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


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.

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Available from: Darrell Cass, Oct 09, 2015
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    • "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). "
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    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.
    Journal of Cell Science 09/2015; DOI:10.1242/jcs.175539 · 5.43 Impact Factor
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    • "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]. "
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    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.
    Matrix biology: journal of the International Society for Matrix Biology 05/2015; 8. DOI:10.1016/j.matbio.2015.05.006 · 5.07 Impact Factor
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    • "Interestingly, although mice lacking the TGF␤-activating integrin ␣v␤8 on immune cells develop autoimmunity, this is not as severe as mice that lack global function of integrins ␣v␤6 and ␣v␤8 (Aluwihare et al. 2009). Global integrin ␣v␤6−/− mice develop only mild inflammation of the lung and skin (Huang et al. 1996). "
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    ABSTRACT: Regulation of an immune response requires complex crosstalk between cells of the innate and adaptive immune systems, via both cell-cell contact and secretion of cytokines. An important cytokine with a broad regulatory role in the immune system is transforming growth factor-β (TGF-β). TGF-β is produced by and has effects on many different cells of the immune system, and plays fundamental roles in the regulation of immune responses during homeostasis, infection and disease. Although many cells can produce TGFβ, it is always produced as an inactive complex that must be activated to bind to the TGFβ receptor complex and promote downstream signalling. Thus, regulation of TGFβ activation is a crucial step in controlling TGFβ function. This review will discuss how TGFβ controls diverse immune responses and how TGFβ function is regulated, with a focus on recent work highlighting a critical role for the integrin αvβ8 expressed by dendritic cells in activating TGFβ.
    Immunobiology 07/2012; 217(12). DOI:10.1016/j.imbio.2012.06.009 · 3.04 Impact Factor
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