AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense

doi:10.1016/j.it.2008.12.003

Trends in Immunology

Volume 30, Issue 3, March 2009, Pages 131-141

https://doi.org/10.1016/j.it.2008.12.003 Get rights and content

Antimicrobial peptides (AMPs) are widely expressed and rapidly induced at epithelial surfaces to repel assault from diverse infectious agents including bacteria, viruses, fungi and parasites. Much information suggests that AMPs act by mechanisms that extend beyond their capacity to serve as gene-encoded antibiotics. For example, some AMPs alter the properties of the mammalian membrane or interact with its receptors to influence diverse cellular processes including cytokine release, chemotaxis, antigen presentation, angiogenesis and wound healing. These functions complement their antimicrobial action and favor resolution of infection and repair of damaged epithelia. Opposing this, some microbes have evolved mechanisms to inactivate or avoid AMPs and subsequently become pathogens. Thus, AMPs are multifunctional molecules that have a central role in infection and inflammation.

Section snippets

Antimicrobial peptides

Initially, the importance of antimicrobial peptides (AMPs) to mammalian immunity was underestimated compared to their role in less complex immune systems such as those found in plants and invertebrates. However, as the importance of innate immune defense systems of mammals was steadily uncovered, the essential role of AMPs in mammalian immunity became firmly established. Today, we are beginning to see that much of the importance of AMPs in mammals might lie in their multifunctional role. To

Expression and regulation of AMPs

Most AMPs are encoded in groups in the genome. For example, the human α-defensins HNP1 and 4 and HD5 and 6, and the β-defensins hBD1 and 2 are all mapped to a similar chromosomal location, 8p23, whereas human cathelicidin is located in chromosome 3p21.3 [24]. Their expression can be regulated both at the transcriptional and post-transcriptional levels, and the coordinated transcriptional regulation of AMP genes can lead to expression of multiple AMPs at a single site. As discussed earlier,

The selective antimicrobial activity of AMPs

In vitro, most AMPs act against many different types of microbes including gram-negative and gram-positive bacteria, protozoa, fungi and some viruses. This is particularly true for the mammalian AMPs that have maximal effectiveness against specific groups of organisms relevant to the tissue where the AMP is expressed. For instance, β-defensins exhibit activity against Staphylococcus aureus and Pseudomonas aeruginosa[38], which are relevant to skin infections, whereas α-defensins expressed in

AMP modulation of host inflammatory responses

As discussed previously, AMPs exhibit multiple functions related to their capacity to disrupt membranes. They have the ability to confer protection against a variety of pathogens and the potential to act as cytotoxic agents against certain type of cancers. However, the direct antimicrobial activity implicit to the term ‘AMP’ has strongly biased interpretation of the function of these peptides as ‘natural antibiotics’. This bias perhaps has delayed discovery of their other roles in immunity.

The

AMPs and their participation in disease

As discussed previously, AMPs have been shown to participate in alerting, mobilizing and amplifying innate and adaptive immune responses of the host, and will confer protection against microbial infections. Decreased expression of AMPs can increase susceptibility to infectious diseases. For example, the expression of AMPs such as cathelicidin, hBD2 and hBD3 is not increased in individuals with atopic dermatitis, despite the presence of skin inflammation. By contrast, patients with psoriasis

Microbial resistance to AMPs

Thus far, we have discussed AMPs as multifunctional peptides, acting directly to kill microbes and also through multiple indirect strategies that influence cellular function in the host. What is the benefit of a multidimensional strategy to respond to microbial invasion? The answer might lie in the lessons learned through use of pharmaceutically produced antibiotics, and how ineffective they can become with the evolution of microbial resistance. By acting through a single approach, antibiotic

Conclusions and perspectives

Great progress has been achieved in the last decade with respect to the mechanisms of AMP action and their complex role in our immune system. Along with the capacity of AMPs to directly kill microbes, AMPs also boost specific innate immune responses and exert selective immunomodulatory effects on the host. Upon exposure to danger, AMPs create an overall balance by inhibiting microbial growth, attenuating exacerbated inflammatory responses and stimulating certain beneficial aspects of

Acknowledgements

Work in the laboratory of R.L.G. is supported by NIH grants R01AR052728, R01AI052453, contract HHSN266200400029 and a VA Merit Award. We apologize to those authors whose work could not be cited because of space constraints.

