Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity

Prabhakara R Nagareddy; Michael Kraakman; Seth L Masters; Roslynn A Stirzaker; Darren J Gorman; Ryan W Grant; Dragana Dragoljevic; Eun Shil Hong; Ahmed Abdel-Latif; Susan S Smyth; Sung Hee Choi; Judith Korner; Karin E Bornfeldt; Edward A Fisher; Vishwa Deep Dixit; Alan R Tall; Ira J Goldberg; Andrew J Murphy

doi:10.1016/j.cmet.2014.03.029

Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity

Cell Metab. 2014 May 6;19(5):821-35. doi: 10.1016/j.cmet.2014.03.029.

Authors

Prabhakara R Nagareddy¹, Michael Kraakman², Seth L Masters³, Roslynn A Stirzaker⁴, Darren J Gorman⁵, Ryan W Grant⁶, Dragana Dragoljevic², Eun Shil Hong⁷, Ahmed Abdel-Latif⁸, Susan S Smyth⁸, Sung Hee Choi⁷, Judith Korner⁹, Karin E Bornfeldt¹⁰, Edward A Fisher¹¹, Vishwa Deep Dixit¹², Alan R Tall⁵, Ira J Goldberg¹³, Andrew J Murphy¹⁴

Affiliations

¹ Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Internal Medicine, University of Kentucky, Lexington, KY 40514, USA.
² Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne VIC 3004, Australia.
³ Division of Inflammation, Walter and Eliza Hall Institute of Medical Research, Melbourne VIC 3052, Australia.
⁴ Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, New York, NY 10032, USA.
⁵ Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA.
⁶ Pennington Biomedical Research Institute, Louisiana State University, Baton Rouge, LA 70803, USA.
⁷ Department of Medicine, Seoul National University, Seoul 151-742, South Korea.
⁸ Department of Internal Medicine, University of Kentucky, Lexington, KY 40514, USA.
⁹ Division of Endocrinology, Department of Medicine, Columbia University, New York, NY 10032, USA.
¹⁰ Department of Medicine and Department of Pathology, University of Washington, Seattle, WA 98109, USA.
¹¹ Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA.
¹² Pennington Biomedical Research Institute, Louisiana State University, Baton Rouge, LA 70803, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
¹³ Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, New York, NY 10032, USA; Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York, NY 10016, USA.
¹⁴ Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne VIC 3004, Australia; Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Immunology, Monash University, Melbourne VIC 3004, Australia. Electronic address: [email protected].

Abstract

Obesity is associated with infiltration of macrophages into adipose tissue (AT), contributing to insulin resistance and diabetes. However, relatively little is known regarding the origin of AT macrophages (ATMs). We discovered that murine models of obesity have prominent monocytosis and neutrophilia, associated with proliferation and expansion of bone marrow (BM) myeloid progenitors. AT transplantation conferred myeloid progenitor proliferation in lean recipients, while weight loss in both mice and humans (via gastric bypass) was associated with a reversal of monocytosis and neutrophilia. Adipose S100A8/A9 induced ATM TLR4/MyD88 and NLRP3 inflammasome-dependent IL-1β production. IL-1β interacted with the IL-1 receptor on BM myeloid progenitors to stimulate the production of monocytes and neutrophils. These studies uncover a positive feedback loop between ATMs and BM myeloid progenitors and suggest that inhibition of TLR4 ligands or the NLRP3-IL-1β signaling axis could reduce AT inflammation and insulin resistance in obesity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue / metabolism*
Animals
Bone Marrow / metabolism
Carrier Proteins / metabolism
Cell Proliferation / physiology
Humans
Inflammasomes / metabolism
Interleukin-1beta / metabolism
Macrophages / metabolism*
Male
Mice
Mice, Inbred C57BL
Monocytes / metabolism*
Myeloid Differentiation Factor 88 / metabolism
Myelopoiesis / physiology*
NLR Family, Pyrin Domain-Containing 3 Protein
Neutrophils / metabolism
Obesity / metabolism*
Receptors, Interleukin-1 / metabolism
Toll-Like Receptor 4 / metabolism

Substances

Carrier Proteins
Inflammasomes
Interleukin-1beta
Myd88 protein, mouse
Myeloid Differentiation Factor 88
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Receptors, Interleukin-1
Tlr4 protein, mouse
Toll-Like Receptor 4

Abstract

Publication types

MeSH terms

Substances

Grants and funding