Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin

Lung Biology Center, University of California, San Francisco 94143, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 06/1996; 133(4):921-8.
Source: PubMed

ABSTRACT

The integrin alpha v beta 6 is only expressed in epithelial cells. In healthy adult epithelia, this receptor is barely detectable, but expression is rapidly induced following epithelial injury. Mice homozygous for a null mutation in the gene encoding the beta 6 subunit had juvenile baldness associated with infiltration of macrophages into the skin, and accumulated activated lymphocytes around conducting airways in the lungs. Beta 6-/- mice also demonstrated airway hyperresponsiveness to acetylcholine, a hallmark feature of asthma. These results suggest that the epithelial integrin alpha v beta 6 participates in the modulation of epithelial inflammation. Genetic or acquired alterations in this integrin could thus contribute to the development of inflammatory diseases of epithelial organs, such as the lungs and skin.

Download full-text

Full-text

Available from: Darrell Cass
  • Source
    • "In humans, αv is up-regulated during wound healing (Cavani et al., 1993; Clark et al., 1996). Young β6 -/-mice do not display wound healing defects; however, wound healing is delayed in aged β6 null mice compared to age-matched controls (AlDahlawi et al., 2006; Huang et al., 1996). In contrast, constitutive expression of β6 in the epidermis leads to formation of chronic wounds (Häkkinen et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Integrins play crucial roles in epithelial adhesion, proliferation, wound healing and cancer. In the epidermis, the roles of many integrin subunits are incompletely defined and mechanistic details regarding their functions are lacking. We performed a multiplexed shRNA screen to define roles for each subunit in human organotypic skin. We show that αv heterodimers are essential for epidermal generation, with αv loss driving a keratinocyte G1-S cell cycle block. Surprisingly, αv is not localized within keratinocyte focal adhesions, and instead maintains proliferation by controlling c-myc translation through FAK, p38 and p90RSK. These phenotypes depend only on αv's binding partners β5 and β6. By inducibly depleting αv in both normal organotypic epidermis and Ras-driven invasive neoplasia, we show that αv is required for de novo tissue generation and neoplastic invasion, but dispensable for epidermal maintenance. Integrins αvβ5 and αvβ6 are similarly required for neoplastic invasion, thus identifying αvβ5 and αvβ6 heterodimers as potential therapeutic targets for epidermal squamous cell carcinoma.
    Full-text · Article · Sep 2015 · Journal of Cell Science
  • Source
    • "A great number of studies have established that integrin binding is the main prerequisite for latent TGF-β1 activation, in particular in conditions of inflammation and fibrosis [110]. Knocking out integrin subunits that activate TGF-β1, including β6 [113], αv [114], and β8 [115], and mutation of the integrin binding site in LAP [116] all produce defects that are similar to the phenotype of the TGF-β1 knockout mouse [103]. Seminal work of Sheppard and coworkers have shown that β6 integrin was unable to active latent TGF-β1 without a functional cytoplasmic tail that intracellularly links to the actin cytoskeleton [117]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Physiological tissue repair aims at restoring the mechano-protective properties of the extracellular matrix. Consequently, redundant regulatory mechanisms are in place ensuring that tissue remodelling terminates once matrix homeostasis is re-established. If these mechanisms fail, stromal cells become continuously activated, accumulate excessive amounts of stiff matrix, and fibrosis develops. In this mini-review, I develop the hypothesis that the mechanical state of the extracellular matrix and the pro-fibrotic transforming growth factor (TGF)-β1 cooperate to regulate the remodelling activities of stromal cells. TGF-β1 is stored in the matrix as part of a large latent complex and can be activated by cell contractile force that is transmitted by integrins. Matrix straining and stiffening lower the threshold for TGF-β1 activation by increasing the mechanical resistance to cell pulling. Different elements of this mechanism can be pharmacologically targeted to interrupt the mechanical positive feedback loop of fibrosis, including specific integrins and matrix protein interactions. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · May 2015 · Matrix biology: journal of the International Society for Matrix Biology
  • Source
    • "In contrast, the expression of integrin b4 in the epidermis of Col1a2-CTGF transgenic mice was irregularly distributed all around the hyperproliferative epithelial cells (Fig. 1A,B, red). Another epithelial specific integrin, avb6, that is barely detectable in quiescent epithelial cells is rapidly induced upon epithelial injury and imparts increased migratory properties to these cells (Huang et al., 1996). Interestingly, we observed a marked enhancement in the expression of integrin b6 in the epidermis of Col1a2-CTGF transgenic mice compared to littermate controls (Fig. 1C,D) suggesting that these cells might have increased migratory properties. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Connective tissue growth factor (CTGF) plays an important role in the pathogenesis of chronic fibrotic diseases. However, the mechanism by which paracrine effects of CTGF control the cell fate of neighboring epithelial cells is not known. In this study, we investigated the paracrine effects of CTGF overexpressed in fibroblasts of Col1a2-CTGF transgenic mice on epithelial cells of skin and lung. The skin and lungs of Col1a2-CTGF transgenic mice were examined for phenotypic markers of epithelial activation and differentiation and stimulation of signal transduction pathways. In addition to an expansion of the dermal compartment in Col1a2-CTGF transgenic mice, the epidermis was characterized by focal hyperplasia and basal cells stained positive for αSMA, Snail, S100A4 and Sox9, indicating that these cells had undergone a change in their genetic program. Activation of p-p38 and pErk1/2 was observed in the granular and cornified layers of the skin. Lung fibrosis was associated with a marked increase in cells co-expressing epithelial and mesenchymal markers in the lesional and unaffected lung tissue of Col1a2-CTGF mice. In epithelial cells treated with TGFβ, CTGF-specific siRNA-mediated knockdown suppressed Snail, Sox9, S100A4 protein levels and restored E-cadherin levels. Both adenoviral expression of CTGF in epithelial cells and treatment with recombinant CTGF induced EMT-like morphological changes and expression of α-SMA. Our in vivo and in vitro data supports the notion that CTGF expression in mesenchymal cells in the skin and lungs can cause changes in the differentiation program of adjacent epithelial cells. We speculate that these changes might contribute to fibrogenesis.
    Preview · Article · Mar 2013 · Journal of Cell Science
Show more