C-reactive protein mediates protection from lipopolysaccharide due to interactions with Fc gamma R. but conserved in their acknowledgement structure. The shared binding site for SAP and IgG results in competition for FcR binding and the inhibition of immune complex-mediated phagocytosis by soluble pentraxins. These results establish the antibody-like functions for pentraxins in the FcR pathway, suggest an evolutionary overlap between the innate and adaptive immune systems, and have novel therapeutic implications for autoimmune diseases. The pentraxin family is divided into two subclasses, the classical short chain pentraxins, CRP and SAP, and the long chain pentraxins3. Both SAP and CRP identify numerous pathogenic bacteria, fungi and yeasts3, and activate the classical match pathway through C1q4. Long pentraxins, such as PTX3 which contain an additional N-terminal domain name, are produced by macrophages and myeloid dendritic cells in response to proinflammatory stimuli9, 10. Human has three classes of activating Fc receptors, FcRI, FcRIIa and FcRIII, and one inhibitory receptor FcRIIb11. In addition to activating phagocytosis through FcR 5-8, both SAP and CRP also induce protective immune responses12, and high levels of CRP safeguard mice from endotoxin shock through FcR13, 14. While pentraxins can both activate and regulate immune responses, the molecular mechanisms and the balance of these antibody-like functions remain unresolved. Here we present structural and functional evidence for the involvement of pentraxins in the activation of Nav1.7-IN-2 FcR and suggest their potential role in modulating antibody-mediated inflammatory responses. While immune complexes are known to activate FcR leading to phagocytosis and cytokine secretion, it is not obvious if pentraxins induce comparable FcR activation7, 8. To investigate whether FcR identify pathogens through pentraxin opsonization, we examined the engulfment of pentraxin-opsonized zymosan by human monocyte-derived macrophages (MDM). Texas red-labeled zymosan Nav1.7-IN-2 particles were efficiently internalized by MDM upon opsonization with human SAP, CRP or IgG compared to unopsonized particles (Fig 1a). The cup-shaped enrichment of FcRIIa (labeled green) surrounding the SAP-and CRP-bound zymosan particles indicates the involvement of FcR in phagocytosis. The addition of soluble IgG reduced phagocytosis of SAP-opsonized zymosan by 90% from 3.8 0.5 to 0.4 0.2 zymosan particles/MDM, further confirming the role of FcR. We then investigated cytokine secretion Nav1.7-IN-2 as a result of SAP-FcR conversation. To avoid zymosan and endotoxin-mediated activation, CD14+ monocytes were treated with purified SAP in either an aggregated or monomeric form without zymosan and in the presence of polymixin B. SAP treatment resulted in dose-dependent secretion of IL-10, IL-8 and IL-6 by monocytes (Fig. 1b), and only the aggregated but not monomeric SAP stimulated cytokines suggesting a requirement for receptor cross-linking by SAP in cytokine production (Fig. 1c). Cytokine secretion was dramatically reduced if SAP was pre-treated with bead-bound proteinase K or pre-cleared with phosphoethanolamine (PE)-conjugated Sepharose (Fig. 1d). In addition, antibodies against FcR as well as a inhibitor, piceatannol that blocks FcR signaling significantly inhibited cytokine secretion, confirming the involvement of FcR (Fig. 1e, f). To assess the contribution of potential contaminating LPS and/or peptidoglycan in Gja5 the SAP sample to cytokine secretion, bone marrow-derived macrophages (BMDM) from MyD88-/- and RIP2 -/- mice were treated with SAP and assayed for cytokine production. Similar or higher levels of IL-6 and CCL2 were detected in SAP-but not PBS-treated BMDM from MyD88-/- mice compared to wild type BMDM (Fig. 1g). TNF- production was lower in SAP-treated MyD88-/- than wild type BMDM but remained 10-20 fold higher compared.