The C-type lectin SIGN-R1 mediates uptake of the capsular polysaccharide ofStreptococcus pneumoniaein the marginal zone of mouse spleen

Abstract

SIGN-R1, a recently discovered C-type lectin expressed at high levels on macrophages within the marginal zone of the spleen, mediates the uptake of dextran polysaccharides by these phagocytes. We now find that encapsulated Streptococcus pneumoniae are rapidly cleared by these macrophages from the bloodstream, and that capture also takes place when different cell lines express SIGN-R1 after transfection. To assess the role of the capsular polysaccharide of S. pneumoniae (CPS) in the interaction of SIGN-R1 with pneumococci, we first studied binding and uptake of serotype 14 CPS in transfected cells. Binding was observed and was of a much higher avidity (3,000-fold) for CPS 14 than dextran. The CPSs from four different serotypes were also cleared by marginal zone macrophages in vivo. To establish a role for SIGN-R1 in this uptake, we selectively down-regulated expression of the lectin by pretreatment of the mice with SIGN-R1 antibodies, including a newly generated hamster monoclonal called 22D1. For several days after this transient knockout, the marginal zone macrophages were unable to take up either CPSs or dextrans. Therefore, marginal zone macrophages in mice have a receptor that interacts with capsular pneumococcal polysaccharides, setting the stage for further studies of the functional consequences of this interaction.T he spleen functions at several points in innate and adaptive immunity. A major innate function is exerted by macrophages that are abundant in vascular regions termed the splenic red pulp, whereas adaptive functions are carried out by B and T lymphocytes, typically located in white pulp nodules. At the junction of each white pulp nodule with the red pulp is a specialized region called the marginal zone, which is composed of several concentric regions (1). Innermost is a ring of macrophages termed marginal metallophils, expressing a hemagglutinin termed sialoadhesin or CD169 (2, 3). Then there is a vascular sinus that receives blood via penetrating small arterial vessels from the white pulp. Surrounding the marginal sinus is a zone composed of large macrophages as well as specialized B lymphocytes (4). Within and surrounding the marginal zone are also dendritic cells (5, 6), possibly in the process of migrating from the blood to the T cell regions of the white pulp.With respect to host defense, the spleen plays a special role during blood-borne infection with encapsulated microorganisms, particularly Streptococcus pneumoniae bacteria (7-12). A critical role of the spleen is the formation of antibodies by marginal zone B cells (13-15), particularly complement-fixing antibodies (16)(17)(18)(19)(20). The role of macrophages in the processes of microbial clearance and resistance and antibody formation to S. pneumoniae needs to be considered (21), particularly given recent data that marginal zone macrophages interact and retain B cells in this region (22). Here we show that marginal zone macrophages express a receptor called SIGN-R1 that is able to bind and internalize the capsular pneumococcal polys...

C‐type lectin SIGNR1 enhances cellular oxidative burst response against C. albicans in cooperation with Dectin‐1

“…SIGNR1 on rpMf was successfully downregulated by 1 day after i.v. injection with anti-SIGNR1 mAb (22D1) without eliminating rpMf (data not shown), as reported in marginal zone Mf [28].…”

“…However, their distributions are strategic for sensing polysaccharides/antigens from pathogens. SIGNR1 resides in the spleen marginal zone [28] and lymph node medulla [34] captures antigens from distal infection sites via blood and lymph, respectively. Therefore, SIGNR1 in confined parts of the body in vivo plays a role as the first sensing machinery against infection.…”

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

“…In this manner, they trigger an innate immune response directly but also an adaptive immune response given their close proximity to the white pulp region, where T‐cells and B‐cells are located 16. Moreover, the spleen contains unique subsets of specialized macrophages that have better recognition for certain pathogens 17, 18, 19, 20. Indeed, this places the spleen as a major player in the clearance of encapsulated bacteria like Mycobacterium tuberculosis and Streptococcus pneumoniae , but also of Staphylococcus aureus , and potentially of viruses 16, 17, 18, 19, 20.…”

“…Moreover, the spleen contains unique subsets of specialized macrophages that have better recognition for certain pathogens 17, 18, 19, 20. Indeed, this places the spleen as a major player in the clearance of encapsulated bacteria like Mycobacterium tuberculosis and Streptococcus pneumoniae , but also of Staphylococcus aureus , and potentially of viruses 16, 17, 18, 19, 20. Moreover, asplenic patients are immunodeficient, are recommended to be on a more stringent immunization schedule, and more aggressive clinical management is initiated at an earlier stage when facing fever or infection 21, 22…”

1α,25-Dihydroxyvitamin D3 modulates the murine antibody response to pneumococcal capsular polysaccharide serotype 3 through IL-12

“…In addition to T lymphocytes, also antigen-presenting cells (APC) seem important in the antibody response to caps-PS. Zamze et al [8] showed that the macrophage mannose receptor, which is expressed on macrophages and dendritic cells, binds to caps-PS, and Kang et al reported that SIGN-R1, a receptor that is expressed at high levels in marginal zone macrophages of the spleen, mediates uptake of encapsulated S. pneumoniae [9]. More direct evidence for the role of APC in the antibody response to caps-PS was provided by Garg et al [10].…”