title: Engagement of Siglec-7 receptor induces a pro-inflammatory response selectively in monocytes.
abstract: Sialic acid binding immunoglobulin-like lectin-7 (Siglec-7) is a trans-membrane receptor carrying immunoreceptor tyrosine based inhibitory motifs (ITIMs) and delivering inhibitory signals upon ligation with sialylated glycans. This inhibitory function can be also targeted by several pathogens that have evolved to express sialic 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-1α, CCL4/MIP-1β, IL-8 and TNF-α. Among the three immune cell subsets known to constitutively express Siglec-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 phosphorylation of the extracellular 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 pathogens not expressing sialylated glycans.
authors.affiliation: Department of Infectious Diseases, Research Laboratories, IRCCS, Fondazione San Matteo and University of Pavia, Pavia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Varchetta
authors.forename: Enrico
authors.initials: E
authors.lastname: Brunetta
authors.forename: Alessandra
authors.initials: A
authors.lastname: Roberto
authors.forename: Joanna
authors.initials: J
authors.lastname: Mikulak
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Hudspeth
authors.forename: Mario U
authors.initials: MU
authors.lastname: Mondelli
authors.forename: Domenico
authors.initials: D
authors.lastname: Mavilio
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002176:Candida albicans / Q000276:immunology / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004926:Escherichia coli / Q000276:immunology / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D037102:Lectins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D061251:Primary Cell Culture; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D015054:Zymosan / Q000737:chemistry / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015815:Cell Adhesion Molecules; D016207:Cytokines; D018836:Inflammation Mediators; D037102:Lectins; C402206:SIGLEC7 protein, human; C412227:SIGLEC9 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D015054:Zymosan; D048049:Extracellular Signal-Regulated MAP Kinases