Chang, Che-Feng and Goods, Brittany A. and Askenase, Michael H. and Hammond, Matthew D. and Renfroe, Stephen C. and Steinschneider, Arthur F. and Landreneau, Margaret J. and Ai, Youxi and Beatty, Hannah E. and Angenendt da Costa, Luis Henrique and Mack, Matthias and Sheth, Kevin N. and Greer, David M. and Huttner, Anita and Coman, Daniel and Hyder, Fahmeed and Ghosh, Sourav and Rothlin, Carla V. and Love, J. Christopher and Sansing, Lauren H. (2018) Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage. JOURNAL OF CLINICAL INVESTIGATION, 128 (2). pp. 607-624. ISSN 0021-9738, 1558-8238
Full text not available from this repository. (Request a copy)Abstract
Macrophages are a source of both proinflammatory and restorative functions in damaged tissue through complex dynamic phenotypic changes. Here, we sought to determine whether monocyte-derived macrophages (MDMs) contribute to recovery after acute sterile brain injury. By profiling the transcriptional dynamics of MDMs in the murine brain after experimental intracerebral hemorrhage (ICH), we found robust phenotypic changes in the infiltrating MDMs over time and demonstrated that MDMs are essential for optimal hematoma clearance and neurological recovery. Next, we identified the mechanism by which the engulfment of erythrocytes with exposed phosphatidylserine directly modulated the phenotype of both murine and human MDMs. In mice, loss of receptor tyrosine kinases AXL and MERTK reduced efferocytosis of eryptotic erythrocytes and hematoma clearance, worsened neurological recovery, exacerbated iron deposition, and decreased alternative activation of macrophages after ICH. Patients with higher circulating soluble AXL had poor 1-year outcomes after ICH onset, suggesting that therapeutically augmenting efferocytosis may improve functional outcomes by both reducing tissue injury and promoting the development of reparative macrophage responses. Thus, our results identify the efferocytosis of eryptotic erythrocytes through AXL/MERTK as a critical mechanism modulating macrophage phenotype and contributing to recovery from ICH.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RECEPTOR TYROSINE KINASE; RED-BLOOD-CELLS; APOPTOTIC CELLS; DENDRITIC CELLS; BRAIN-INJURY; HEMATOMA RESOLUTION; TAM RECEPTORS; PROTEIN-S; MONOCYTES; PHOSPHATIDYLSERINE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Nephrologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Mar 2020 08:48 |
| Last Modified: | 19 Mar 2020 08:48 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15122 |
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