Epithelial antimicrobial defence of the skin and intestine

Division of Dermatology, Department of Medicine, University of California-San Diego, San Diego, California 92093, USA.
Nature Reviews Immunology (Impact Factor: 34.99). 06/2012; 12(7):503-16. DOI: 10.1038/nri3228
Source: PubMed


Surface tissues of the body such as the skin and intestinal tract are in direct contact with the external environment and are thus continuously exposed to large numbers of microorganisms. To cope with the substantial microbial exposure, epithelial surfaces produce a diverse arsenal of antimicrobial proteins that directly kill or inhibit the growth of microorganisms. In this Review, we highlight new advances in our understanding of how epithelial antimicrobial proteins protect against pathogens and contribute to microbiota-host homeostasis at the skin and gut mucosae. Further, we discuss recent insights into the regulatory mechanisms that control antimicrobial protein expression. Finally, we consider how impaired antimicrobial protein expression and function can contribute to disease.

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    • "Antimicrobial peptides (AMPs) are evolutionarily conserved peptides found in almost all plants and animals. In mammals, they are expressed by epithelial cells under steady-state conditions and by infiltrating immune cells during inflammation (Gallo and Hooper, 2012). AMPs are cationic polypeptides with the ability to kill microorganisms by disrupting the integrity of their membrane (Zasloff, 2002). "
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    ABSTRACT: Antimicrobial peptides (AMPs) expressed by epithelial and immune cells are largely described for the defense against invading microorganisms. Recently, their immunomodulatory functions have been highlighted in various contexts. However how AMPs expressed by non-immune cells might influence autoimmune responses in peripheral tissues, such as the pancreas, is unknown. Here, we found that insulin-secreting β-cells produced the cathelicidin related antimicrobial peptide (CRAMP) and that this production was defective in non-obese diabetic (NOD) mice. CRAMP administrated to prediabetic NOD mice induced regulatory immune cells in the pancreatic islets, dampening the incidence of autoimmune diabetes. Additional investigation revealed that the production of CRAMP by β-cells was controlled by short-chain fatty acids produced by the gut microbiota. Accordingly, gut microbiota manipulations in NOD mice modulated CRAMP production and inflammation in the pancreatic islets, revealing that the gut microbiota directly shape the pancreatic immune environment and autoimmune diabetes development. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Immunity
    • "These functions, in addition to those mentioned above, also include the activities of the epidermal and follicular pigmentary systems protecting the skin against the damaging effects of solar radiation and other physicochemical stresses [15] [16], and by determining skin pigmentation playing a role in social communication and camouflage [7]. The innate and adaptive skin immune systems provide defense against infectious agents (viruses, rickets, bacteria, fungi and parasites), and are also involved in the integration of the response to foreign and self-antigens through interactions with the central immune system, or protect against cancer development [17] [18] [19]. Adnexal (secretory in nature) structures participate in thermoregulatory and sensory functions, regulation of electrolyte balance, release of substances strengthening the epidermal barrier, as well as being involved in social communication [1] [6] [9]. "
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    ABSTRACT: The mammalian skin is a heterogeneous organ/tissue covering our body, showing regional variations and endowed with neuroendocrine activities. The latter is represented by its ability to produce and respond to neurotransmitters, neuropeptides, hormones and neurohormones, of which expression and phenotypic activities can be modified by ultraviolet radiation, chemical and physical factors, as well as by cytokines. The neuroendocrine contribution to the responses of skin to stress is served, in part, by local synthesis of all elements of the hypothalamo-pituitary-adrenal axis. Skin with subcutis can also be classified as a steroidogenic tissue because it expresses the enzyme, CYP11A1, which initiates steroid synthesis by converting cholesterol to pregnenolone, as in other steroidogenic tissues. Pregnenolone, or steroidal precursors from the circulation, are further transformed in the skin to corticosteroids or sex hormones. Furthermore, in the skin CYP11A1 acts on 7-dehydrocholesterol with production of 7-dehydropregnolone, which can be further metabolized to other Δ7steroids, which after exposure to UVB undergo photochemical transformation to vitamin D like compounds with a short side chain. Vitamin D and lumisterol, produced in the skin after exposure to UVB, are also metabolized by CYP11A1 to several hydroxyderivatives. Vitamin D hydroxyderivatives generated by action of CYP11A1 are biologically active and are subject to further hydroxylations by CYP27B1, CYP27A1 and CP24A. Establishment of which intermediates are produced in the epidermis in vivo and whether they circulate on the systemic level represent a future research challenge. In summary, skin is a neuroendocrine organ endowed with steroid/secosteroidogenic activities. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · May 2015 · Steroids
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    • "The mucosal immune system in fish is in direct contact with the external environment and represents one of the primary barriers against pathogens. In higher vertebrates, intestinal epithelial cells (IECs) function as both physical barrier and immunocompetent cells producing a number of immune related molecules such as cytokines and host defense peptides (Gallo and Hooper, 2012). It is well established that teleost fish IECs produce a number of innate humoral defense factors (Gomez et al., 2013; Lazado and Caipang, 2014) and that they are also capable of overexpressing proinflammatory cytokines like IL-1β and TNF-α following a bacterial infection, suggesting their active contribution to the fish mucosal immune system (Komatsu et al., 2009; Mulder et al., 2007). "
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    ABSTRACT: The aim of the present study was to characterize intestinal immune mechanisms involved in the response to β-glucans in rainbow trout. Among the immune effectors regulated in response to immunostimulants, host defense peptides (HDPs) are abundantly expressed in epithelial linings, suggesting their important role in the mucosal immune response. Therefore, the immunomodulatory properties of expressed HDPs in the epithelial intestinal cells of rainbow trout in response to the β-glucan, zymosan, were assessed. The results showed that zymosan increased the production of the HDP, cathelicidin, and the cytokine, IL-1β, in the intestinal epithelial RTgutGC cell line at the transcript and protein levels. Thus, cathelicidin-2 variants were produced and were shown to (i) induce the production of IL-1β in RTgutGC cells and (ii) display a synergic effect with zymosan in IL-1β upregulation. Importantly, the colocalization of both rtCATH-2 and IL-1β was detected in the intestinal epithelial cells of rainbow trout fed with a 0.3% zymosan-supplemented diet. We propose that trout cathelicidins are expressed by intestinal epithelial cells and exert immunomodulatory effects to improve the local intestinal immune response triggered by immunostimulants. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Mar 2015 · Developmental and comparative immunology
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