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Cathelicidin antimicrobial peptide
Cathelicidin antimicrobial peptide
Cathelicidin antimicrobial peptide
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CAMP
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesHGNC:11998 CAMP, IPR001894, CAP-18, CAP18, CRAMP, HSD26, gene FALL39, gene LL37, FALL39, LL37, FALL-39, cathelicidin antimicrobial peptide, Cathelicidins
External IDsOMIM: 600474; MGI: 108443; HomoloGene: 110678; GeneCards: CAMP; OMA:CAMP - orthologs
Orthologs
SpeciesHumanMouse
Entrez

820

12796

Ensembl

ENSG00000164047

ENSMUSG00000038357

UniProt

P49913

P51437

RefSeq (mRNA)

NM_004345

NM_009921

RefSeq (protein)

NP_004336

NP_034051

Location (UCSC)Chr 3: 48.22 – 48.23 MbChr 9: 109.68 – 109.68 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cathelicidin antimicrobial peptide (CAMP) is an antimicrobial peptide encoded in the human by the CAMP gene.[5] The active form is LL-37, a 37 amino acid peptide having sequence LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES.[6] In humans, CAMP encodes the peptide precursor CAP-18 (18 kDa), which is processed by proteinase 3-mediated extracellular cleavage into the active form LL-37.[7][5]

The cathelicidin family includes 30 types of which LL-37 is the only cathelicidin in the human.[8] Cathelicidins are stored in the secretory granules of neutrophils and macrophages and can be released following activation by leukocytes.[9] Cathelicidin peptides are dual-natured molecules called amphiphiles: 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.[10] The cathelicidin family of peptides are classified as antimicrobial peptides (AMPs). The AMP family also includes the defensins. Whilst the defensins share common structural features, cathelicidin-related peptides are highly heterogeneous.[10] Members of the cathelicidin family of antimicrobial polypeptides are characterized by a highly conserved region (cathelin domain) and a highly variable cathelicidin peptide domain.[10]

Cathelicidin peptides have been isolated from many different species of mammals, including marsupials.[11] Cathelicidins are mostly found in neutrophils, monocytes, mast cells, dendritic cells and macrophages[12] after activation by bacteria, viruses, fungi, parasites or the hormone 1,25-D, which is the hormonally active form of vitamin D.[13] They have been found in some other cells, including epithelial cells and human keratinocytes.[14] Some viruses evolved immunomodulatory mechanisms to avoid cathelicidin exposure by downregulating the cellular vitamin D receptor.[15]

Etymology

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The term was coined in 1995 from cathelin, due to the characteristic cathelin-like domain present in cathelicidins.[16] The name cathelin itself is coined from cathepsin L inhibitor in 1989.[17]

Mechanism of antimicrobial activity

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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.[9]

Cathelicidins rapidly destroy the lipoprotein membranes of microbes enveloped in phagosomes after fusion with lysosomes in macrophages. Therefore, LL-37 can inhibit the formation of bacterial biofilms.[18]

The pleiotropic properties of LL-37 in relation to the different cells and tissues

Other activities

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LL-37 plays a role in the activation of cell proliferation and migration, contributing to the wound closure process.[19] 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),[20] purinergic receptor P2X7, epidermal growth factor receptor (EGFR).[21]

Furthermore, it induces angiogenesis[22] and regulates apoptosis.[23]

Characteristics

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Cathelicidins range in size from 12 to 80 amino acid residues and have a wide range of structures.[24] 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 (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 motifs forming extended polyproline-type structures.[10]

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.[25][26]

The cathelicidin family shares primary sequence homology with the cystatin[27] family of cysteine proteinase inhibitors, although amino acid residues thought to be important in such protease inhibition are usually lacking.

Cleavage products

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LL-37 is cleaved into a number of smaller fragments which retain anti-microbial and anti-cancer effects but generally have a lower toxicity to human cells. RK-31, KS-30 and KR-20 are naturally occurring fragments, while other related peptides have been made synthetically based on natural fragments of LL-37 during research into cathlicidins, and in some cases have amino acid substitutions.[28]

