CD73 regulates anti-inflammatory signaling between apoptotic cells and endotoxin-conditioned tissue macrophages

Abstract

The phagocytosis of apoptotic cells (efferocytosis) shifts macrophages to an anti-inflammatory state through a set of still poorly understood soluble and cell-bound signals. Apoptosis is a common feature of inflamed tissues, and efferocytosis by tissue macrophages is thought to promote the resolution of inflammation. However, it is not clear how the exposure of tissue macrophages to inflammatory cues (e.g., PAMPs, DAMPs) in the early stages of inflammation affects immune outcomes of macrophage-apoptotic cell interactions occurring at later stages of inflammation. To address this, we used low-dose endotoxin conditioning (LEC, 1 ng/ml LPS 18 h) of mouse resident peritoneal macrophages (RPMФ) to model the effects of suboptimal (i.e., non-tolerizing), antecedent TLR activation on macrophage inflammatory responses to apoptotic cells. Compared with unconditioned macrophages (MФ), LEC-MФ showed a significant enhancement of apoptotic cell-driven suppression of many inflammatory cytokines (e.g., TNF, MIP-1β, MCP-1). We then found that enzymatic depletion of adenosine or inhibition of the adenosine receptor A2a on LEC-MФ abrogated apoptotic cell suppression of TNF, and this suppression was entirely dependent on the ecto-enzyme CD73 (AMPadenosine) but not CD39 (ATPAMP), both of which are highly expressed on RPMФ. In addition to a requirement for CD73, we also show that Adora2a levels in macrophages are a critical determinant of TNF suppression by apoptotic cells. LEC treatment of RPMФ led to a ~3-fold increase in Adora2a and a ~28-fold increase in adenosine sensitivity. Moreover, in RAW264.7 cells, ectopic expression of both A2a and CD73 was required for TNF suppression by apoptotic cells. In mice, mild, TLR4-dependent inflammation in the lungs and peritoneum caused a rapid increase in macrophage Adora2a and Adora2b levels, and CD73 was required to limit neutrophil influx in this peritonitis model. Thus immune signaling via the CD73-A2a axis in macrophages links early inflammatory events to subsequent immune responses to apoptotic cells.

NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

“…A chronic hyperglycemic stimulus increases the production of mitochondrial ROS, establishing glomerular oxidative [57,58]. Redox imbalance initiates cellular damage by modifying phospholipids and proteins in the mitochondrial membrane [6,59]. According to previous studies, hyperglycemiamediated oxidative stress reduces the expression and activity of the mitochondrial respiratory complex, impairing mitochondrial energy metabolism [10,60].…”

STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke mice

“…Effective efferocytosis sequesters dead or dying cells to reduce the release of damage-associated molecular patterns and ameliorate inflammation. In addition, efferocytosis engages several metabolic-sensing molecules such as LXRα, LXRβ, PPARγ, PPARδ, RXRα, and the CD73-adenosine receptor A2a axis to control inflammatory responses in phagocytes and promotes inflammation resolution (28,29). Previous studies suggested that Arg1 might be a downstream target regulated by STAT6 (30,31).…”

Zearalenone regulates endometrial stromal cell apoptosis and migration via the promotion of mitochondrial fission by activation of the JNK/Drp1 pathway

“…Western blot analysis. Cyt-c release triggers the formation of the apoptosome, a complex comprising of apoptotic peptidase activating factor 1, cyt-c, dATP (deoxy-adenosine triphosphate) and pro-caspase-9 (45). The apoptosome triggers caspase-9 activation, which subsequently cleaves caspase-3 to its active form.…”