Inflammation-resolution is a protective response that is mediated by specialized pro-resolving mediators (SPMs) including Resolvin D1 (RvD1). The clearance of dead cells or efferocytosis is a critical cellular program of inflammation-resolution. Mechanisms associated with the clearance of necroptotic cells (NCs) are not known. Here we present evidence that NCs are inefficiently taken up by macrophages because they have increased surface expression of a well-known “don’t eat me” signal called CD47. High levels of CD47 on NCs promoted macrophages to “nibble” as opposed to engulf cells in whole. Blockade of CD47 on NCs promoted efficient, whole-cell clearance of NCs. Mechanistically, we observed that high levels of CD47 promoted RhoA signaling in macrophages. Moreover, we observed that macrophages exhibited stress fibers when “nibbling” NCs. Inhibition of RhoA promoted efficient and whole-cell engulfment of NCs, and a branched-actin at the phagocytic synapse that is defined as the region where macrophage interacts with NCs. Because SPMs have been shown to enhance the clearance of apoptotic cells, we next questioned whether RvD1 was also able to enhance the clearance of NCs. Indeed, we found that RvD1 enhanced the engulfment of NCs and promoted phagocytic synapses that had branched actin. Mechanistically, we found that RvD1 not only limited RhoA signaling but also activated CDC42. Together, these results suggest new molecules and signaling associated with the clearance of NCs, provide a new paradigm for the regulation of inflammation-resolution, and shed light on cytoskeletal morphologies for different forms of macrophage engulfment.
|Commitee:||Barroso, Margarida, MacNamara, Kate, Vincent, Peter|
|School:||Albany Medical College|
|Department:||Molecular and Cellular Physiology|
|School Location:||United States -- New York|
|Source:||MAI 58/05M(E), Masters Abstracts International|
|Subjects:||Cellular biology, Physiology|
|Keywords:||Atheroslcerosis, Inflammation, Macrophage, Necroptosis, Phagocytosis, Resolvin d1|
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