Ablation of Siglec-E enhances adipose tissue inflammation through CXCR3 activation and induces monocytic myeloid-derived suppressor cells

Abstract Obesity is a worldwide epidemic associated with dysregulated metabolism and chronic low-grade inflammation in adipose tissue (AT). AT infiltrates with several immune cells, which secrete proinflammatory cytokines that mediate the severity of AT inflammation during obesity. During our ongoing studies, we observed the downregulation of various genes, particularly sialic acid-binding Ig-like lectin E (Siglec-E) by RNA-seq analysis in AT immune cells isolated from high-fat diet (HFD) fed mice as compared to normal diet (ND) mice. Siglec-E is mainly expressed in the cells of myeloid lineages, including macrophages, dendritic cells (DCs), and neutrophils. We confirmed the RNA-seq data of downregulation of Siglec-E in AT derived from HFD-fed mice by RT-PCR analysis. To determine the role of Siglec-E in mediating AT inflammation, we fed ND and HFD to wild-type (WT) and Siglec-E knockout mice (Siglec-E −/−), respectively. HFD consumption increased the body weight and blood glucose levels in Siglec-E −/−mice as compared to WT mice. Further, we observed increased infiltration of macrophages and decreased frequency of DCs in HFD-fed Siglec-E −/−mice AT compared to WT HFD-fed mice. We also noticed an increase in the frequency of CD8 +CXCR3 +cells and monocytic myeloid-derived suppressor cells (M-MDSCs) in AT of HFD-fed Siglec-E −/−mice as compared to WT HFD-fed mice. We also noticed the increased expression of AKT, and TNF receptor-associated factor 3 (TRAF3) in HFD-fed Siglec-E −/−mice. These results suggest that Siglec-E deletion plays a role in AT inflammation and obesity through the activation of CXCR3 and M-MDSCs. This study supports the notion that modulating Siglec-E pathways protect from AT inflammation and metabolic disorders. This research is supported by NIH grant R01 AI140405