Efferocytes release extracellular vesicles to resolve inflammation and tissue injury via prosaposin-GPR37 signaling
Purbasha Bhattacharya,
Umesh Kumar Dhawan,
Mohammed Tayab Hussain,
Praveen Singh,
Karran Kiran Bhagat,
Aarushi Singhal,
Shani Austin-Williams,
Shantanu Sengupta,
Manikandan Subramanian
Affiliations
Purbasha Bhattacharya
CSIR – Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
Umesh Kumar Dhawan
William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK
Mohammed Tayab Hussain
William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK
Praveen Singh
CSIR – Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
Karran Kiran Bhagat
William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK
Aarushi Singhal
William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK
Shani Austin-Williams
William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK
Shantanu Sengupta
CSIR – Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
Manikandan Subramanian
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK; Corresponding author
Summary: 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.
