antimicrobial peptides

Heterogeneous group of naturally occurring, small, cationic amphiphilic peptides, consisting of 6-50 amino acids, with broad microbicidal activity, known as"endogenous antibiotics". Antimicrobial peptides (AMPs) form the host's first line of defense against infections in vertebrates. They are mainly produced by keratinocytes in the skin. AMPs are part of theinnate immune system and have other functions in addition to their direct antimicrobial function , for example they act as inflammatory mediators by activating cytokines such as interleukin-1.

Based on their structure, antimicrobial peptides can be divided into different families. Peptides from the following families are found in humans:

• defensins
• Cathelicidins
• dermcidins
• Other AMPs

Defensins (AMPs consisting of 30-40 amino acids; depending on their disulfide pattern, defensins are divided into alpha- or beta-defensins.

• Defensin, alpha 1
• Defensin, alpha 2
• Defensin, alpha 3
• Defensin, alpha 4
• Defensin, alpha 5
• Defensin, alpha 6

The beta-defensins (keratinocytes form beta-defensins) include the human beta-defensins (HBD-1 to HBD-4).

• Defensin, beta 1
• Defensin, beta 2
• Defensin, beta 3
• Defensin, beta 4

Cathelicidins (AMPs including the human cathelicidin LL37). In humans, only LL-37 is produced by neutrophil granulocytes, mast cells and keratinocytes. It has a broad antimicrobial effect against both gram-positive and gram-negative bacteria. It has a chemotactic effect on mast cells, neutrophil granulocytes, monocytes and T-cells. LL-37 acts as a Z-cell autoantigen in psoriasis.

Dermcidins (DCD) are antimicrobial peptides that are produced in human sweat glands and excreted through sweat. One derivative is dermcidin DCD-1L, an antimicrobial peptide.

• Dermcidin D-1 (important AMP in sweat). Proteolytic cleavage produces DCD-1, a peptide consisting of 47 amino acids with a broad antimicrobial effect. DCD-1 appears to be reduced in patients with atopic eczema .

Other AMPs of human skin. These include proteinase inhibitors, chemokines and neuronal peptides. The main representatives of this group are RNase and psoriasin (see S100A15 below).

Antimicrobial peptides (AMP) are small molecules (< than 100 amino acids) synthesized by insects, plants, bacteria, invertebrates and vertebrates. They play an important role in the innate, non-specific immune defense (see below Immunity, innate) within the epithelial barrier function of the respiratory, urogenital and gastrointestinal tract as well as the skin in the defense against infectious pathogens and the modulation of the cutaneous microbiota (Schröder 2016).

In addition to their original, direct defense function, AMPs can also activate cells of the immune system. They are therefore also referred to as effector substances of the innate immune system. The upregulation of AMPs in psoriasis could play a role in this specific inflammatory reaction. LL-37 is upregulated in psoriasis. LL-37-specific T cells express interferon-gamma and Il-17. In patients with rosacea, abnormal processing of cathelicidin LL-37 is thought to be responsible for the inflammatory reaction.

AMPs are formed in various cell types (in particular in macrophages, neutrophil granulocytes and epithelial cells).

Some AMPs, such as S100A7/S100A15, beta-defensin-3(HBD-3 = human beta-defensin-3), and RNAse 7, are constitutively expressed by keratinocytes.

In contrast, other AMPs such as HBD1, NBD2 and cathelicidin are produced on demand. Their expression is mainly induced by microbial factors and inflammatory cytokines.

Cathelicidins and beta-defensins are the best characterized AMP families in the skin.

Diseases with reduced activity of antimicrobial peptides are characterized by immune deficiencies. These include: patients with STAT3 mutation(hyper-IgE syndrome), tumor patients in whom the epidermal growth receptor(EGF receptor) has been therapeutically blocked. Disturbed AMP expressions are also discussed in Crohn's disease and atopic eczema (tendency to infection).

Studies have shown that high concentrations of antimicrobial peptides (e.g. the endogenous antimicrobial peptide LL-37 - belongs to the cathelicidins) were found in extracts of lesional scales of patients with psoriasis vulgaris. This probably explains that psoriatics have less skin infections (see here for atopic eczema).

Physiologically, antimicrobial peptides are also produced on the skin. The protein "RNAse-7" has an antimicrobial potency against vancomycin-resistant enterococci (Enterococcus faecium).

In neonates, there is an increased expression of cathelicidin LL-37 and β-defensin-2 by a factor of 10 to 100 compared to adult skin (compensatory mechanism in still immature immune system).

Pathological colonization of the skin with microbes equally induces antimicrobial control. For example, the saprophytic yeast Malassezia furfur triggers the expression of β-defensin-2 in human keratinocytes. The antimicrobial activity of AMP against multidrug-resistant microorganisms is 1-8 μg/ml in vitro, within the range of conventional synthetic antibiotics; development of resistance is rare.

Patients with atopic eczema show a low concentration of HBD-2 and LL-37 on the skin compared to psoriasis patients (infections e.g. with Staph. aureus may be favoured by this). Probably the reason for this is the up-regulation of the TH-2 cytokines IL-4 and IL-13 which inhibit the AMP`s. The AMP dermidicin is also inhibited in atopic eczema. In principle, the reduction of AMP`s in atopic eczema also leads to reduced control of vaccinia virus replication, which explains the increased susceptibility to generalized herpes simplex infections.

Defensins are also produced in the small intestine, ensuring low bacterial counts. Deficiency of defensins is associated with Crohn's disease.

1. Dombrowski Y et al (2010) Alarmine and its significance for inflammatory skin diseases. Act Dermatol 36: 467-470
2. Hader J et al (2007) Human antimicrobial proteins effectors of innate immunity.J Endotoxin Res 13: 317-338
3. Korting HC et al (2013) Antimicrobial peptides and the skin: A paradigm of translational medicine. Karger Compass Dermatology 1:11-21
4. Lande R et al (2014)The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis. Nat Commun 5:5621
5. Rieg S et al (2006) Generation of multiple stable dermcidin-derived antimicrobial peptides in sweat of different body sites. J Invest Dermatol 126: 354-365
6. Schröder JM (2016) Antimicrobial peptide (AMP) research at the Kiel University Dermatology Clinic: Akt Dermatol 42: 20-22.
7. Volz T et al (2015) On the role of the innate immune system in atopic dermatitis. Dermatologist 66: 90-95
8. Wehkamp J et al (2007) Defensins and cathelicidins in gastrointestinal infections. Curr Opin Gastroenterol 23: 32-38