Cathelicidin antimicrobial peptide (CAMP) is an
antimicrobial peptide
Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for ...
encoded in the human by the ''CAMP'' gene.
The active form is LL-37. In humans, ''CAMP'' encodes the
peptide precursor
A protein precursor, also called a pro-protein or pro-peptide, is an inactive protein (or peptide) that can be turned into an active form by post-translational modification, such as breaking off a piece of the molecule or adding on another molecule ...
CAP-18 (18 kDa), which is processed by
proteinase 3
Proteinase 3, also known as PRTN3, is an enzyme that in humans is encoded by the ''PRTN3'' gene.
Function
PRTN3 is a serine protease enzyme expressed mainly in neutrophil granulocytes. Its exact role in the function of the neutrophil is unknown ...
-mediated extracellular cleavage into the active form LL-37.
The cathelicidin family includes 30 types of which LL-37 is the only cathelicidin in the human.
Cathelicidins are stored in the secretory granules of neutrophils and macrophages and can be released following activation by leukocytes.
Cathelicidin peptides are dual-natured molecules called
amphiphile
In chemistry, an amphiphile (), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'', nonpolar) properties. Such a compound is called amphiphilic or amphipathic. Amphiphilic ...
s: one end of the molecule is attracted to water and repelled by fats and proteins, and the other end is attracted to fat and proteins and repelled by water. Members of this family react to pathogens by disintegrating, damaging, or puncturing cell membranes.
Cathelicidins thus serve a critical role in mammalian innate immune defense against invasive bacterial infection.
The cathelicidin family of peptides are classified as antimicrobial peptides (AMPs). The AMP family also includes the
defensin
Defensins are small cysteine-rich cationic proteins across cellular life, including vertebrate and invertebrate animals, plants, and fungi. They are host defense peptides, with members displaying either direct Antimicrobial, antimicrobial activit ...
s. 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 (cathelin domain) and a highly variable cathelicidin peptide domain.
Cathelicidin peptides have been isolated from many different species of
mammals
A mammal () is a vertebrate animal of the class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three middle e ...
, including marsupials. Cathelicidins are mostly found in
neutrophils
Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in different ...
,
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s,
mast cell
A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a p ...
s,
dendritic cell
A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
s and
macrophage
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s after activation by bacteria, viruses, fungi, parasites or the hormone
1,25-D
Calcitriol is a hormone and the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the exp ...
, which is the hormonally active form of
vitamin D
Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions. In humans, the most important compo ...
.
They have been found in some other cells, including
epithelial
Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
cells and human
keratinocyte
Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...
s.
Etymology
The term was coined in 1995 from ''cathelin'', due to the characteristic cathelin-like domain present in cathelicidins. The name ''cathelin'' itself is coined from ''
cathepsin L inhibitor'' in 1989.
Mechanism of antimicrobial activity
The general rule of the mechanism triggering cathelicidin action, like that of other antimicrobial peptides, involves the disintegration (damaging and puncturing) of cell membranes of organisms toward which the peptide is active.
Cathelicidins rapidly destroy the lipoprotein membranes of microbes enveloped in
phagosome
In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs).
A phagosome is formed by the fusion of the cel ...
s after fusion with
lysosome
A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...
s in
macrophage
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s. Therefore, LL-37 can inhibit the formation of bacterial
biofilm
A biofilm is a Syntrophy, syntrophic Microbial consortium, community of microorganisms in which cell (biology), cells cell adhesion, stick to each other and often also to a surface. These adherent cells become embedded within a slimy ext ...
s.
Other activities
LL-37 plays a role in the activation of cell proliferation and migration, contributing to the wound closure process. All these mechanisms together play an essential role in tissue homeostasis and regenerative processes. Moreover, it has an agonistic effect on various pleiotropic receptors, for example,
formyl peptide receptor like-1 (FPRL-1),
purinergic receptor P2X
P2X purinoceptor 7 is a protein that in humans is encoded by the ''P2RX7'' gene.
The product of this gene belongs to the family of purinoceptors for ATP. Multiple alternatively spliced variants which would encode different isoforms have been i ...
7,
epidermal growth factor receptor
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor (biochemistry), receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligand (biochemistry ...
(EGFR).
Furthermore, it induces
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
and regulates apoptosis.
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
An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix).
The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...
. Additionally cathelicidins may also be small-sized molecules (12-18 residues) with beta-hairpin structures, stabilized by one or two disulphide bonds. Even larger cathelicidin peptides (39-80 amino acid residues) are also present. These larger cathelicidins display repetitive
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...
motifs forming extended
polyproline
A polyproline helix is a type of protein secondary structure which occurs in proteins comprising repeating proline residues. A left-handed polyproline II helix (PPII, poly-Pro II, κ-helix) is formed when sequential residues all adopt (φ,ψ) backb ...
-type structures.
In 1995, Gudmundsson et al. assumed that the active antimicrobial peptide is formed of a 39-residue C-terminal domain (termed FALL-39). However, only a year later stated that the matured AMP, now called LL-37, is in reality two amino acids shorter than FALL-39.
The cathelicidin family shares primary sequence homology with the
cystatin
The cystatins are a family of cysteine protease inhibitors which share a sequence homology and a common tertiary structure of an alpha helix lying on top of an anti-parallel beta sheet. The family is subdivided as described below.
Cystatins sho ...
