Macrophages transfer antigens to dendritic cells by releasing exosomes containing dead‐cell‐associated antigens partially through a ceramide‐dependent pathway to enhance CD4⁺ T‐cell responses

Abstract

SummaryDefects in rapid clearance of apoptotic cells lead to an accumulation of dead cells (late apoptotic or secondary necrotic cells), which results in an aberrant immune response. However, little is known about whether and how macrophages (Mφs) cooperate with dendritic cells (DCs) in the presentation of dead-cell-associated antigens in this process. By transferring high numbers of dead cells to mimic a failure of apoptotic cell clearance in vivo, we found that Mφs and neutrophils were the predominant phagocytes in the uptake of dead cells in the spleen. Moreover, both Mφs and DCs were required for an optimal CD4 + T-cell response triggered by dead-cell-associated antigens. Importantly, although Mφs alone had a poor capacity for antigen presentation, they could transfer phagocytosed antigens to DCs for potent antigen presentation to enhance T-cell responses. Finally, we found that exosomes released from Mφs acted as a transmitter to convey antigens to DCs partially in a ceramide-dependent manner, since treatment with the neutral sphingomyelinase inhibitor GW4869 and spiroepoxide resulted in a significant reduction of T-cell proliferation in vitro and in vivo. These findings point to a novel pathway of cross-talk between Mφs and DCs, which will be helpful to explain possible mechanisms for autoimmune diseases characterized by increased rates of apoptosis.

Human airway epithelial extracellular vesicle miRNA signature is altered upon asthma development

“…Albeit, as EVs contain surface molecules such as HLA‐DR, we figured that the cellular interaction might be subject‐specific and thus question the use of DCs from different human donors. It has however been shown several times that miRNAs can be functionally transferred to target cells and that DC function is modulated by EVs . Thus, it is intriguing to speculate that sEVs‐associated epithelial miRNAs are involved in regulating the immune responses by underlying DCs.…”

“…It has however been shown several times that miRNAs can be functionally transferred to target cells [48][49][50][51][52][53] and that DC function is modulated by EVs. [54][55][56] Thus, it is intriguing to speculate that sEVs-associated epithelial…”

WITHDRAWN: Loss of miR-494 by exosomes promotes melanoma proliferation and metastasis

“…For example, colorectal cancer exosomes transfer mRNAs, which promote endothelial cell proliferation and facilitate angiogenesis [22], whereas glioblastoma-derived exosomes promote tubule formation by recipient endothelial cells [23]. Furthermore, tumour exosomes secrete factors that suppress natural killer cell activity and induce T-cell apoptosis [24].…”

Role of sphingolipids in the biogenesis and biological activity of extracellular vesicles

“…As in A, before n-SMase action SM stabilizes membrane structure, while Cer production by n-SMase induces spontaneous negative curvature to the membrane of endosomes, thus promoting the formation of internal vesicles inside MVBs. Subsequent in vitro works reported that, while exogenous cell permeable C6 Cer dose-dependently increases the number of exosomes released from multiple myeloma cells (51), pharmacological or genetic block of n-SMase inhibited packaging of the prion protein into exosomes (52) and reduced exosome release among others in HEK cells (53), T cells (54), N2a cells (55), astrocytes (56), microglia (57), macrophages (58), hepatocytes (59), and multiple myeloma cells (51). Also, in vivo, in the brain and serum of 5XFAD mice, a transgenic model of Alzheimer's disease (AD), the n-SMase inhibitor, GW4869, decreased exosome concentration (60).…”