Cathelicidin


Cathelicidin antimicrobial peptides LL-37 and FALL-39 are polypeptides that are primarily stored in the lysosomes of macrophages and polymorphonuclear leukocytes ; in humans, the CAMP gene encodes the peptide precursor CAP-18, which is cleaved into the active forms LL-37 and FALL-39.
Cathelicidins serve a critical role in mammalian innate immune defense against invasive bacterial infection. The cathelicidin family of peptides are classified as antimicrobial peptides. The AMP family also includes the defensins. Whilst the defensins share common structural features, cathelicidin-related peptides are highly heterogeneous. Members of the cathelicidin family of antimicrobial polypeptides are characterized by a highly conserved region and a highly variable cathelicidin peptide domain.
Cathelicidin peptides have been isolated from many different species of mammals. Cathelicidins were originally found in neutrophils, but have since been found in many other cells including epithelial cells and macrophages after activation by bacteria, viruses, fungi, or the hormone 1,25-D, which is the hormonally active form of vitamin D.

Mechanism of antimicrobial activity

The general rule of the mechanism triggering cathelicidin action, like that of other antimicrobial peptides, involves the disintegration of cell membranes of organisms toward which the peptide is active. Cathelicidin rapidly destroys the lipoprotein membranes of microbes enveloped in phagosomes after fusion with lysosomes in macrophages.

Characteristics

Cathelicidins range in size from 12 to 80 amino acid residues and have a wide range of structures. Most cathelicidins are linear peptides with 23-37 amino acid residues, and fold into amphipathic α-helices. Additionally cathelicidins may also be small-sized molecules with beta-hairpin structures, stabilized by one or two disulphide bonds. Even larger cathelicidin peptides are also present. These larger cathelicidins display repetitive proline motifs forming extended polyproline-type structures.
The cathelicidin family shares primary sequence homology with the cystatin family of cysteine proteinase inhibitors, although amino acid residues thought to be important in such protease inhibition are usually lacking.

Non-human orthologs

Cathelicidin peptides have been found in humans, monkeys, mice, rats, rabbits, guinea pigs, pandas, pigs, cattle, frogs, sheep, goats, chickens, and horses.
Currently identified cathelicidin peptides include the following:
Patients with rosacea have elevated levels of cathelicidin and elevated levels of stratum corneum tryptic enzymes. Cathelicidin is cleaved into the antimicrobial peptide LL-37 by both kallikrein 5 and kallikrein 7 serine proteases. Excessive production of LL-37 is suspected to be a contributing cause in all subtypes of Rosacea. Antibiotics have been used in the past to treat rosacea, but antibiotics may only work because they inhibit some SCTEs.
Higher plasma levels of human cathelicidin antimicrobial protein appear to significantly reduce the risk of death from infection in dialysis patients. Patients with a high level of this protein were 3.7 times more likely to survive kidney dialysis for a year without a fatal infection. The production of cathelicidin is up-regulated by Vitamin D.
SAAP-148 is a modified version of LL-37 that has enhanced antimicrobial activities compared to LL-37. In particular, SAAP-148 was more efficient in killing bacteria under physiological conditions.
LL-37 is thought to play a role in psoriasis pathogenesis. In psoriasis, damaged keratinocytes release LL-37 which forms complexes with self-genetic material from other cells. These complexes stimulate dendritic cells which then release interferon α and β which contributes to differentiation of T-cells and continued inflammation. LL-37 has also been found to be a common auto-antigen in psoriasis; T-cells specific to LL-37 were found in the blood and skin in two thirds of patients with moderate to severe psoriasis.