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, horses and wallabies. Antibodies to the human LL-37/hCAP-18 have been used to find cathelicidin-like compounds in a marsupial. About 30 cathelicidin family members have been described in mammals, with only one (LL-37) found in humans.
Currently identified cathelicidin peptides include the following:
* Human: hCAP-18 (cleaved into LL-37)
* Rhesus monkey: RL-37
* Mice:CRAMP-1/2, (Cathelicidin-related Antimicrobial Peptide
* Rats:
* Rabbits: CAP-18
* Guinea pig: CAP-11
* Pigs: PR-39, Prophenin, PMAP-23,36,37
* Cattle: BMAP-27,28,34 (Bovine Myeloid Antimicrobial Peptides); Bac5, Bac7
* Frogs: cathelicidin-AL (found in ''
Amolops loloensis
''Amolops loloensis'' is a species of frog in the family Ranidae that is found in southern and western Sichuan and one locality in north-central Yunnan, China. Its natural habitats are small mountain streams in forests and grasslands. It is thre ...
'')
* Chickens: Four cathelicidins, fowlicidins 1,2,3 and cathelicidin Beta-1
* Tasmanian Devil: Saha-CATH5
* Salmonids: CATH1 and CATH2
Clinical significance
Patients with
rosacea
Rosacea is a long-term skin condition that typically affects the face. It results in redness, pimples, swelling, and small and superficial dilated blood vessels. Often, the nose, cheeks, forehead, and chin are most involved. A red, en ...
have elevated levels of cathelicidin and elevated levels of
stratum corneum tryptic enzyme
Kallikrein-5, formerly known as stratum corneum tryptic enzyme (SCTE), is a serine protease expressed in the epidermis. In humans it is encoded by the ''KLK5'' gene.
This gene is one of the fifteen kallikrein subfamily members located in a clust ...
s (SCTEs). Cathelicidin is cleaved into the antimicrobial peptide
LL-37
Cathelicidin antimicrobial peptide (CAMP) is an antimicrobial peptide
encoded in the human by the ''CAMP'' gene. The active form is LL-37. In humans, ''CAMP'' encodes the peptide precursor CAP-18 (18 kDa), which is processed by proteinase 3-media ...
by both
kallikrein 5
Kallikrein-5, formerly known as stratum corneum tryptic enzyme (SCTE), is a serine protease expressed in the epidermis. In humans it is encoded by the ''KLK5'' gene.
This gene is one of the fifteen kallikrein subfamily members located in a clust ...
and
kallikrein 7 serine proteases. Excessive production of LL-37 is suspected to be a contributing cause in all subtypes of
Rosacea
Rosacea is a long-term skin condition that typically affects the face. It results in redness, pimples, swelling, and small and superficial dilated blood vessels. Often, the nose, cheeks, forehead, and chin are most involved. A red, en ...
.
Antibiotics have been used in the past to treat rosacea, but antibiotics may only work because they inhibit some SCTEs.
Lower plasma levels of human cathelicidin antimicrobial protein (
hCAP18) appear to significantly increase the risk of death from infection in
dialysis
Dialysis may refer to:
* Dialysis (chemistry), a process of separating molecules in solution
**Electrodialysis, used to transport salt ions from one solution to another through an ion-exchange membrane under the influence of an applied electric po ...
patients.
The production of cathelicidin is up-regulated by
vitamin D
Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions. In humans, the most important compo ...
.
SAAP-148 (a
synthetic
antimicrobial and
antibiofilm
peptide) 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. In addition, SAAP-148 synergises with the repurposed antibiotic
halicin against antibiotic-resistant bacteria and biofilms.
LL-37 is thought to play a role in
psoriasis
Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...
pathogenesis (along with other anti-microbial peptides). In psoriasis, damaged
keratinocytes
Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes refer ...
release LL-37 which forms complexes with self-genetic material (DNA or RNA) from other cells. These complexes stimulate
dendritic cells
A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
(a type of antigen presenting cell) 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.
LL-37 binds to the peptide Ab, which is associated with Alzheimer's disease. An imbalance between LL-37 and Ab may be a factor affecting AD-associated fibrils and plaques. Chronic, oral ''
Porphyromonas gingivalis
''Porphyromonas gingivalis'' belongs to the phylum Bacteroidota and is a nonmotile, Gram-negative, rod-shaped, anaerobic, pathogenic bacterium. It forms black colonies on blood agar.
It is found in the oral cavity, where it is implicated in ...
'', and herpesvirus (HSV-1) infections may contribute to the progression of Alzheimer's dementia.
Applications
Research into the AMP family—particularly in regards to their mechanism of action—has been ongoing for nearly 20 years. Despite sustained interest, treatments derived or utilizing AMPs have not been widely adopted for clinical use for several reasons. One, drug candidates from AMPs have a narrow window of bioavailability, because peptides are quickly broken down by proteases. Two, peptide drugs are more expensive than small molecule drugs to produce, which is problematic since peptide drugs must be given in large doses to counter rapid enzymatic breakdown. These qualities also limit routes of administration, typically to injection, infusion, or slow release therapy.
See also
*
Antimicrobial peptides
Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between Prokaryote, prokaryotic and eukaryota, eukaryotic cells that may ...
*
Innate immune system
The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates (the other being the adaptive immune system). The innate immune system is an alternate defense strategy and is the dominant immune s ...
*
Peptoid
References
Further reading
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
External links
*
{{Pore-forming toxins
Immune system
Antimicrobial peptides
Leukocytes
Protein families