Appropriate macrophage activation requires metabolic reprogramming, but the underlying basis remains poorly understood. This knowledge gaps contrasts with the extensive literature on other aspects of macrophage activation, including signal transduction and transcriptional regulation. Here we show that during M2 activation, activation of Akt/mTORC1 signaling by IL-4 leads to increased production of Acetyl-CoA (Ac-CoA), leading to enhanced histone acetylation and transcriptional control of the M2 program. Importantly, only a subset of M2 genes is regulated by the Akt-mTORC1 axis. Our preliminary data also indicates that Akt signaling may integrate signals reflecting the cellular and organismal metabolic state to control of M2 activation. Physiological feeding increases Akt signaling and M2 polarization of adipose tissue macrophages (ATMs), while diet-induced obesity reduces Akt activity and M2 activation in ATMs. Because ATM M2 activation is important for maintaining insulin sensitivity, Akt signaling may couple physiological increases in metabolic signals to an adaptive M2 response, while chronic metabolic stress corrupts the Akt pathway to impair M2 polarization and promote metabolic dysregulation. Here we will pursue these findings in two Aims. First, we will determine the basis by which Akt/mTORC1 signaling couple's histone acetylation to the induction of a subset of the M2 program. Second, we will examine a role for Akt signaling in ATM M2 activation and metabolic homeostasis using a mouse model of diet-induced obesity.

Public Health Relevance

Macrophage activation or polarization to distinct functional states is a critical component of host defense, inflammatory diseases, tissue repair, metabolic homeostasis, and other physiological and pathophysiological processes. Such polarization requires the integrated activities of intracellular signaling pathways and gene induction, and presumably also cellular metabolism although little information is available. Here we seek to elucidate how a metabolic pathway and nutrient availability modulates macrophage activation, which could lead to new therapeutic strategies to control macrophage metabolism and polarization in diverse disease settings.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI119763-02
Application #
9210595
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Palker, Thomas J
Project Start
2016-01-27
Project End
2017-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Harvard University
Department
Genetics
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Covarrubias, Anthony J; Aksoylar, Halil Ibrahim; Yu, Jiujiu et al. (2016) Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. Elife 5: