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