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.
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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

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Figure 5

DAB2 in myeloid cells regulates HFD-induced adipose tissue inflammation and insulin resistance.

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DAB2 in myeloid cells regulates HFD-induced adipose tissue inflammation ...
Dab2fl/fl and Dab2fl/fl Lysm-Cre female mice were fed an HFD for 12 weeks. (A) Serum IL-6 levels after an HFD for 12 weeks as analyzed by ELISA. (B) Il6 and Tnfa mRNA levels in adipose tissue were analyzed by qPCR. (C) pPCR phenotypic characterization of cells isolated from the SVF in adipose tissue. (D–G) Cells isolated from the SVF in gonadal adipose tissue of HFD-fed Dab2fl/fl and Dab2fl/fl Lysm-Cre mice were stained with CD45-APC-Cy7, CD11b-FITC, CD206-PE, and CD11c-AF647 Abs and subjected to FACS analysis. CD45+CD11b+ cells were analyzed for the percentage of cells that were CD11c+ and for the MFI of CD11c (D), and CD45+CD11b+ cells were analyzed for the percentage of cells that were CD206+ and for the MFI of CD206 (E). Each point represents 1 mouse in the MFI graphs in D and E. *P = 0.003, by 2-tailed, unpaired Student’s t test (D) and *P = 0.004, by 2-tailed, unpaired Student’s t test with Welch’s correction (E). Absolute numbers of CD45+ (F) and CD45+CD11b+ (G) cells per gram of gonadal adipose tissue were quantified and showed no difference in cell infiltration levels between HFD-fed Dab2fl/fl and Dab2fl/fl Lysm-Cre mice. For glucose tolerance tests (H) and insulin tolerance tests (I), mice were fasted for 6 hours and injected i.p. with a 1 g/kg glucose bolus or 0.75 U/kg insulin, respectively, and blood glucose levels were measured in tail blood by glucometer. Data were analyzed by calculating the AUC and represent the mean ± SEM. n = 10–12. *P < 0.05, by 2-tailed, unpaired Student’s t test.