Extracellular inflammasome particles promote chronic inflammation of the visceral adipose tissue in metabolic syndrome

Julius Wissemann (Freiburg)1, A. Heidenreich (Freiburg)1, D. Suchanek (Freiburg)1, P. Stachon (Freiburg)1, D. Wolf (Freiburg)1, D. Westermann (Freiburg)1, J. Merz (Freiburg)1

1Universitäts-Herzzentrum Freiburg - Bad Krozingen Klinik für Kardiologie und Angiologie I Freiburg, Deutschland


Background: The chronic, low-grade inflammation seen in the metabolic syndrome increases the risk for cardiovascular events. Specific therapies against chronic inflammatory processes are needed to provide a cardiovascular benefit without compromising host defense mechanisms. This study sought a better understanding of the underlying pathomechanism, by investigating a potential role for extracellular inflammasome particles.

Methods: Male C57BL6/J mice received standard (chow) or high-fat diet (HFD) for 7, 14 or 21 weeks. Cells from different organs were isolated and analyzed by flow cytometry for inducibility of inflammasome particles. The visceral fat was further investigated for inflammasome particle formation using fluorescence microscopy. Inflammasome particles were isolated and incubated with adipocytes, macrophages and human endothelial cells to assess their effects. Human visceral fat from patients with metabolic syndrome was investigated in the same manner.

Results: Mice receiving a high-fat diet show increased inducibility of NLRP3-inflammasome particles in the visceral (chow: 656±150 inflammasome particles per 100.000 cells, HFD: 2012±198, n≥10, p<0.001) but not the subcutaneous adipose tissue (chow: 321±50, HFD 431±106, n=11, p=0.732). Inducibility of inflammasome particles in the visceral fat correlates with clinical markers of the metabolic syndrome (e.g. bodyweight: r=0.832, n=34, p<0.001,) and increasing adipose tissue macrophage frequency (r=0.827, n=34, p<0.001). Inflammasome particles originate from myeloid cells in crown-like structures of the metabolically altered visceral fat and are being externalized.  Extracellular inflammasome particles evoke an inflammatory response in adipocytes and modulate macrophage polarization by promoting endoplasmic reticulum stress. This translates to humans with metabolic syndrome, where extracellular inflammasome particles are present in the visceral fat and promote endothelial cell activation.

Conclusions: This study shows for the first time that extracellular inflammasome particles are involved in the pathomechanism of the metabolic syndrome and promote chronic inflammation in the visceral adipose tissue. Our discoveries highlight the potential for extracellular inflammasome particles as a pharmacological target against the chronic, low-grade inflammation that puts so many patients at cardiovascular risk.

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