Cleavage products of LL-37
Code Fragment Amino acid sequence
LL-37 1-37 LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES
RK-31 7–37 RKSKEKIGKEFKRIVQRIKDFLRNLVPRTES
KS-30 8–37 KSKEKIGKEFKRIVQRIKDFLRNLVPRTES
KR-20 18–37 KRIVQRIKDFLRNLVPRTES
FK-13 17–29 FKRIVQRIKDFLR
FK-16 17–32 FKRIVQRIKDFLRNLV
KR-12 18–29 KRIVKLIKKWLR
GF-17 16-32 GFKRIVQRIKDFLRNLV
GI-20 12–32 GIKEFKRIVQRIKDFLRNLV

Non-human orthologs

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Cathelicidin peptides have been found in humans, monkeys, mice, rats, rabbits, guinea pigs, pandas, pigs, cattle, frogs, sheep, goats, chickens, horses and wallabies.[29] Antibodies to the human LL-37/hCAP-18 have been used to find cathelicidin-like compounds in a marsupial.[30] About 30 cathelicidin family members have been described in mammals, with only one (LL-37) found in humans.[9] Currently identified cathelicidin peptides include the following:[10]

  • Human: hCAP-18 (cleaved into LL-37)
  • Rhesus monkey: RL-37
  • Mice:CRAMP-1/2, (Cathelicidin-related Antimicrobial Peptide[31]
  • Rats: rCRAMP
  • 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)[32]
  • Chickens: Four cathelicidins, fowlicidins 1,2,3 and cathelicidin Beta-1 [33]
  • Tasmanian Devil: Saha-CATH5 [34]
  • Salmonids: CATH1 and CATH2

Clinical significance

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Patients with rosacea have elevated levels of cathelicidin and elevated levels of stratum corneum tryptic enzymes (SCTEs). 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.[35] Antibiotics have been used in the past to treat rosacea, but antibiotics may only work because they inhibit some SCTEs.[36]

Lower plasma levels of human cathelicidin antimicrobial protein (hCAP18) appear to significantly increase the risk of death from infection in dialysis patients.[37] The production of cathelicidin is up-regulated by vitamin D.[38][39]

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.[40] In addition, SAAP-148 synergises with the repurposed antibiotic halicin against antibiotic-resistant bacteria and biofilms.[41]

LL-37 is thought to play a role in psoriasis pathogenesis (along with other anti-microbial peptides). In psoriasis, damaged keratinocytes release LL-37 which forms complexes with self-genetic material (DNA or RNA) from other cells. These complexes stimulate dendritic cells (a type of antigen presenting cell) which then release interferon α and β which contributes to differentiation of T-cells and continued inflammation.[42] 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.[42]

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, and herpesvirus (HSV-1) infections may contribute to the progression of Alzheimer's dementia.[43][44]

Applications

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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.[45] 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.[46] Research into new and improved variations derived from cathelicidin continues.[47]

See also

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Cathelicidin antimicrobial peptide

View on Grokipedia
from Grokipedia
Cathelicidins are a family of cationic antimicrobial peptides integral to the innate immune system of vertebrates, defined by a conserved N-terminal cathelin-like domain in their precursor proteins that is proteolytically processed to yield diverse C-terminal antimicrobial domains exhibiting broad-spectrum activity against pathogens. These peptides, first identified in the 1980s and extensively characterized since the 1990s, are produced as inactive propeptides stored primarily in neutrophil granules and epithelial cells, with activation occurring via cleavage by proteases such as elastase. In humans, the sole cathelicidin is encoded by the CAMP gene on chromosome 3, which produces the 18-kDa precursor hCAP-18, subsequently processed into the mature 37-amino-acid peptide LL-37. Structurally, cathelicidins display remarkable diversity across species and even within the same organism, with the antimicrobial domains adopting one of five main conformations: α-helical (common in mammals, including LL-37), β-hairpin, - or arginine-rich linear forms, tryptophan-rich peptides, or unstructured variants. This variability allows for tailored responses to different threats, with the peptides' amphipathic and cationic nature enabling membrane disruption in microbes through mechanisms like barrel-stave pore formation or carpet-like . Beyond direct effects against Gram-positive and , enveloped viruses, and fungi, cathelicidins modulate innate and adaptive immunity by recruiting immune cells, promoting and , and influencing production, though dysregulation can contribute to inflammatory disorders. Expression of cathelicidins is tightly regulated and inducible by microbial products like , cytokines such as interleukin-6, and environmental factors including , which upregulates the human CAMP gene via the . While mammals typically encode multiple cathelicidin genes (e.g., up to 11 in pigs), humans and mice possess only one each—CAMP yielding LL-37 and Camp yielding , respectively—highlighting evolutionary conservation dating back over 300 million years to . These peptides' roles extend to non-infectious contexts, such as protecting against UV-induced skin damage and facilitating tissue repair, underscoring their multifaceted contributions to host defense.

