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

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

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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.

Original language	English
Pages (from-to)	821-835
Number of pages	15
Journal	Cell Metabolism
Volume	19
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2014.03.029
State	Published - 6 May 2014
Externally published	Yes

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Nagareddy, P. R., Kraakman, M., Masters, S. L., Stirzaker, R. A., Gorman, D. J., Grant, R. W., Dragoljevic, D., Hong, E. S., Abdel-Latif, A., Smyth, S. S., Choi, S. H., Korner, J., Bornfeldt, K. E., Fisher, E. A., Dixit, V. D., Tall, A. R., Goldberg, I. J., & Murphy, A. J. (2014). Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metabolism, 19(5), 821-835. https://doi.org/10.1016/j.cmet.2014.03.029

@article{d615598480d34ff5a58c7ad5a6e29436,

title = "Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity",

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.",

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

note = "Funding Information: We thank Bristol-Myers Squibb for the SGLT2 inhibitor. We thank Melinda Coughlan (Baker IDI) for the db/db mice and the Flow Cytometry and Imaging facilities at Columbia University. This project was funded by grants from the NIH (U01-HL087945 and DK095684 to I.J.G. and E.A.F.; HL45095 to I.J.G.; HL87123 to A.R.T.; P01HL092969, R01HL097365, and R01HL062887 to K.E.B.; and AG031797, AG043608, AI105097, and DK090556 to V.D.D.), grants from the National Institute of Diabetes and Digestive and Kidney Diseases (RO1DK072011 to J.K. and UL1TR000117 and P20 GM103527 to A.A.-L.), and a Pilot and Feasibility Award from the Diabetes Complications Consortium (to I.J.G.). R.W.G. was supported by NIH T32 training grant DK064584-10. P.R.N. was supported by a postdoctoral fellowship from the Canadian Institutes of Health Research and a Pathway to Independence Award from the NIH (1K99HL122505). A.J.M. was supported in part by a postdoctoral fellowship from the American Heart Association (12POST11890019), a Viertel award from Diabetes Australia Research Trust Australia, and a National Health and Medical Research Council program grant (APP10363652). The authors acknowledge support from BMS Pharmaceutical Company. ",

year = "2014",

month = may,

day = "6",

doi = "10.1016/j.cmet.2014.03.029",

language = "English",

volume = "19",

pages = "821--835",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "5",

}

Nagareddy, PR, Kraakman, M, Masters, SL, Stirzaker, RA, Gorman, DJ, Grant, RW, Dragoljevic, D, Hong, ES, Abdel-Latif, A, Smyth, SS, Choi, SH, Korner, J, Bornfeldt, KE, Fisher, EA, Dixit, VD, Tall, AR, Goldberg, IJ & Murphy, AJ 2014, 'Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity', Cell Metabolism, vol. 19, no. 5, pp. 821-835. https://doi.org/10.1016/j.cmet.2014.03.029

TY - JOUR

T1 - Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity

AU - Nagareddy, Prabhakara R.

AU - Kraakman, Michael

AU - Masters, Seth L.

AU - Stirzaker, Roslynn A.

AU - Gorman, Darren J.

AU - Grant, Ryan W.

AU - Dragoljevic, Dragana

AU - Hong, Eun Shil

AU - Abdel-Latif, Ahmed

AU - Smyth, Susan S.

AU - Choi, Sung Hee

AU - Korner, Judith

AU - Bornfeldt, Karin E.

AU - Fisher, Edward A.

AU - Dixit, Vishwa Deep

AU - Tall, Alan R.

AU - Goldberg, Ira J.

AU - Murphy, Andrew J.

N1 - Funding Information: We thank Bristol-Myers Squibb for the SGLT2 inhibitor. We thank Melinda Coughlan (Baker IDI) for the db/db mice and the Flow Cytometry and Imaging facilities at Columbia University. This project was funded by grants from the NIH (U01-HL087945 and DK095684 to I.J.G. and E.A.F.; HL45095 to I.J.G.; HL87123 to A.R.T.; P01HL092969, R01HL097365, and R01HL062887 to K.E.B.; and AG031797, AG043608, AI105097, and DK090556 to V.D.D.), grants from the National Institute of Diabetes and Digestive and Kidney Diseases (RO1DK072011 to J.K. and UL1TR000117 and P20 GM103527 to A.A.-L.), and a Pilot and Feasibility Award from the Diabetes Complications Consortium (to I.J.G.). R.W.G. was supported by NIH T32 training grant DK064584-10. P.R.N. was supported by a postdoctoral fellowship from the Canadian Institutes of Health Research and a Pathway to Independence Award from the NIH (1K99HL122505). A.J.M. was supported in part by a postdoctoral fellowship from the American Heart Association (12POST11890019), a Viertel award from Diabetes Australia Research Trust Australia, and a National Health and Medical Research Council program grant (APP10363652). The authors acknowledge support from BMS Pharmaceutical Company.

PY - 2014/5/6

Y1 - 2014/5/6

N2 - 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.

AB - 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.

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U2 - 10.1016/j.cmet.2014.03.029

DO - 10.1016/j.cmet.2014.03.029

M3 - Article

C2 - 24807222

AN - SCOPUS:84899948384

SN - 1550-4131

VL - 19

SP - 821

EP - 835

JO - Cell Metabolism

JF - Cell Metabolism

IS - 5

ER -

Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity

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