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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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 6

Efferocytosis modulates human MDM phenotype and is associated with ICH recovery in patients.

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Efferocytosis modulates human MDM phenotype and is associated with ICH r...
(A) Left: Representative immunofluorescence images show engulfment of PHK-26–labeled control erythrocytes (R) and heat-shocked erythrocytes (HS) (red) in thrombin-stimulated CD11b-positive (green) MDMs with or without annexin V incubation. Right: Quantification of erythrophagocytosis. n = 3/group; each independent experiment includes 3 technical replicates. *P < 0.05 versus thrombin+R; #P < 0.05 versus thrombin+HS by 1-way ANOVA and Bonferroni’s post hoc test. (B) Gene expression of TNF and HMOX1 in human macrophages after thrombin, HS, and thrombin+HS stimulation for 3, 6, and 14 hours. n = 3/group. *P < 0.05 versus HS group by 1-way ANOVA and Bonferroni’s post hoc test. (C) TNF and HMOX1 gene expression in human macrophages after thrombin, thrombin+R, and thrombin+HS treatment for 3 hours (TNF) and 6 hours (HMOX1). n = 3/ group. *P < 0.05 versus thrombin group by Student’s t test. (D) Representative immunofluorescence images show MERTK (red), IBA1 (green), and AXL (pink) signals in the day 0 and day 3 ICH patient brain sections, with enlarged and merged image of the boxed area shown for colocalization. An.V, annexin V; C, control; T, thrombin.