Ubiquitous antimicrobial peptides with function as "endogenous antibiotics Occurs in all animal organisms and plants.
Defensins, like cathelicidins, belong to the group of antimicrobial peptides which play an essential role in innate immunity.
So far, 10 defensins have been described in humans. Beta-defensin-2 (HBD-2) and human beta-defensin-3 (HBD-3) are defensins that are formed in the skin and are broadly effective against bacteria and yeasts. The peptides are only produced "on demand".
Defensins consist of 33-47 amino acids and have 3 intramolecular disulfide bridges.
Defensins are expressed via NOD receptors.
Abundant occurrence on skin and mucosal surfaces of mammals.
Granulae of neutrophil granulocytes consist of up to 30% defensins.
The body's own production of defensins increases during inflammatory reactions.
Presumed mechanism of action: Defensins have a large number of cationic and hydrophobic amino acid residues. The positive charges react with negatively charged phospholipid groups of the external bacterial cell membrane. A so-called electrostatic "peptide carpet" is induced by these attractive forces, which leads to the formation of pores in the bacterial membrane and ultimately to its destruction.
Healthy skin has a diverse microbiome and a strong immune system to defend against infections. Defensins play a key role in this. They activate orphan G protein-coupled receptors (Mrgpra2a/b) on neutrophil granulocytes. This defensin-Mrgpra2 signaling pathway is an important signaling pathway between epithelial cells and neutrophils. It plays a major role in skin immunity and the homeostasis of the skin microbiome (Dong X et al. 2022).
The Mrgpr family of GPCRs is now accepted as an important regulator of innate immune functions (Arifuzzaman et al. 2019). In animal experiments, the Mrgpra2a and a2b proteins show highly specific expression in neutrophils of mice and were crucial for their antibacterial functions. However, it is reasonable to assume that other immune cells besides neutrophils also contribute to defensin-mediated immunity and that other defensin receptors of neutrophils besides Mrgpra2 are also important (Tseng PY et al. 2022). Neutrophils are scarcely present in naïve skin, but are immediately and rapidly recruited from the bloodstream after infections or non-microbial neutrophilic inflammation (Arifuzzaman et al. 2019).
This finding also has implications for the pathology of skin diseases (e.g. psoriasis). Studies of the skin microbiota have provided important insights into the functions of the commensal microbiota during the development of the host immune system and the causal relationships between dysbiosis and inflammatory skin diseases (Dong X et al. 2022). However, the host factors that determine the microenvironment for the microbiota are still largely unclear. It is known, among other things, that physical and chemical properties of the skin surface such as moisture and acidity have a profound influence on the composition of the microbiome (Grice et al. 2011). However, the influence of the host's immune system, whose primary function is to interact with the microbial world, is still largely unknown. Defects in defensin production and neutrophil recruitment have been linked to skin diseases associated with severe dysbiosis of the microbiome (Chiang et al. 2019).
Animal studies show that there is a direct causal link between genetic deletion of the defensin-Mrgpra2 signaling pathway and skin dysbiosis. The results suggest that normal skin maintains baseline immune activity and strongly influences the composition of the microbiome on the skin surface (Dong X et al. 2022; Matsumoto et al. 2021). The interaction between epithelium and neutrophils via AMPs and their GPCRs is an important component of this basic immune activity. Exactly how this system maintains a balanced microbiome that enables colonization by commensal bacteria while limiting the spread of pathogenic bacteria is not yet understood.