Efferocytes release extracellular vesicles to resolve inflammation and tissue injury via prosaposin-GPR37 signaling

Bhattacharya, Paramita; Dhawan, Umesh Kumar; Hussain, Mumtaz; Singh, Praveen; Bhagat, K; Singhal, Aarushi; Austin-Williams, Shani; Sengupta, Shantanu; Subramanian, Manikandan

doi:10.1016/j.celrep.2023.112808

Cited by 9 publications

(14 citation statements)

References 57 publications

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“…S7A). While it was not within the scope of this study to characterise EVs following efferocytosis, it is interesting to speculate that this may be the case, as it has been recently shown that efferocytic macrophages secrete EVs 4 . Transmission electron microscopy (TEM) of cleared supernatants following ultracentrifugation did indeed show the presence of EVs in both control and efferocytosis conditions (Fig.…”

Section: Resultsmentioning

confidence: 96%

“…It has been shown that both macrophages and apoptotic cells secrete factors that promote a wound-healing phenotype in neighbouring cells to resolve inflammation 3,4 . In order to investigate this concept further using our SILAC workflow, we collected the supernatants from the BMDMs 6 h and 18 h following efferocytosis for mass spectrometry analysis.…”

Section: Resultsmentioning

confidence: 99%

“…The secretion of pro-resolving factors by both immune cells and apoptotic cells is an emerging theme in innate immunity 3,4 . Here, we applied our SILAC approach to study these secreted factors, in addition to their effect on naïve BMDMs.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, it has been shown that metabolites secreted by apoptotic cells 3 and extracellular vesicles produced by efferocytic macrophages 4 can induce a pro-resolving phenotype in neighbouring cells and promote efferocytosis.…”

Section: Introductionmentioning

confidence: 99%

“…While studies have investigated transcriptomic changes in macrophages following the early stages of efferocytosis 2 , no study has investigated changes in the proteome in order to specifically map the phenotype of efferocytic cells. Notably, it has been shown that metabolites secreted by apoptotic cells 3 and extracellular vesicles produced by efferocytic macrophages 4 can induce a pro-resolving phenotype in neighbouring cells and promote efferocytosis.…”

Section: Introductionmentioning

confidence: 99%

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Proteomic mapping of macrophages in response to the clearance of apoptotic cells reveals a unique reprogramming profile

Raymond,

Frey,

Trost

2023

Preprint

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During the daily process of healthy cellular turnover, billions of cells undergo apoptosis in the human body. These cells are removed by phagocytic cells, namely macrophages through a process known as efferocytosis, which triggers a cascade of reprogramming events in the cell, with a shift towards a pro-resolving or ‘wound healing’ phenotype. To date, no study has attempted to investigate these phenotypic changes from a proteomic perspective. Here, we present a novel and robust workflow for the investigation of proteome and secretome changes in bone marrow-derived macrophages (BMDMs) following efferocytosis using stable isotope labelling by amino acids in cell culture (SILAC) combined with data-independent acquisition (DIA) mass spectrometry. We show that using this workflow we can dissect the mixed proteomes of BMDMs and apoptotic cells to specifically map the reprogramming events occurring in macrophages in the later stages of efferocytosis. Specifically, we find that efferocytic macrophages adopt an alternatively activated phenotype underpinned by an increase in efferocytic and anti-inflammatory markers. We also show that the secretome contains factors that can reprogram naïve BMDMs towards an efferocytosis-like, pro-resolving, phenotype. Our results provide an unprecedented view of the efferocytic landscape of macrophages and will aid in further understanding this important immunological process in the larger context of immune homeostasis and inflammatory disorders.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%