Fundamentals

Etymology

The term "cathelicidin" was coined in 1995 by Zanetti et al. to designate a novel family of mammalian precursors, deriving from "cathelin"—a conserved proregion domain—and the suffix "-cidin," denoting their bactericidal function. This nomenclature originated from earlier findings on cathelin, a protein isolated in 1989 from porcine neutrophils as a low-molecular-mass inhibitor of the cathepsin L, with the name serving as an for "cathepsin L inhibitor."81093-2) In the and early , discoveries of analogous proteins in bovine and porcine leukocytes revealed sequence similarities in their proregions to cathelin, prompting the broader classification as cathelicidins to encompass this evolving family across species. The designation "cathelicidin" specifically applies to the full propeptide precursors, distinguishing them from the mature, active antimicrobial peptides generated by proteolytic cleavage, such as human LL-37, which derives from the CAMP gene encoding the cathelicidin antimicrobial protein.

Discovery and Definition

Cathelicidins were first identified in the late through the isolation of from bovine s, marking the initial recognition of this class of host defense molecules as inducible cationic peptides with broad antibacterial activity. Specifically, two bactenecins, Bac5 and Bac7, were purified and characterized from bovine granules in 1989, demonstrating potent activity against both Gram-positive and . These early discoveries highlighted their role in innate immunity, as they were stored in large granules and released upon activation to combat microbial infections. The term "cathelicidin" was coined in 1995 to unify a growing family of related proteins identified across mammals, characterized by a highly conserved N-terminal prodomain known as cathelin and a variable C-terminal domain that yields the mature antimicrobial peptide upon proteolytic cleavage. This nomenclature reflected the structural similarity among precursors, where the cathelin domain serves as a regulatory proregion, while the C-terminal segment exhibits the functional diversity. Cathelicidins are defined as multifunctional host defense peptides that contribute to innate immunity by directly killing pathogens and modulating immune responses.01050-O) Key characteristics of mature cathelicidins include their cationic nature, amphipathicity, and variable lengths ranging from 12 to 100 , enabling membrane disruption in microbes through electrostatic and hydrophobic interactions. These peptides are integral to the across vertebrates, from to mammals, where they provide rapid, non-specific defense against bacterial, fungal, and viral threats. In humans, the cathelicidin family is represented by a single , CAMP (cathelicidin antimicrobial peptide), which encodes the precursor hCAP-18, underscoring the evolutionary conservation of this despite species-specific variations in peptide diversity.

Structure and Biosynthesis

Molecular Structure

Cathelicidins are synthesized as prepropeptides consisting of a highly conserved N-terminal cathelin domain and a C-terminal antimicrobial domain. The cathelin domain comprises approximately 100 residues, exhibiting a cystatin-like fold with a long N-terminal α-helix, a twisted four-stranded antiparallel β-sheet, and stabilizing bonds, which confers structural similarity to inhibitors. This domain spans about 99–114 residues across species and maintains high , underscoring its evolutionary conservation. The C-terminal antimicrobial domain, linked to the cathelin region, varies significantly in length (12–100 residues) and , allowing for diverse mature forms upon proteolytic cleavage. In their mature state, cathelicidin often adopt α-helical conformations in environments, characterized by amphipathicity that segregates hydrophobic and hydrophilic faces to facilitate interactions, while remaining largely unstructured or extended in aqueous solutions. In humans, the sole cathelicidin is encoded as the 18 kDa propeptide hCAP-18, which yields the mature LL-37 peptide of 37 residues following cleavage. LL-37 features a leucine-rich N-terminus and forms a bent α-helical structure in membrane mimics, with disordered termini contributing to its flexibility. Its physicochemical properties include a net positive charge of +6, enabling electrostatic interactions, and a hydrophobicity gradient with approximately 35% hydrophobic residues that supports amphipathic organization.

