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Epithelial antimicrobial defence of the skin and intestine

Nature Reviews Immunology volume 12, pages 503–516 (2012)Cite this article

Subjects

Key Points

  • Mammalian intestine and skin interface with the external environment and are thus in contact with both pathogenic and commensal microorganisms. Antimicrobial proteins produced by epithelial cells are essential for defending against microbial challenges at these tissue sites.

  • Mammalian antimicrobial proteins are members of a diverse array of protein families and kill microorganisms through various mechanisms, including enzymatic attack and membrane disruption.

  • Several antimicrobial proteins also function as potent immune regulators that modulate downstream immune responses to microorganisms.

  • The expression, secretion and activity of antimicrobial proteins are tightly controlled. Regulation is multifaceted, encompassing both transcriptional and post-translational mechanisms.

  • Antimicrobial proteins function in vivo to limit pathogen colonization, to determine microbiota composition and to restrict microbiota access to host tissues.

  • Dysregulation of antimicrobial protein function is associated with diseases of the intestine and skin. These include inflammatory bowel disease and skin disorders such as atopic dermatitis, rosacea and psoriasis.

Abstract

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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Figure 1: Epithelial barriers of the intestine and skin.
Figure 2: Regulatory mechanisms that shape antimicrobial protein expression and function.
Figure 3: Functions of antimicrobial proteins in the defence of body surfaces.
Figure 4: Dysregulation of antimicrobial proteins in disease.

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Acknowledgements

R.L.G. and L.V.H. thank their students and colleagues for the many discussions that contributed to the ideas in this manuscript. Work in R.L.G.'s laboratory is supported by US National Institutes of Health grants AR052728, AI052453, AI083358, contract HHSN272201000020C and a Merit Award from the Veterans Administration. Work in L.V.H.'s laboratory is supported by the Howard Hughes Medical Institute, the US National Institutes of Health (DK070855), the Burroughs Wellcome Foundation and the Crohn's and Colitis Foundation.

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Authors and Affiliations

  1. Division of Dermatology, Department of Medicine, and Department of Pediatrics, University of California-San Diego, San Diego, 92093, California, USA

    Richard L. Gallo

  2. VA San Diego Healthcare System, San Diego, 92161, California, USA

    Richard L. Gallo

  3. The Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Lora V. Hooper

  4. Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Lora V. Hooper

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  1. Richard L. Gallo
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Glossary

Commensal microorganisms

The microorganisms that are present in normal, healthy individuals. These microorganisms live in the gastrointestinal tract and at other body sites, and generally engage in mutually beneficial relationships with their hosts.

C-type lectins

A large family of receptors that have carbohydrate recognition domains. The designation 'C-type' is based on the structure of the carbohydrate recognition domain. Several epithelial antimicrobial proteins, including regenerating islet-derived protein 3γ (REG3γ) and hepatointestinal pancreatic/pancreatitis-associated protein (HIP/PAP), are members of the C-type lectin family.

Ribonucleases

(RNases). Enzymes that catalyse the breakdown of RNA. Several antimicrobial proteins (for example, RNase7 and angiogenin 4) have RNase activity, although the significance of this for the antibacterial activity of these proteins is not known.

Cryptdins

Mouse α-defensins are frequently designated as 'cryptdins', which stands for 'crypt α-defensins'.

Peptidoglycan

A polymer of sugars, crosslinked by short peptides, that is a crucial component of the bacterial cell wall.

Enterocytes

Absorptive columnar epithelial cells that are the major epithelial lineage of the intestine.

Paneth cells

A specialized epithelial cell lineage that produces most of the antimicrobial proteins in the small intestine.

Crypts of Lieberkühn

Invaginations of the small intestinal surface that contain both Paneth cells and intestinal stem cells.

Pattern recognition receptors

(PRRs). Host receptors (such as Toll-like receptors (TLRs) or NOD-like receptors (NLRs)) that can sense pathogen-associated molecular patterns and initiate signalling cascades that lead to an innate immune response. These can be membrane bound (for example, TLRs) or soluble cytoplasmic receptors (for example, RIG-I, MDA5 and NLRs).

Germ-free animals

Animals that are reared in isolators, without exposure to microorganisms.

WNT pathway

A signalling pathway that controls several physiological processes, including embryogenesis and cancer development. It also controls normal biological functions in adult animals and is essential for the expression of α-defensins in the small intestine.

Conventionally raised mice

Mice that have been raised with normal exposure to microorganisms.

Innate lymphoid cells

(ILCs). A diverse family of immune cells that produce cytokines and function to coordinate immunity and inflammation in body surface tissues such as the intestine and the lung. Although their developmental origins are still unclear, they phenotypically resemble natural killer cells.

Climax community

A mature, stable community of organisms that develops through a process of ecological succession and remains in a steady state for an extended period of time.

Anaerobes

Microorganisms that grow in the absence of oxygen.

16S ribosomal RNA gene sequencing

Determination of the sequences of the variable regions of bacterial ribosomal RNA genes, which are conserved within a species but differ between species. It is frequently used as a culture-independent technique for evaluating the composition of bacterial communities.

Segmented filamentous bacteria

(SFB). A group of Gram-positive bacteria that are members of the intestinal microbiota of mice. They are characterized by their ability to adhere to the intestinal surface and are frequently immunostimulatory.

Quorum sensing

A system used by bacteria to coordinate gene expression as a function of population density.

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Gallo, R., Hooper, L. Epithelial antimicrobial defence of the skin and intestine. Nat Rev Immunol 12, 503–516 (2012). https://doi.org/10.1038/nri3228

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