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Antimicrobial peptides (AMPs), which are widely present in animals and plants, have a broad distribution, strong broad-spectrum antibacterial activity, low likelihood of developing drug resistance, high thermal stability and antiviral properties. The present study investigated the effects of adding AMPs from Hermetia illucens larvae on the growth performance, muscle composition, antioxidant capacity, immune response, gene expression, antibacterial ability and intestinal microbiota of Cherax quadricarinatus (red claw crayfish). Five experimental diets were prepared by adding 50 (M1), 100 (M2), 150 (M3) and 200 (M4) mg/kg of crude AMP extract from H. illucens larvae to the basal diet feed, which was also used as the control (M0). After an eight-week feeding experiment, it was discovered that the addition of 100–150 mg/kg of H. illucens larvae AMPs to the feed significantly improved the weight gain rate and specific growth rate of C. quadricarinatus. Furthermore, the addition of H. illucens larvae AMPs to the feed had no significant effect on the moisture content, crude protein, crude fat and ash content of the C. quadricarinatus muscle. The addition of 100–150 mg/kg of H. illucens larvae AMPs in the feed also increased the antioxidant capacity, nonspecific immune enzyme activity and related gene expression levels in C. quadricarinatus, thereby enhancing their antioxidant capacity and immune function. The H. illucens larvae AMPs improved the structure and composition of the intestinal microbiota of C. quadricarinatus, increasing the microbial community diversity of the crayfish gut. Finally, the addition of 100–150 mg/kg of H. illucens larvae AMPs in the feed enhanced the resistance of C. quadricarinatus against Aeromonas hydrophila, improving the survival rate of the crayfish. Based on the aforementioned findings, it is recommended that H. illucens larvae AMPs be incorporated into the C. quadricarinatus feed at a concentration of 100–150 mg/kg.
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Trends in Immunology

ReviewFeature ReviewAMPed up immunity: how antimicrobial peptides have multiple roles in immune defense

Section snippets

Antimicrobial peptides

Expression and regulation of AMPs

The selective antimicrobial activity of AMPs

AMP modulation of host inflammatory responses

AMPs and their participation in disease

Microbial resistance to AMPs

Conclusions and perspectives

Acknowledgements

Peptides

Vet. Immunol. Immunopathol.

Peptides

FEBS Lett.

J. Invest. Dermatol.

J. Immunol. Methods

Blood

Blood

J. Invest. Dermatol.

Trends Microbiol

Mol. Immunol.

Mol. Immunol.

J. Invest. Dermatol.

J. Invest. Dermatol.

Curr. Opin. Immunol.

J. Allergy Clin. Immunol.

Biochim. Biophys. Acta

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

Peptides

J. Biol. Chem.

Mol. Immunol.

J. Invest. Dermatol.

Trends Immunol.

J. Biol. Chem.

J. Invest. Dermatol.

Biochem. Pharmacol.

J. Biol. Chem.

J. Invest. Dermatol.

Peptides

J. Invest. Dermatol.

Am. J. Hum. Genet.

Genomics

Antimicrobial peptides: an essential component of the skin defensive barrier

Curr. Top. Microbiol. Immunol.

Snake cathelicidin from Bungarus fasciatus is a potent peptide antibiotics

PLoS One

Overexpression and structural study of the cathelicidin motif of the protegrin-3 precursor

Biochemistry

Purification and structural characterization of bovine cathelicidins, precursors of antimicrobial peptides

Eur. J. Biochem.

Expression and secretion of cathelicidin antimicrobial peptides in murine mammary glands and human milk

Pediatr. Res.

Postsecretory processing generates multiple cathelicidins for enhanced topical antimicrobial defense

J. Immunol.

The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface

Proc. Natl. Acad. Sci. U. S. A.

The human cationic antimicrobial protein (hCAP-18) is expressed in the epithelium of human epididymis, is present in seminal plasma at high concentrations, and is attached to spermatozoa

Infect. Immun.

Cathelicidins, multifunctional peptides of the innate immunity

J. Leukoc. Biol.

Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin

FASEB J.

Solution structures of human LL-37 fragments and NMR-based identification of a minimal membrane-targeting antimicrobial and anticancer region

J. Am. Chem. Soc.

Expression of beta-defensin 1 and 2 mRNA by human monocytes, macrophages and dendritic cells

Immunology

Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense

Science

Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense

Annu. Rev. Immunol.

Developmental switch of intestinal antimicrobial peptide expression

J. Exp. Med.

An antimicrobial peptide gene found in the male reproductive system of rats

Science

Review
Feature Review
AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense