Notch Signaling Modulates Macrophage Polarization and Phagocytosis Through Direct Suppression of Signal Regulatory Protein ? Expression.

ABSTRACT: The Notch pathway plays critical roles in the development and functional modulation of myeloid cells. Previous studies have demonstrated that Notch activation promotes M1 polarization and phagocytosis of macrophages; however, the downstream molecular mechanisms mediating Notch signal remain elusive. In an attempt to identify Notch downstream targets in bone marrow-derived macrophages (BMDMs) using mass spectrometry, the signal regulatory protein ? (SIRP?) appeared to respond to knockout of recombination signal-binding protein Jk (RBP-J), the critical transcription factor of Notch pathway, in macrophages. In this study, we validated that Notch activation could repress SIRP? expression likely via the Hes family co-repressors. SIRP? promoted macrophage M2 polarization, which was dependent on the interaction with CD47 and mediated by intracellular signaling through SHP-1. We provided evidence that Notch signal regulated macrophage polarization at least partially through SIRP?. Interestingly, Notch signal regulated macrophage phagocytosis of tumor cells through SIRP? but in a SHP-1-independent way. To access the translational value of our findings, we expressed the extracellular domains of the mouse SIRP? (mSIRP?^ext) to block the interaction between CD47 and SIRP?. We demonstrated that the soluble mSIRP?^ext polypeptides could promote M1 polarization and increase phagocytosis of tumor cells by macrophages. Taken together, our results provided new insights into the molecular mechanisms of notch-mediated macrophage polarization and further validated SIRP? as a target for tumor therapy through modulating macrophage polarization and phagocytosis.

SUBMITTER: Lin Y 

PROVIDER: S-EPMC6077186 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature