Abstract 553: Siglec-1 (CD169) on Monocytes/Macrophages: A New Receptor For Extracellular Self-RNA in Triggering Inflammatory Responses via the Sheddase TACE/ADAM17
As an important component of atherosclerosis, monocytes/macrophages respond to external stimuli with rapid changes in their expression of many inflammation-related genes to undergo polarization towards the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotype. Although sialoadhesin (Sn), also known as SIGLEC-1 or CD169, is a transmembrane protein receptor expressed on monocytes and macrophages whether it has a role in macrophage polarization and ultimately, macrophage-driven atherogenesis, has not been investigated. We have previously shown that, independently of Toll-like receptor signaling, extracellular RNA (eRNA) could exert pro-thrombotic and pro-inflammatory properties in the cardiovascular system by inducing cytokine mobilization. In the current study, recombinant mouse macrophage CSF[[Unable to Display Character: –]]driven bone marrow-derived macrophage (BMDM) differentiation was found to be skewed towards the M1 phenotype by exposure of cells to eRNA. This resulted in up-regulation of inflammatory markers, whereas anti-inflammatory genes were significantly down-regulated by eRNA. Interestingly, eRNA was released from BMDM under hypoxia and induced TNF-α liberation by activating TNF-α converting enzyme (TACE) to provoke inflammation. Conversely, TNF-α promoted eRNA release, especially under hypoxia, feeding a vicious cycle of cell damage. Administration of RNase1 or TAPI (a TACE-inhibitor) prevented the production of inflammatory mediators. Murine BMDM isolated from mice deficient in sialoadhesin had the opposite reaction to eRNA treatment with a prominent down-regulation of pro-inflammatory cytokines/M1 phenotype markers, while anti-inflammatory cytokines/M2 phenotype markers were significantly raised. In keeping with the proposed role of eRNA as a pro-inflammatory “alarm signal”, these data further shed light on the role of eRNA in macrophage function in the context of chronic inflammatory diseases such as atherosclerosis. The identification of sialoadhesin as putative eRNA recognition site on macrophages may allow further investigation of the underlying mechanisms of eRNA-macrophage interaction and related signal transduction pathways. Siglec-1 thereby may provides a new target to treat eRNA-mediated vascular diseases.
Author Disclosures: H.A. Cabrera-Fuentes: None. K.T. Preissner: None. W.A. Boisvert: None.
- © 2015 by American Heart Association, Inc.