Visualized macrophage dynamics and significance of S100A8 in obese fat

Abstract

Chronic low-grade inflammation of adipose tissue plays a crucial role in the pathophysiology of obesity. Immunohistological microscopic analysis in obese fat tissue has demonstrated the infiltration of several immune cells such as macrophages, but dynamics of immune cells have not been fully elucidated and clarified. Here, by using intravital multiphoton imaging technique, to our knowledge for the first time, we analyzed and visualized the inflammatory processes in adipose tissue under high-fat and high-sucrose (HF/HS) diet with lysozyme M-EGFP transgenic (LysMEGFP) mice whose EGFP was specifically expressed in the myelomonocytic lineage. Mobility of LysMEGFP-positive macrophages was shown to be activated just 5 d after HF/HS diet, when the distinct hypertrophy of adipocytes and the accumulation of macrophages still have not become prominent. Significant increase of S100A8 was detected in mature adipocyte fraction just 5 d after HF/HS diet. Recombinant S100A8 protein stimulated chemotactic migration in vitro and in vivo, as well as induced proinflammatory molecules, both macrophages and adipocytes, such as TNF-α and chemokine (C-C motif) ligand 2. Finally, an antibody against S100A8 efficiently suppressed the HF/HS diet-induced initial inflammatory change, i.e., increased mobilization of adipose LysMEGFP-positive macrophages, and ameliorated HF/HS diet-induced insulin resistance. In conclusion, time-lapse intravital multiphoton imaging of adipose tissues identified the very early event exhibiting increased mobility of macrophages, which may be triggered by increased expression of adipose S100A8 and results in progression of chronic inflammation in situ.

Testosterone Deficiency Induces Changes of the Transcriptomes of Visceral Adipose Tissue in Miniature Pigs Fed a High-Fat and High-Cholesterol Diet

“…Our data are consistent with those observed by Sekimoto et al (2012) and Yamaoka et al (2013) [39,40], who found the expression levels of S100A8 , S100A9 , and S100A12 were positively correlated with VAT adiposity in human and overexpression of S100A8 and S100A9 could increase adipose inflammation. Most recently, upregulated S100A8 expression levels were shown to contribute to the very early stage of pathogenesis of obesity and induce local inflammation [41]. Obviously, our data strongly supported that testosterone deficiency with HFC might enhance the risk of inflammation via upregulating the expression levels of inflammatory markers.…”

Aberrant Expression of Long Non-Coding RNAs in Newly Diagnosed Type 2 Diabetes Indicates Potential Roles in Chronic Inflammation and Insulin Resistance

“…S100A8 and S100A12, belonging to the calgranulin gene family, play key immune response roles in inflammatory disorders, like diabetes and cardiovascular disease [32]. In addition, S100A8 can recruit macrophages to adipose tissue during inflammation and in the setting of hyperglycemia and obesity [33, 34]. It was reported that the elevated expression of TLR8 found in the adipose tissue of patients with obesity or T2D had consensus with inflammatory signatures and may represent an immune marker of metabolic inflammation [35].…”

Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes

“…MCP1 plays an important role in M1 macrophage recruitment to obese adipose tissue and obesity-associated inflammation (Weisberg et al, 2006). S100A8 was also increased in responders versus non-responders; this gene encodes a damage-associated molecular pattern protein (Sekimoto et al, 2015). The heterodimeric complex of S100A8/S100A9 promotes inflammation by acting as a ligand for TLR4 and is linked to activation of the Nlrp3 inflammasome (Nagareddy et al, 2014).…”