aut | |
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