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Published on: October 4, 2021
Efferocytes release extracellular vesicles to resolve inflammation and tissue injury via prosaposin-GPR37 signaling
Purbasha Bhattacharya1, Umesh Kumar Dhawan2, Mohammed Tayab Hussain2
1CSIR - Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
Abstract:
Macrophages release soluble mediators following efferocytic clearance of apoptotic cells to facilitate intercellular communication and promote the resolution of inflammation. However, whether inflammation resolution is modulated by extracellular vesicles (EVs) and vesicular mediators released by efferocytes is not known. We report that efferocyte-derived EVs express prosaposin, which binds to macrophage GPR37 to increase expression of the efferocytosis receptor Tim4 via an ERK-AP1-dependent signaling axis, leading to increased macrophage efferocytosis efficiency and accelerated resolution of inflammation. Neutralization and knockdown of prosaposin or blocking GRP37 abrogates the pro-resolution effects of efferocyte-derived EVs in vivo. Administration of efferocyte-derived EVs in a murine model of atherosclerosis is associated with an increase in lesional macrophage efferocytosis efficiency and a decrease in plaque necrosis and lesional inflammation. Thus, we establish a critical role for efferocyte-derived vesicular mediators in increasing macrophage efferocytosis efficiency and accelerating the resolution of inflammation and tissue injury.
Insights
Efferocyte-derived extracellular vesicles (EVs) carrying prosaposin enhance macrophage efferocytosis and accelerate inflammation resolution. Blocking prosaposin or GPR37 hinders these beneficial effects, highlighting a novel mechanism in tissue repair.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Macrophages resolve inflammation via soluble mediators after clearing apoptotic cells.
- The role of extracellular vesicles (EVs) from efferocytes in inflammation resolution remains unclear.
Purpose of the Study:
- To investigate the role of efferocyte-derived EVs in modulating inflammation resolution.
- To identify the specific mediators within these EVs and their mechanisms of action.
Main Methods:
- Characterization of efferocyte-derived EVs for prosaposin expression.
- Analysis of prosaposin-GPR37 interaction and downstream signaling (ERK-AP1).
- Assessment of Tim4 expression and efferocytosis efficiency in macrophages.
- In vivo studies using neutralization, knockdown, and GPR37 blocking in atherosclerosis models.
Main Results:
- Efferocyte-derived EVs express prosaposin, which binds macrophage GPR37.
- Prosaposin binding increases Tim4 expression via an ERK-AP1 pathway, enhancing efferocytosis.
- Neutralization or knockdown of prosaposin, or GPR37 blockade, abrogates the pro-resolution effects.
- EV administration in atherosclerosis models improved efferocytosis, reduced necrosis, and decreased inflammation.
Conclusions:
- Efferocyte-derived EVs, via prosaposin, enhance macrophage efferocytosis and accelerate inflammation resolution.
- This pathway is critical for tissue repair and reducing inflammatory injury.
- Prosaposin-GPR37 signaling represents a novel therapeutic target for inflammatory diseases.
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