Skin Defense Dynamics by Antimicrobial Peptides

Antimicrobial peptides are mainly small cationic polypeptides that are classified together due to their capacity to obstruct the growth of microbes.

As effectors of innate immunity, antimicrobial peptides instantly kill a ample spectrum of bacteria, fungi, and viruses. In addition, these peptides alter the local inflammatory response and activate mechanisms of adaptive and cellular immunity. Cathelicidins and defensins comprise the major families of antimicrobial peptides in the skin, although other cutaneous peptides, such as chemokines, proteinase inhibitors and neuropeptides also indicate antimicrobial action.

Cutaneous defense mechanisms by antimicrobial peptides.

Braff MH , Bardan A , Nizet V , Gallo RL . Department of Medicine, University of California San Diego, and VA San Diego Healthcare System, San Diego, California, USA.

Multifunctional antimicrobial peptides play a significant role in skin immune defense and disease pathogenesis

Antimicrobial peptides, which are synthesized in the skin at sites of potential microbial entry, provide a soluble barrier that acts as an obstruction to germs. In the case of infection or injury, antimicrobial peptide expression in the skin is upregulated due to enlarged synthesis by keratinocytes and deposition from degranulation of recruited neutrophils. Although antimicrobial peptides evidently demonstrate in vitro antimicrobial activity, investigations have shown that many such peptides, including cathelicidins and defensins, are inactivated by physiological salt concentrations (Goldman et al, 1997).

In fact, a recent study has shown that mammalian skin contains an essential antimicrobial-enhancing factor that renders bacteria susceptible to cathelicidin in vitro, despite the existence of physiological salt and serum (Dorschner et al, 2004). The in vivo relevance of antimicrobial peptides in the physiological environment is further highlighted by the laboratory animal models and human skin diseases that are discussed below.

Cathelicidins are defined by an N-terminal signal peptide, a highly sustained cathelin domain and a structurally variable cationic antimicrobial peptide at the C-terminus. The cathelin domain functions as both a protease inhibitor and as an antimicrobial peptide in humans (Zaiou et al, 2003). Mature cathelicidin peptides show rapid, potent, and broad-spectrum antimicrobial activity and have been implicated in various immunomodulatory functions(Koczulla et al, 2003).

Human cathelicidin, LL-37, assumes an a-helical structure in solutions with ion compositions similar to intestinal fluid, human plasma, or intracellular fluid. Processing of LL-37 from the cathelicidin precursor is essential for activation of its antimicrobial activity and is practiced by neutrophil proteases such as proteinase 3 (Sorensen et al, 2001).

LL-37 expression in squamous epithelia is differentially regulated in several inflammatory contexts (Frohm et al, 1997; Dorschner et al, 2001). LL-37 is generated in eccrine structures, where it is secreted and transformed in sweat, suggesting a further barrier function against topical skin infection (Murakami et al, 2004).

In addition, LL-37 is generated by mast cells and recruits mast cells (Di Nardo et al, 2003), thereby participating in innate immunity both by direct antimicrobial activity and by recruitment of cellular human b-defensin defenses. LL-37 production is upregulated in neonatal skin, where it may compensate for the empirical immaturity of adaptive immune reactions (Dorschner et al, 2003). A true immunomodulatory effector molecule, LL-37 has direct antimicrobial activity, acts synergistically with other antimicrobial peptides, works as a chemoattractant for neutrophils, monocytes and T cells, and triggers endothelial cell proliferation by binding to formyl peptide receptor-like 1(FPRL-1) (Koczulla et al, 2003).

The multilayered expression and multifunctionality of cathelicidin in the skin present a formidable innate defense system against infection.

Cathelicidins Cathelicidins are strategically expressed and contribute multiple functions to skin defense. The human cathelicidin precursor protein hCAP18 is expressed by several cell types in the skin including keratinocytes, neutrophils, eccrine ducts, and mast cells. Cathelicidins are processed to active peptides such as LL-37 in neutrophils and more potent peptides in sweat.

These peptides have been best characterized as natural antibiotics, killing a variety of bacterial, fungal, and viral pathogens. Other functions include chemotactic and angiogenic behaviors, and an ability to modify fibroblast proteoglycan synthesis. The N-terminal cathelin-like domain of the hCAP18 precursor protein contains both antimicrobial and proteinase inhibitor activity.

Defensins Defensins have six cysteine remnants that form characteristic disulfide bridges. Disulfide bridge alignment and molecular structure separate this principal antimicrobial peptide group into a-, b-, and y-defensins. Mammalian defensins present antimicrobial activity against fungi,bacteria and enveloped viruses. á-Defensins have three disulfide bridges in a 1-6, 2-4, 3-5 alignment. Human neutrophils express four á-defensins, which are also referred to as human neutrophil peptides 1 through 4 (HNP-1 to -4) (Harwig et al, 1994). Human defensins 5 and 6 (HD-5 and -6) are abundantly expressed as propeptides in Paneth cells of small intestinal crypts and in epithelial cells of the female urogenital tract.

In humans, defensins are stored in azurophil granules of neutrophils as fully processed, mature peptides. Like cathelicidins, á -defensins alter both microbes and the host. For example, HNP-1, -2, and -3 upregulate tumor necrosis factor alpha (TNF- á) and IL-1 in human monocytes that have been stimulated by bacteria; these peptides also diminish the expression of the adhesion molecule VCAM-1 in endothelial cells stimulated by TNF-a (Chaly et al, 2000).

b-Defensins have three disulfide bridges that are spaced in a 1-5, 2-4, 3-6 pattern. The four best-known human b-defensins, hBD-1 to -4, have been identified in various cell types, along with epithelial and peripheral blood mononuclear cells (Harder et al, 2001; Fang et al, 2003; Liu et al, 2003). hBD-1 is constitutively expressed in epithelia, whereas hBD-2 is highly upregulated in inflamed skin. hBD- 3, which was purified from human psoriatic scales and calluses (Harder et al, 2001), is inducible in a range of tissues. b-Defensins have broad-spectrum antimicrobial action and additional immune-related cellular functions.

