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Clinical Updates

Sélim Aractingi, MD, PhD

The Importance of Antimicrobial Peptides in the Skin

Selim Aractingi

Monday, November 01, 2004

Skin maintains a continuously renewing barrier against environmental insults such as ultraviolet radiation, physical and chemical injury, and infectious microorganisms. With respect to attack by microorganisms, skin must protect deep tissues as well as itself from invasion by a wide variety of agents. This antimicrobial function relies on various mechanisms, including the special architecture of stratum corneum with its dense juxtaposition of keratin filaments and desmosomes, as well as several cells responsible for adaptive immunity, such as Langerhans' cells and T lymphocytes. In the last decade, however, interest has focused on the role of innate immunity in skin. This aspect of immunity - in contrast with adaptive immunity - is present without modification throughout life. Adaptive immunity was first considered to rely on neutrophils (for phagocytosis) and natural killer cells (for cytotoxicity) alone, but it has now been expanded to include the production of endogenous peptides that protect against infection.

Antimicrobial peptides are known to target the phospholipid membranes of bacteria, fungi, and viruses, acting like antiseptic agents. They disrupt or, more rarely, penetrate and inhibit cellular function.1 Since it is difficult for microorganisms to change their own target membranes, resistance to these peptides is uncommon. In mammals, there are essentially 2 classes of antimicrobial peptides: defensins and cathelicidins (see Table 1).

Table 1: Cutaneous Antimicrobial Peptides

Beta Defensins
HBD1: Constitutively expressed
HBD2: Induced by inflammation (TNF-α) and microorganisms
Induced after linking of microbes to Toll-Like Receptors
Induction inhibited by Th2 cytokines (IL-4, IL-13)
Effective in killing gram-negative organisms and Candida
Found in lesions of psoriasis
Reduced in atopic dermatitis
Cathelicidins
LL37: Induced in keratinocytes from inflammatory diseases such as psoriasis and by wounding
Found in vernix caseosa of infants
Reduced in atopic dermatitis
Absence causes increased susceptibility to infection

Defensins are themselves divided into α and β families. β-defensins are synthesized by epithelial cells: The human β-defensin 1 (HBD1) is constitutively expressed, while the others are inducible. The cathelicidins are secreted by polymorphonuclear neutrophils. Importantly, several of these peptides also serve as chemokines by attracting inflammatory cells.1 One member of the cathelicidin family (LL37) may attract neutrophils, for instance.

Several studies have focused on the importance of antimicrobial peptides in skin. In 1997, based on the fact that patients with psoriasis had fewer cutaneous infections than expected, Harder et al. purified peptides with affinity for bacteria from psoriatic scales and demonstrated the presence of the consensus sequence of the β-defensin family.2 They also found HBD2 in these cutaneous specimens2 and showed that this molecule was present at low levels in normal skin. Interestingly, the expression of HBD2 was highly stimulated by incubation with TNF-α - mimicking inflammatory diseases - as well as by contact with microorganisms.2 HBD2 was effective in killing several gram-negative bacteria as well as the yeast Candida albicans, but it was only bacteriostatic against S. aureus.2 Lung and tracheal tissues, but not other tissues, were able to express HBD2. Frohm et al. also obtained interesting results with the cathelicidin member LL37: They demonstrated that the production of this molecule was induced in keratinocytes in inflammatory conditions such as psoriasis.3 Of note, HBD1 - as said above - is present constitutively in the suprabasal keratinocytes of normal skin4 as well as in sweat ducts.

