Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage
Che-Feng Chang, … , J. Christopher Love, Lauren H. Sansing
Che-Feng Chang, … , J. Christopher Love, Lauren H. Sansing
Published December 18, 2017
Citation Information: J Clin Invest. 2018;128(2):607-624. https://doi.org/10.1172/JCI95612.
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Research Article Inflammation Neuroscience

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

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.

Authors

Che-Feng Chang, Brittany A. Goods, Michael H. Askenase, Matthew D. Hammond, Stephen C. Renfroe, Arthur F. Steinschneider, Margaret J. Landreneau, Youxi Ai, Hannah E. Beatty, Luís Henrique Angenendt da Costa, Matthias Mack, Kevin N. Sheth, David M. Greer, Anita Huttner, Daniel Coman, Fahmeed Hyder, Sourav Ghosh, Carla V. Rothlin, J. Christopher Love, Lauren H. Sansing

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Figure 1

MDMs contribute to hematoma clearance and functional recovery after ICH.

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MDMs contribute to hematoma clearance and functional recovery after ICH....
(A) Left: Representative brain coronal sections show hematoma from WT and Ccr2–/– bone marrow chimeras (BMCs) at days 7 and 15 after ICH. Right: Quantification of residual hematoma volume in the WT and Ccr2–/– BMCs. n = 11 at day 7; n = 9 at day 15. *P < 0.05 by Student’s t test. (B) Cylinder test and apomorphine turning test from WT and Ccr2–/– BMCs at day 15 after ICH. n = 6/group for cylinder test; n = 8/group for apomorphine turning test. *P < 0.05 by Student’s t test. (C) Cylinder test, neurological deficit score, and corner test in control- and anti-CCR2 antibody–treated mice at days 1 and 3 after collagenase ICH. n = 7/group. *P < 0.05 by 1-way repeated-measures ANOVA and Bonferroni’s post hoc test. (D) Top: Representative coronal sections show hematoma from control- and anti-CCR2 antibody–treated WT mice after blood injection ICH at 7 days. Bottom: Quantification of hematoma volume, n = 3/ group. *P < 0.05 versus control by Student’s t test. (E) Top: Representative coronal sections show hematoma in the isotype control– and anti-CCR2 antibody–treated mice from collagenase model at day 12. Bottom: Quantification of hematoma volume. n = 8/group. *P < 0.05 versus control by Student’s t test. (F) The cylinder test, neurological deficit score, and corner test in isotype control– and anti-CCR2 antibody–treated ICH mice at days 3, 5, 7, 9, and 11 after collagenase ICH surgery. n = 8/group. *P < 0.05 versus isotype control group by 1-way repeated-measures ANOVA and Bonferroni’s post hoc test. αCCR2, anti-CCR2 antibody.