Disabled homolog 2 controls macrophage phenotypic polarization and adipose tissue inflammation
Samantha E. Adamson, … , Thurl E. Harris, Norbert Leitinger
Samantha E. Adamson, … , Thurl E. Harris, Norbert Leitinger
Published February 29, 2016
Citation Information: J Clin Invest. 2016;126(4):1311-1322. https://doi.org/10.1172/JCI79590.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 2

Disabled homolog 2 controls macrophage phenotypic polarization and adipose tissue inflammation

Abstract

Acute and chronic tissue injury results in the generation of a myriad of environmental cues that macrophages respond to by changing their phenotype and function. This phenotypic regulation is critical for controlling tissue inflammation and resolution. Here, we have identified the adaptor protein disabled homolog 2 (DAB2) as a regulator of phenotypic switching in macrophages. Dab2 expression was upregulated in M2 macrophages and suppressed in M1 macrophages isolated from both mice and humans, and genetic deletion of Dab2 predisposed macrophages to adopt a proinflammatory M1 phenotype. In mice with myeloid cell–specific deletion of Dab2 (Dab2fl/fl Lysm-Cre), treatment with sublethal doses of LPS resulted in increased proinflammatory gene expression and macrophage activation. Moreover, chronic high-fat feeding exacerbated adipose tissue inflammation, M1 polarization of adipose tissue macrophages, and the development of insulin resistance in DAB2-deficient animals compared with controls. Mutational analyses revealed that DAB2 interacts with TNF receptor–associated factor 6 (TRAF6) and attenuates IκB kinase β–dependent (IKKβ-dependent) phosphorylation of Ser536 in the transactivation domain of NF-κB p65. Together, these findings reveal that DAB2 is critical for controlling inflammatory signaling during phenotypic polarization of macrophages and suggest that manipulation of DAB2 expression and function may hold therapeutic potential for the treatment of acute and chronic inflammatory disorders.

Authors

Samantha E. Adamson, Rachael Griffiths, Radim Moravec, Subramanian Senthivinayagam, Garren Montgomery, Wenshu Chen, Jenny Han, Poonam R. Sharma, Garrett R. Mullins, Stacey A. Gorski, Jonathan A. Cooper, Alexandra Kadl, Kyle Enfield, Thomas J. Braciale, Thurl E. Harris, Norbert Leitinger

×

Figure 4

Dab2 deficiency promotes M1 macrophage phenotypic polarization and regulates phenotypic switching.

Options: View larger image (or click on image) Download as PowerPoint
Dab2 deficiency promotes M1 macrophage phenotypic polarization and regu...
(A) qPCR analysis of Il1b, Tnfa, Il6, and Ccl2 mRNA expression in Dab2fl/fl and Dab2fl/fl Lysm-Cre BMDMs polarized to M1 for 3 hours. Results were normalized to B2m mRNA and are presented as fold change relative to Dab2fl/fl. Data represent the mean ± SEM of 4 technical replicates and are representative of 2 independent experiments. *P < 0.05, by 2-tailed, unpaired Student’s t test or Mann-Whitney U test. (B) BMDMs from Dab2fl/fl and Dab2fl/fl Lysm-Cre mice were serum starved for 3 hours (M0) and then polarized to M2 (IL-4) or M1 (LPS and IFN-γ) for 8 hours. Media were removed, and then M2 macrophages were treated with M1 stimuli (LPS and IFN-γ), and M1 macrophages were treated with M2 stimuli (IL-4) for an additional 8 hours. qPCR was performed to measure Nos2 and Il6 gene expression in M2 macrophages polarized to M1. Arg1 and Mgl1 expression was measured in M1 macrophages polarized to M2. Data represent the mean ± SEM of quadruplicate experiments. *P < 0.05, by 2-tailed, unpaired Student’s t test or Mann-Whitney U test.