In addition to the constitutively expressed HBD1, inducible peptides - such as HBD2 - are expressed after linking of microbes to the toll-like receptors (TLRs) that are present on keratinocytes.4 The scenario is therefore as follows: A microorganism penetrates the epidermis, perhaps after physical disruption of the stratum corneum. A moiety from its surface is then recognized by one of the TLRs present on keratinocytes, and the production of antimicrobial peptides is induced. These peptides are directly cytotoxic against this organism, and at the same time they chemoattract inflammatory cells. Accordingly, in knockout mice missing the unique cathelicidin gene, a counterpart of the human LL37, investigators have observed normal fetal development, normal fertility, and a normal phenotype when housed under sterile conditions.5 However, skin infection with group A streptococci leads to more severe infections in the knockout mice than in control mice: Cutaneous lesions increase more rapidly, reach larger size, and persist longer, together with a more prolonged persistence of the colonization.5 Of note, the neutrophilic infiltrates are similar in experimental and control mice, showing that reduced protection against infection is linked only to the cathelicidin defect. In addition, aiming to demonstrate the importance of the LL37 pathway in protecting the skin under normal conditions, the same investigators studied the fate of skin infections in normal mice, comparing classical strains of group A streptococci with engineered ones that became resistant to cathelicidin. The cathelicidin-resistant streptococci again had cutaneous lesions of longer duration and larger size,5 with prolonged time for clearing of the microbe. This animal model illustrates, therefore, the role of this pathway in protecting against streptococcal infections of the skin.

Antimicrobial peptides are present early in life, since LL37 was found in the vernix caseosa of infants by Western blotting.6 Their production is also induced greatly by other important physiological phenomena, such as wounding, with increased synthesis by keratinocytes and their release from neutrophilic granules.7 All of these observations illustrate the importance of this pathway in protecting skin from microorganisms throughout life.

Recently, another way to "see" the role of antimicrobial peptides was shown in atopic dermatitis (AD). This disease is characterized - in contrast to psoriasis - by an increased risk for bacterial and viral infections. In 1997, inducible HBD2 was found in psoriasis. In 2002, Ong et al. using a range of techniques, including immunohistochemistry, Western blotting, and RT-PCR analysis of transcripts, found that both HBD2 and LL37 were reduced in patients with AD.8 Indeed, they found that staining for HBD2 and LL37 was decreased in acute and in chronic AD, as compared to psoriasis. By Western blotting, there was almost no measurable levels of these 2 molecules.8 Going further in understanding these observations, the investigators studied the expression of these peptides in cultures of keratinocytes. AD is known to be mediated - at least initially - by Th2 cytokines such as IL4 and IL13. Ong et al. showed that the incubation of keratinocytes with IL4 or IL13 inhibited the stimulated release of HBD2 that is normally produced by TNF-α.8

Synthesizing all of these data is important in understanding skin physiology. Indeed, in resting skin, only a limited number of antimicrobial peptides are available to protect against invasion. When an inflammatory condition develops, the production of other peptides, such as HBD2 and LL37, is induced. This is indeed the case in psoriasis, allowing protection of the skin from infection through abnormally permeable skin. However, certain cytokines - Th2 primarily - are able to repress this induction: In atopy, the absence of these peptides probably plays a role in the observed increased susceptibility to infection.

In sum, the antimicrobial peptides are a naturally occurring defense system that plays a daily role in the physiology and pathology of the skin.

References

  1. Zasloff M. Antimicrobial peptides in health and disease. N Engl J Med. 2002;347:1199-2000.
  2. Harder J, Bartel J, Christophers E, Schroeder JM. A peptide antibiotic from human skin. Nature. 1997;387:861-864.
  3. Frohm M, Agerberth B, Ahangari G. The expression of the gene coding for antibacterial peptide LL37 is induced in human keratinocytes under inflammatory conditions. J Biol Chem. 1997;272:15258-15263.
  4. Fulton C, Anderson M, Zasloff M, Bull R, Quinn AG. Expression of natural peptide antibiotics in human skin. Lancet. 1997;350:1750-1751.
  5. Nizet V, Ohtake T, Lauth X, et al. Innate antimicrobial peptides protect the skin from invasive bacterial infection. Nature. 2002;414:454-457.
  6. Dorschner RA, Pestonjamasp VK, Tamakuwala S, et al. Cutaneous injury induces the release of cathelicidin antimicrobial peptides active against group A Streptococcus. J Invest Dermatol. 2001;117:91-97.
  7. Marchini G, Lindow S, Brismar H, et al. The newborn infant is protected by an innate antimicrobial barrier: peptide antibiotics are present in the skin and vernix caseosa. Br J Dermatol. 2002;147:1127-1134.
  8. Ong PY, Ohtake T, Brandt C, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347:1151-1160.
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