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

Abstract

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. Antimicrobial peptidesInitially, 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 understand this topic, we must first discuss the extreme diversity of molecules referred to as AMPs.So far, more than 1200 antimicrobial peptides of different origins have been identified or predicted. For a list of some of these, see the Antimicrobial Peptide Database (APD: http://aps.unmc.edu/AP/main.php). Most of these peptides maintain certain common features, such as being small (12-50 amino acids), containing positive charge and an amphipathic structure. Based on their amino acid composition, size and conformational structures, AMPs can be divided into several categories, such as peptides with α-helix structures, peptides with β-sheet structures stabilized by disulfide bridges or peptides with extended or loop structures (Figure 1). The expression of AMPs differs depending on the cell and tissue type, but in most cases AMPs are co-expressed as groups that act together. For example, in skin, more than 20 antimicrobial peptides and proteins have been identified [1], including cathelicidins, β-defensins and others. Relatively little information is available on the immunological function for most of these peptides, and it is unlikely that the immunomodulatory actions of the mammalian AMPs are also a component of the biology of the hundreds of AMPs produced by most prokaryotes and invertebrates. Thus, the first important concept to confer in a discussion of the AMPs is that they are similar only by their capacity to directly kill or inhibit the growth NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of microbes. Because this function is often through their capacity to influence lipid membrane structu...

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“…In mammals, CAMPs are produced and secreted by epithelial cells ( i.e. , skin, gastrointestinal, respiratory, and urogenital cells) and various cells of the immune system (e.g., monocytes, macrophages, neutrophils, and other granulocytes; for review see [15], Fig. 1).…”

“…CAMPs produced in eukaryotic species not only play a direct role in the killing of bacterial pathogens, but also in the modulation of the immune response by, for example, decreasing inflammation and attracting various types of immune cells during infection (i.e., chemotaxis). 15 Additionally, certain CAMPs stimulate production of chemokines and cytokines from a variety of cell types, constituting an indirect mechanism for stimulating the immune response. 15

10.1080/15476286.2017.1356980-f0001Figure 1.Multiple functions of CAMPs in host defense.

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“…15 Additionally, certain CAMPs stimulate production of chemokines and cytokines from a variety of cell types, constituting an indirect mechanism for stimulating the immune response. 15

10.1080/15476286.2017.1356980-f0001Figure 1.Multiple functions of CAMPs in host defense. CAMPs induce a variety of responses in host innate immune cells.

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Innate Immune Defense System of the Skin

“…19 Cathelicidins and b-defensins are the well-characterized AMPs. 11,28,29 Key features of human cathelicidin and b-defensins are summarized in Table 1.…”

“…60 LL-37 also binds extracellular self-DNA fragments, enabling them to enter plasmacytoid dendritic cells, which initiates TLR9 activation to produce type I interferons. 28 LL-37 changes the expression of phagocytic receptors, significantly enhancing the ability of dendritic cells to undergo phagocytosis. 61 The immunomodulatory mechanisms of cathelicidin complements its antimicrobial properties and reinforce its role as an integral defense molecule in innate immune responses.…”