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Siglec-E is a murine CD33-related siglec that functions as an inhibitory receptor and is expressed mainly on neutrophils and macrophage populations. Recent studies have suggested that siglec-E is an important negative regulator of lipopolysaccharide (LPS)-toll-like receptor 4 (TLR4) signaling and one report ( 1 ) claimed that siglec-E is required for TLR4 endocytosis following uptake of  Escherichia coli  by macrophages and dendritic cells (DCs). Our attempts to reproduce these observations using cells from wild-type (WT) and siglec-E-deficient mice were unsuccessful. We used a variety of assays to determine if siglec-E expressed by different macrophage populations can regulate TLR4 signaling in response to LPS, but found no consistent differences in cytokine secretion  in vitro  and  in vivo , comparing three different strains of siglec-E-deficient mice with matched WT controls. No evidence was found that the siglec-E deficiency was compensated by expression of siglecs-F and -G, the other murine inhibitory CD33-related siglecs. Quantitative proteomics was used as an unbiased approach and provided additional evidence that siglec-E does not suppress inflammatory TLR4 signaling. Interestingly, proteomics revealed a siglec-E-dependent alteration in macrophage protein composition that could be relevant to functional responses in host defense. In support of this, siglec-E-deficient mice exhibited enhanced growth of  Salmonella enterica  serovar Typhimurium in the liver following intravenous infection, but macrophages lacking siglec-E did not show altered uptake or killing of bacteria  in vitro . Using various cell types including bone marrow-derived DCs (BMDCs), splenic DCs, and macrophages from WT and siglec-E-deficient mice, we showed that siglec-E is not required for TLR4 endocytosis following  E. coli  uptake or LPS challenge. We failed to see expression of siglec-E by BMDC even after LPS-induced maturation, but confirmed previous studies that splenic DCs express low levels of siglec-E. Taken together, our findings do not support a major role of siglec-E in regulation of TLR4 signaling functions or TLR4 endocytosis in macrophages or DCs. Instead, they reveal that induction of siglec-E by LPS can modulate the phenotype of macrophages, the functional significance of which is currently unclear.

frontiers in immunology

Expression of Siglec-E Alters the Proteome of Lipopolysaccharide (LPS)-Activated Macrophages but Does Not Affect LPS-Driven Cytokine Production or Toll-Like Receptor 4 Endocytosis