Gene Expression and Regulation

The human CAMP gene, which encodes the cathelicidin antimicrobial peptide, is located on the short arm of at position 3p21.31. This gene spans approximately 2 kb in the and comprises four s. The first three exons primarily encode the N-terminal and the conserved cathelin domain, while the fourth exon encodes the C-terminal domain that gives rise to the mature antimicrobial following proteolytic cleavage. Expression of the CAMP gene is regulated by multiple transcription factors that respond to environmental and immune signals. The (VDR), activated by the hormone 1,25-dihydroxyvitamin D3, binds directly to response elements in the CAMP promoter, potently inducing transcription in myeloid cells and . In addition, cyclic AMP () signaling pathways activate CAMP expression through the transcription factors CREB (cAMP-responsive element-binding protein) and AP-1 (activator protein-1), which bind to specific response elements in the promoter region of epithelial cells.49387-8/fulltext) Pathogen-associated signals, such as those detected by Toll-like receptors (TLRs), trigger activation and coordinate with VDR to upregulate CAMP during innate immune responses. CAMP is expressed at low constitutive levels in epithelial cells of the skin, gastrointestinal tract, and respiratory mucosa, as well as in innate immune cells including neutrophils and macrophages. During inflammation, expression is strongly induced in these sites, particularly via TLR-mediated pathways in macrophages and neutrophils, enhancing local antimicrobial defenses. The has expanded through tandem events during mammalian , resulting in varying copy numbers across that reflect adaptations to diverse pathogens. Humans retain a single CAMP gene, while other mammals exhibit expansions, such as 11 genes in pigs and up to 15 in certain marsupials like the , often organized in genomic clusters.76299-1/fulltext) These duplications, which occurred after the divergence from non-mammalian vertebrates, have driven diversification of antimicrobial peptide sequences while preserving the conserved cathelin domain structure.

Proteolytic Processing

Cathelicidins are synthesized as inactive precursor proteins, known as prepropeptides, which undergo proteolytic processing to release the mature, bioactive C-terminal . This maturation step is essential for their function in innate immunity, as the full-length precursors lack direct activity. The processing typically involves cleavage of the N-terminal prodomain, allowing the C-terminal domain to adopt its active conformation. In humans, the primary precursor hCAP-18 is activated by proteinase 3, a released from azurophil granules. This enzyme cleaves hCAP-18 extracellularly at the specific bond between at position 106 and at position 107, generating the mature 37-residue LL-37. The cleavage occurs following during or , ensuring targeted at sites of microbial invasion. Alternative host proteases contribute to processing in tissue-specific contexts; for instance, in the skin, kallikrein-related peptidases 5 (KLK5) and 7 (KLK7) cleave hCAP-18 to produce LL-37 as well as unique shorter fragments with enhanced or modified and proinflammatory properties. These kallikreins are secreted by and maintain a balanced proteolytic environment at epithelial surfaces. Processing mechanisms vary across , reflecting adaptations to diverse physiological needs. In bovines, proteolytically matures the precursor proBMAP-28 into the active 27- or 28-residue α-helical BMAP-28, which exhibits broad-spectrum activity. This cleavage often occurs extracellularly in inflamed tissues but can also proceed intracellularly within granules prior to secretion. Such species-specific variations highlight the evolutionary divergence in cathelicidin activation, with intracellular processing more common in some ruminants to facilitate rapid release of mature forms during . The N-terminal prodomain, termed the cathelin domain due to its homology with cystatins, plays a crucial regulatory role by inhibiting the antimicrobial activity of the tethered C-terminal peptide in the precursor form. This inhibition occurs through electrostatic interactions between the acidic cathelin residues and the cationic peptide, preventing self-damage to host cells and microbial killing during storage in secretory granules. Upon proteolytic cleavage, the cathelin domain is released separately, allowing the mature peptide to exert its effects without interference; notably, the isolated cathelin shows no intrinsic antibacterial or protease inhibitory activity against common targets like cathepsin L. Recent investigations since 2020 have uncovered alternative processing pathways influenced by microbial and pathological environments. For example, proteases from pathogens like can degrade mature LL-37, thereby subverting host defenses, though this represents an inactivation rather than activation mechanism. In cancer microenvironments, dysregulated host proteases such as matrix metalloproteinases and kallikreins alter cathelicidin processing, generating bioactive fragments that promote tumor progression, , and immune evasion in contexts like hepatocellular and pancreatic carcinomas. These findings underscore the context-dependent nature of cathelicidin maturation in disease states.

