Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids

Abstract

The phagocytic clearance of apoptotic cells is essential to prevent chronic inflammation and autoimmunity. The phosphatidylserine-binding protein milk fat globule-EGF factor 8 (MFG-E8) is a major opsonin for apoptotic cells, and MFG-E8 À / À mice spontaneously develop a lupus-like disease. Similar to human systemic lupus erythematosus (SLE), the murine disease is associated with an impaired clearance of apoptotic cells. SLE is routinely treated with glucocorticoids (GCs), whose anti-inflammatory effects are consentaneously attributed to the transrepression of pro-inflammatory cytokines. Here, we show that the GC-mediated transactivation of MFG-E8 expression and the concomitantly enhanced elimination of apoptotic cells constitute a novel aspect in this context. Patients with chronic inflammation receiving high-dose prednisone therapy displayed substantially increased MFG-E8 mRNA levels in circulating monocytes. MFG-E8 induction was dependent on the GC receptor and several GC response elements within the MFG-E8 promoter. Most intriguingly, the inhibition of MFG-E8 induction by RNA interference or genetic knockout strongly reduced or completely abolished the phagocytosis-enhancing effect of GCs in vitro and in vivo. Thus, MFG-E8-dependent promotion of apoptotic cell clearance is a novel anti-inflammatory facet of GC treatment and renders MFG-E8 a prospective target for future therapeutic interventions in SLE.

Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic ‘eat-me’ signals: cleavage and inhibition of phagocytosis by Lp-PLA2

“…On the other hand, lower GAS-6 expression and/or higher expression of MFG-E8/alphav-beta5 might shift the receptor preference, and hence post-phagocytic signaling towards anti-inflammatory pathways. 38,39 In line with the marked suppressive effects of Lp-PLA2-catalyzed hydrolysis of PSox on phagocytosis of apoptotic cells, lyso-PS did not reveal any significant binding in dot blot experiments.…”

Recombinant Milk Fat Globule–EGF Factor-8 Reduces Oxidative Stress via Integrin β3/Nuclear Factor Erythroid 2–Related Factor 2/Heme Oxygenase Pathway in Subarachnoid Hemorrhage Rats

“…MFGE8 plays important roles in several biological processes, including apoptotic cell clearance 19 , angiogenesis 7 , and anti-inflammation 10 . Recent studies showed that MFGE8-mediated potential therapeutic benefits in several models of central nervous system diseases.…”

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

“…Human peripheral blood mononuclear cells (PBMCs) were prepared from heparinized blood from healthy donors by density gradient centrifugation (Biocoll density = 1.077 g/ml, Biochrom, Berlin, Germany) as described. 62 Monocytes and T cells were isolated from PBMCs by positive selection with anti-CD14 or anti-CD3 magnetic beads (Miltenyi Biotec, Bergisch Gladbach, Germany), respectively, according to the manufacturer’s protocol. Monocytes were differentiated into DCs with 40 ng/ml IL-4 and 20 ng/ml GM-CSF (both from R&D Systems, Heidelberg, Germany) in X-Vivo 15 medium (Lonza) supplemented with 100 units/ml penicillin, 0.1 mg/ml streptomycin, and 10% autologous serum for a minimum of 5 days.…”