Dean Sheppard, MD
In vivo function of integrins and molecular basis of lung diseases

Dr. Sheppard’s research focuses on how cells use members of the integrin family to detect, modify and respond to spatially restricted extracellular clues. Much of the work is focused on five members of this family, the epithelial-restricted integrin, αvβ6, and the widely expressed integrins α9β1, αvβ5, αvβ3 and αvβ8. αvβ6 has two distinct functions: enhancement of cell proliferation, and activation of latent transforming growth factor beta (TGFβ), that depend on distinct sequences in the β6 cytoplasmic domain. We have shown that the latter function plays a central role in tissue fibrosis, acute lung injury, protection from pulmonary emphysema, tumor invasion and in the airway hyperresponsiveness that follows chronic allergen challenge. Currently we are identifying pathways that regulate each of these responses. We have also identified several components of the signaling pathways by which cells regulate integrin-dependent TGFβ activation and are currently determining the injury-related stimuli that activate these pathways. In parallel we are examining the mechanisms by which TGFβ activity is regulated in liver and cardiac fibrosis.

The αvβ8 integrin also activates TGFβ. Mice we have generated lacking this integrin on dendritic cells develop auto-immunity and colitis, suggesting αvβ8-mediated TGFβ activation on dendritic cells can negatively regulate adaptive immunity. However, these mice are protected from CNS injury in a model of experimental auto-immune encephalitis and are also protected in a model of allergic asthma, effects that appear to depend on roles for TGFβ in induced Th17 cells and a novel role in facilitating recall responses to antigens. Mice lacking this integrin only in T cells develop exaggerated auto-immune responses. We are currently characterizing the mechanisms underlying these effects, the mechanisms by which this process is regulated during the induction of adaptive immune responses, and the relevance of these pathways in various models of immune-mediated disease.

α9β1 is expressed by a wide variety of cells and recognizes at least 15 distinct ligands. α9β1 is critical for cell migration, an effect that depends on unique sequences in the a9 cytoplasmic domain. We are identifying and characterizing proteins that specifically bind to these sequences and the downstream signals that mediate enhanced migration. As α9 ko mice are not viable, we have generated mice expressing a conditional null allele to better the role of this integrin in vivo. α9 knockout mice die from a defect in lymphatic development, and we are currently working to identify the molecular mechanisms by which this integrin contributes to lymphangiogenesis and angiogenesis. Mice lacking this integrin only in smooth muscle cells develop exaggerated airway narrowing similar to human asthma. We are currently characterizing the molecular mechanisms by which this integrin normal prevents exaggerated contraction of airway smooth muscle.

αvβ5 is also widely expressed, but mice lacking this integrin are phenotypically normal. However, these mice are dramatically protected in multiple models of acute lung injury and of septic shock. This phenotype is explained, at least in part, by a central role for this integrin in regulating reorganization of the actin cytoskeleton in activated endothelial cells. We are currently examining the mechanisms by which this integrin, and its close relative, αvβ3, exert opposing effects on actin organization, vascular permeability and tissue edema.

Munger JS, Huang XZ , Kawakatsu H , Griffiths MJD, Dalton SL, Wu JF, Pittet JF, Kaminiski N, Garat C, Matthay MA, Rifkin DB, Sheppard D. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999, 96: 319-328.

Morris DG, Huang X, Kaminski N, Wang Y, Shapiro SD, Dolganov G, Glick, A, Sheppard D. Loss of integrin αvβ6-mediated TGFβ activation causes Mmp12-dependent emphysema. Nature 2003 422:169-173.