Mechanisms of Action

Antimicrobial Activity

Cathelicidins exert their antimicrobial effects primarily through disruption of microbial membranes, leveraging their cationic nature to interact with negatively charged bacterial surfaces. The peptides initially bind electrostatically to anionic phospholipids in bacterial membranes, leading to membrane destabilization via mechanisms such as the carpet model, where peptides cover the membrane surface and induce detergent-like , or the toroidal pore model, in which they insert into the bilayer to form water-filled pores that compromise membrane integrity. For instance, the human cathelicidin LL-37 adopts an amphipathic α-helical structure upon membrane association, facilitating insertion and pore formation in like . These peptides demonstrate broad-spectrum activity against a diverse array of pathogens, including such as Staphylococcus aureus, Gram-negative bacteria like , fungi including , and enveloped viruses such as HIV-1. Their efficacy stems from the high density of anionic in microbial membranes, which contrasts with the zwitterionic composition of eukaryotic cell membranes, conferring selectivity and minimizing to host cells under physiological salt concentrations. This selective targeting is evident in the low hemolytic activity of many cathelicidins, such as bovine BMAP-28, which effectively kills bacteria at micromolar concentrations while sparing mammalian erythrocytes. Beyond membrane disruption, cathelicidins can translocate into microbial cells to target intracellular components, binding DNA or RNA to inhibit nucleic acid synthesis and interfering with protein production. For example, LL-37 penetrates bacterial cytoplasm to suppress transcription by binding to DNA and inhibiting enzymes like topoisomerase, while peptides like porcine PR-39 block mRNA translation and induce protein degradation via proteasome activation. These multi-faceted actions contribute to a low propensity for resistance development, as bacteria exhibit limited adaptive mechanisms against such diverse targets compared to conventional antibiotics; studies indicate limited and primarily temporary resistance development in P. aeruginosa exposed to LL-37 over extended periods. Additionally, cathelicidins often synergize with traditional antimicrobials, enhancing their potency—for instance, LL-37 potentiates β-lactam antibiotics against resistant strains by permeabilizing bacterial envelopes.

Immunomodulatory and Other Functions

Cathelicidins, particularly the ortholog LL-37, exhibit significant chemotactic that facilitate the of various immune cells to sites of or injury. LL-37 binds to formyl receptor-like 1 (FPRL1, also known as FPR2), promoting the migration of neutrophils, monocytes, , mast cells, and T cells through the formation of concentration gradients. This chemotactic activity is mediated by the 's N-terminal alpha-helical structure and involves downstream signaling pathways such as p38 MAPK and ERK, which enhance cell motility and infiltration. For instance, LL-37 induces the secretion of like CXCL8 (IL-8), , and from epithelial cells and , further amplifying the of neutrophils and Th1/Th17 lymphocytes. Additionally, LL-37 promotes the release of antimicrobial microvesicles from neutrophils, enhancing extracellular bacterial clearance. In addition to , cathelicidins modulate production in a context- and concentration-dependent manner, displaying both pro- and effects. At higher concentrations (e.g., 20 μg/mL), LL-37 stimulates the release of pro-inflammatory such as TNF-α, IL-6, IL-8, and IL-18 from monocytes, neutrophils, and via activation of and MAPK pathways. Conversely, at lower physiological concentrations, it exerts actions by promoting IL-10 production in macrophages and inhibiting excessive TNF-α and IL-12 responses, thereby dampening . This dose-dependent duality allows LL-37 to fine-tune immune responses, transitioning from amplification during early infection to resolution in later stages. Furthermore, LL-37 neutralizes endotoxins like (LPS) by binding to its moiety through its C-terminal region, preventing TLR4 activation and reducing septic in macrophages. Beyond immune cell recruitment and cytokine regulation, cathelicidins contribute to tissue repair and through roles in , , and modulation. LL-37 induces (VEGF) expression in endothelial cells via FPRL1 signaling and EGFR transactivation, promoting endothelial proliferation and tube formation essential for neovascularization during repair processes. In , it enhances migration, proliferation, and re-epithelialization, while indirectly supporting synthesis by stimulating fibroblast activity and remodeling. Regarding , LL-37 exhibits dual effects: it suppresses to aid tissue integrity but can induce in neutrophils and osteoblasts through P2X7 receptor activation and caspase-independent pathways, facilitating immune resolution. Additionally, LL-37 supports gut health and resistance to gastrointestinal infections as part of its broader protective and immunomodulatory functions. It maintains intestinal epithelial barrier integrity through direct promotion of epithelial cell migration, mucin expression, and anti-apoptotic effects, as well as indirect stimulation of growth factors. LL-37 also contributes to mucosal homeostasis by regulating gut microbiota composition, preventing dysbiosis, and enhancing defense against enteric pathogens such as Escherichia coli O157:H7, thereby reducing inflammation and supporting overall intestinal health. These multifaceted functions underscore cathelicidins' role in orchestrating balanced host responses.

