CD73 regulates anti-inflammatory signaling between apoptotic cells and endotoxin-conditioned tissue macrophages
| Autor: | William J. Janssen, Samir P. Bhagwat, Michael R. Elliott, Jing Wang, Terry W. Wright, Patrick S. Murphy, Joshua Munger |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Lipopolysaccharides Programmed cell death Adenosine Receptor Adenosine A2A medicine.drug_class Chemokine CXCL2 Apoptosis Biology Receptor Adenosine A2B Anti-inflammatory 03 medical and health sciences Mice Antigen Antigens CD medicine Animals Receptor Molecular Biology 5'-Nucleotidase Lung RAW 264.7 Cells Cells Cultured Mice Knockout Original Paper Mice Inbred BALB C Cell growth Neurodegeneration Apyrase Cell Biology medicine.disease Coculture Techniques Cell biology Chemokine CXCL10 Mice Inbred C57BL Toll-Like Receptor 4 030104 developmental biology Macrophages Peritoneal Cytokines Signal Transduction |
| Popis: | 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 (AMPadenosine) but not CD39 (ATPAMP), 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. |
| Databáze: | OpenAIRE |
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