title: 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.forename: Samantha E
authors.initials: SE
authors.lastname: Adamson
authors.forename: Rachael
authors.initials: R
authors.lastname: Griffiths
authors.forename: Radim
authors.initials: R
authors.lastname: Moravec
authors.forename: Subramanian
authors.initials: S
authors.lastname: Senthivinayagam
authors.forename: Garren
authors.initials: G
authors.lastname: Montgomery
authors.forename: Wenshu
authors.initials: W
authors.lastname: Chen
authors.forename: Jenny
authors.initials: J
authors.lastname: Han
authors.forename: Poonam R
authors.initials: PR
authors.lastname: Sharma
authors.forename: Garrett R
authors.initials: GR
authors.lastname: Mullins
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Gorski
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Cooper
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kadl
authors.forename: Kyle
authors.initials: K
authors.lastname: Enfield
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Braciale
authors.forename: Thurl E
authors.initials: TE
authors.lastname: Harris
authors.forename: Norbert
authors.initials: N
authors.lastname: Leitinger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D033942:Adaptor Proteins, Vesicular Transport / Q000096:biosynthesis* / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D015434:Panniculitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; C478773:Dab2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C498143:RELA protein, human; C498144:Rela protein, mouse; C120635:TAX1BP1 protein, human; D051996:Transcription Factor RelA; D025521:Tumor Suppressor Proteins; D051550:I-kappa B Kinase