For example, hBD-2 binds to CCR6 and is chemotactic for immature dendritic cells and memory T cells (Yang et al, 1999). hBD-2 also promotes histamine release and prostaglandin D2 production in mast cells, suggesting a potential immunotherapeutic role as a vaccine adjuvant to improve antibody production (Befus et al, 1999). hBD-2 is virtually missing in normal skin and its expression in human keratinocytes requires activation by cytokines or bacteria (Liu et al, 2003). The upregulation of hBD-2 by keratinocytes illustrates the crucial role that defensins play in host defense against cutaneous pathogens.

Interestingly, the interdependence of the antimicrobial activity of these peptides on their originally described function varies, and no clear tendency is noted. For example, the antimicrobial activity of ECP/RNase 3 does not require ribonuclease activity, which is essential for the antiviral activity of both ECP/RNase 3 and EDN/RNase 2 (Domachowske et al, 1998a, b). P-cystatin a frustrates bacterial proteinase activity as a mechanism of microbial growth inhibition (Takahashi et al, 1994), whereas cystatin C antimicrobial activity does not depend on its ability to inhibit bacterial proteinases (Blankenvoorde et al, 1998). The antiviral activity of cystatin C, however, appearsto remain in the proteinase-binding domain. Calprotectin contains zinc-binding sites and inhibits microbial growth through competition for metals (Sohnle et al, 2000), whereas NGAL interferes with bacterial iron acquisition (Goetz et al, 2002).

Antimicrobial Peptides in the Skin: Clinical Relevance

Differential expression of antimicrobial peptides appears to play a role in the susceptibility of patients with chronic inflammatory skin disorders to infectious complications.

For example, LL-37 is stimulated in human keratinocytes during psoriasis, lupus erythematosus and contact dermatitis (Frohm et al, 1997). hBD-2 and hBD-3 are also upregulated in keratinocytes of inflamed psoriatic lesions (Harder et al, 2001; Nomura et al, 2003).

The magnified expression of antimicrobial peptides in psoriasis correlates with a low rate of secondary infection. In contrast, the expression of LL-37 and hBD-2 is not upregulated in individuals with atopic dermatitis, who are highly susceptible to bacterial and viral infections (Ong et al, 2002). The differences in antimicrobial peptide expression between these two disorders achieve immunological importance in light of the antimicrobial activity of LL-37 against S. pyogenes (Dorschner et al, 2001) and its synergistic activity with b-defensins against S. aureus (Ong et al, 2002), a leading agent of human skin infections.

LL-37 expression is upregulated in inflammatory skin lesions of erythema toxicum neonatorum and immunolocalizes within CD15-expressing neutrophils, EG-2-expressing eosinophils, and CD1a-expressing dendritic cells (Marchini et al, 2002). LL-37 is also stimulated within the epidermis during development of verruca vulgaris and condyloma accuminata, suggesting that it represents a component of the natural immune reaction to papillomavirus infection (Conner et al, 2002).

Both hBD-1 and hBD-2 are upregulated in the lesions of acne vulgaris and may therefore be included in the pathogenesis or resolution of this condition (Philpott, 2003).

In addition, hBD-2 and the HNP are abundant in lesions of superficial folliculitis, a typical skin disease characterized by inflammation of the hair follicle and infection with S. aureus (Oono et al, 2003). These investigations indicate potential roles for antimicrobial peptides in host immune defense against skin infection.

Cathelicidin is generated at high levels in the skin after wounding (Dorschner et al, 2001) and is strongly expressed in healing skin epithelium (Heilborn et al, 2003). After cutaneous wounding, growth factors trigger tissue remodeling until the physical boundary conserving the skin from microbial infections has been re-established.

Growth factors crucial in skin wound healing, such as insulin-like growth factor-1 (IGF-1) and transforming growth factor-a (TGF-a, produce the expression of cathelicidins and defensins in human keratinocytes (Sorensen et al, 2003). LL-37 antibodies frustrate post-wounding re-epithelialization in a concentration-dependent manner and cathelicidin expression is low or absent in chronic ulcers (Heilborn et al, 2003).

The ability of LL-37 to produce angiogenesis further highlights the relevance of cathelicidin in wound healing and tissue repair (Koczulla et al, 2003). Moreover, the expression of hBD-2 is dramatically diminished in burn wounds and blister fluid from partial thickness burns (Ortega et al,2000), presenting evidence that natural immune defects may contribute to the risk of burn wound sepsis and infection.

After injury, antimicrobial peptide levels in the skin rise quickly due to increased synthesis by keratinocytes and deposition from degranulation of recruited neutrophils. The chemoattractant properties of cathelicidins and defensins may further amplify this process through their functional interactions with leukocyte surface receptors. The growing number of multifunctional peptides found to frustrate microbial growth further expands the mammalian antimicrobial arsenal, showing that the host antimicrobial peptide defense system acts both directly and indirectly to avoid skin infection.

Disruption of the skin by acne inflammation, invading micro-organisms, sun damage, disease, injury due to trauma, surgery, burns, accidents, or by chemical, dermabrasion or laser procedures used for skin renewal, generates a signal to the natural immune system and initiates responses that may or may not be effective in a) preventing an impending invasion from microbes by a secretion of antimicrobial peptides on the surface of the skin and b) in triggering the regeneration of new healthy cells to replace those damaged.

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