Disabled homolog 2 controls macrophage phenotypic polarization and adipose tissue inflammation.

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 ß-dependent (IKKß-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.

Recent insights into pulmonary repair following virus-induced inflammation of the respiratory tract.

A hallmark of infection by respiratory viruses is productive infection of and the subsequent destruction of the airway epithelium. These viruses can also target other stromal cell types as well as in certain instances, CD45(+) hematopoietic cells either resident in the lungs or part of the inflammatory response to infection. The mechanisms by which the virus produces injury to these cell types include direct infection with cytopathic effects as a consequence of replication. Host mediated damage is also a culprit in pulmonary injury as both innate and adaptive immune cells produce soluble and cell-associated pro-inflammatory mediators. Recently, it has become increasingly clear that in addition to control of excess inflammation and virus elimination, the resolution of infection requires an active repair process, which is necessary to regain normal respiratory function and restore the lungs to homeostasis. The repair response must re-establish the epithelial barrier and regenerate the microarchitecture of the lung. Emerging areas of research have highlighted the importance of innate immune cells, particularly the newly described innate lymphoid cells, as well as alternatively activated macrophages and pulmonary stem cells in the repair process. The mechanisms by which respiratory viruses may impede or alter the repair response will be important areas of research for identifying therapeutic targets aimed at limiting virus and host mediated injury and expediting recovery.