Thromb Haemost 2021; 121(11): 1464-1475
DOI: 10.1055/s-0041-1726346
Blood Cells, Inflammation and Infection

Methylglyoxal Drives a Distinct, Nonclassical Macrophage Activation Status

Foivos-Filippos Tsokanos*
1  Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
2  Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany
3  German Center for Diabetes Research, Neuherberg, Germany
,
Carolin Muley*
1  Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
2  Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany
3  German Center for Diabetes Research, Neuherberg, Germany
4  Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
,
Sajjad Khani**
1  Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
2  Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany
3  German Center for Diabetes Research, Neuherberg, Germany
4  Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
,
Daniela Hass**
1  Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
2  Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany
3  German Center for Diabetes Research, Neuherberg, Germany
,
Thomas Fleming
2  Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany
3  German Center for Diabetes Research, Neuherberg, Germany
,
Gretchen Wolff
1  Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
2  Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany
3  German Center for Diabetes Research, Neuherberg, Germany
,
Alexander Bartelt
1  Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
3  German Center for Diabetes Research, Neuherberg, Germany
4  Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
5  German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Technische Universität München, Munich, Germany
,
Peter Nawroth
2  Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany
3  German Center for Diabetes Research, Neuherberg, Germany
,
Stephan Herzig
1  Institute for Diabetes and Cancer, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
2  Joint Heidelberg-IDC Transnational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany
3  German Center for Diabetes Research, Neuherberg, Germany
6  Chair Molecular Metabolic Control, Medical Faculty, Technical University Munich, Germany
› Author Affiliations
Funding This work was supported by the Collaborative Research Center 1118 “Reactive metabolites and diabetic complications” awarded to P.N. and S.H, the Helmholtz Future Topic AMPro to S.H., and by the Deutsche Forschungsgemeinschaft Sonderforschungsbereich 1123 (B10) as well as the Deutsches Zentrum für Herz-Kreislauf-Forschung Junior Research Group Grant awarded to A.B.

Abstract

Metabolic complications in diabetic patients are driven by a combination of increased levels of nutrients and the presence of a proinflammatory environment. Methylglyoxal (MG) is a toxic byproduct of catabolism and has been strongly associated with the development of such complications. Macrophages are key mediators of inflammatory processes and their contribution to the development of metabolic complications has been demonstrated. However, a direct link between reactive metabolites and macrophage activation has not been demonstrated yet. Here, we show that acute MG treatment activated components of the p38 MAPK pathway and enhanced glycolysis in primary murine macrophages. MG induced a distinct gene expression profile sharing similarities with classically activated proinflammatory macrophages as well as metabolically activated macrophages usually found in obese patients. Transcriptomic analysis revealed a set of 15 surface markers specifically upregulated in MG-treated macrophages, thereby establishing a new set of targets for diagnostic or therapeutic purposes under high MG conditions, including diabetes. Overall, our study defines a new polarization state of macrophages that may specifically link aberrant macrophage activation to reactive metabolites in diabetes.

Author Contributions

F-F.T., C.M., and D.H. performed the majority of experiments. S.K. analysed the RNA-Seq data. T.F. performed the quantification of Methylglyoxal. G.W., A.B., and P.N. contributed with experimental advice and discussion of the data. F-F.T., CM., and S.H. conceptually designed the study and analysed the data. F.T., C.M., and S.H. wrote the manuscript.


* F.F.T. and C.M. contributed equally and share the first authorship position.


** S.K. and D.H. share the second authorship position.


Supplementary Material



Publication History

Received: 04 November 2020

Accepted: 09 February 2021

Publication Date:
09 May 2021 (online)

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany