Engagement of Siglec-7 receptor induces a pro-inflammatory response selectively in monocytes

Sialic acid binding immunoglobulin-like lectin-7 (Siglec-7) is a trans-membrane receptor carryng immunoreceptor trosine based inhibitory motifs (ITIMs) and delivering inhibitory signals upon ligation with sialylated glycans. This inhibitory function can be also targeted by seveeral pathogens that have evolved to express siliac acids on their surface to escape host immune responses. Here, we demonstrate that cross-linking of Siglec-7 by a specific monoclonal antibody (mAb) induces a remarkably high production of IL-6, IL-1a, CCL4/MIP-1B, IL-8 and TNF-a. Among the three immune cell subsets known to constitutively express Singlec-7, the production of these pro-inflammatory cytokines and chemokines selectively occurs in monocytes and not in Natural Killer or T lymphocytes. This Siglec 7 mediated activating function is associated with the prosporylation of the extracellar signal-regulated kinase (ERK) pathway. The present study also shows that sialic acid-free Zymosan yeast particles are able to bind SIglec-7 on monocytes and that this interaction mimics the ability of the anti SIglec-7 mAb to induce the production of pro-inflammatory mediators. Indeed, blocking or silencing Siglec-7 in primary monocytes greatly reduced the production of inflammatory cytokines and chemokines in response to Zymosan thus confirming that SIglec-7 participates in generating a monocyte-mediated inflammatory outcome following pathogen recognition. The presence of an activating form of Siglec-7 in monocytes provides the host with a new and alternative mechanism to encounter pathogenes not expressing sialylated glycans.