Comparative Aspects

Human Cathelicidin (LL-37)

The human cathelicidin antimicrobial peptide, known as LL-37, represents the sole member of the cathelicidin family in humans. It is encoded by the CAMP gene on chromosome 3p21.3, which produces a precursor protein (hCAP-18) that undergoes proteolytic cleavage to yield the mature peptide. The active LL-37 consists of 37 amino acid residues with the sequence LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES, characterized by its amphipathic α-helical structure essential for membrane interaction. LL-37 exhibits broad tissue distribution, with high abundance in barrier sites such as the skin (produced by ), lungs (epithelial cells of the ), and (colon epithelial cells). It is prominently stored in the specific granules of neutrophils, from which it is released during to contribute to innate defense at mucosal and epithelial surfaces. Expression of the CAMP gene and subsequent LL-37 production is tightly regulated, with a notable induction by 1,25-dihydroxyvitamin D3 in via the pathway, enhancing antimicrobial responses in and other epithelia. However, LL-37 levels can be lower in certain populations, including those of African descent, compounded by higher prevalence of insufficiency. Functionally, LL-37 displays enhanced immunomodulatory potency relative to cathelicidins in some non-human species, promoting of immune cells like neutrophils and monocytes while modulating release to balance pro- and anti-inflammatory responses. It also exerts antiviral effects, notably inhibiting HIV-1 replication by binding and disrupting the , thereby preventing entry into host cells.

Non-Human Orthologs

Cathelicidins exhibit significant diversity across non-human species, reflecting evolutionary adaptations to diverse microbial challenges, while sharing a conserved cathelin domain with the ortholog LL-37. In mammals, multiple genes encode these peptides, leading to varied mature forms that contribute to innate immunity in and rodents. Among mammalian orthologs, porcine cathelicidins include PMAP-36 and PMAP-37, which are α-helical peptides of 36 and 37 , respectively, produced in neutrophils and exhibiting broad-spectrum activity against Gram-positive and as well as fungi through disruption. Bovine cathelicidins encompass - and arginine-rich BAC5, a 43-amino-acid β-hairpin structure with one bond that targets by binding lipopolysaccharides without full lysis, and the α-helical BMAP family (e.g., BMAP-27, -28), which shows broad activity against , fungi, and viruses; truncated variants like BMAP-18 reduce while retaining efficacy. In mice, the single cathelicidin ortholog CRAMP (cathelicidin-related peptide), encoded by the Camp gene, is a potent agent expressed in tissues such as the testis, , and intestine, homologous in function to human LL-37. Non-mammalian orthologs further highlight this variability. In , pleurocidin from the (Pseudopleuronectes americanus) is an α-helical peptide isolated from mucus, contributing to epithelial defense with activity against Gram-positive and . Avian cathelicidins include the three fowlicidins (fowlicidin-1 to -3) in chickens, clustered within a 7.5-kb genomic region, which display potent broad-spectrum antibacterial effects, including against antibiotic-resistant strains, and are expressed in heterophils and tissues like the . In amphibians, cathelicidin-MH from the frog Microhyla heymonsivogt features novel sequence motifs in its mature peptide, enabling activity against and endotoxins, with expression in secretions for mucosal protection. Structurally, non-human cathelicidins show greater diversity than their counterparts, with mature C-terminal peptides varying in length from 10 to 80 residues and adopting conformations such as α-helices, β-sheets, or extended structures depending on the environment and species. For instance, bovine BAC5 forms a β-hairpin fold stabilized by a bond, contrasting the predominantly α-helical human LL-37, which enhances specificity for certain pathogens. Functional adaptations underscore their ecological roles; in bats, cathelicidins like those from Myotis lucifugus (ML-CATH) and Phyllostomus discolor (PD-CATH) demonstrate enhanced broad-spectrum antimicrobial activity with low and potential antiviral effects against viruses such as coronaviruses, supporting bats' tolerance to high viral loads. In , these peptides, such as porcine PMAPs and bovine BMAPs, bolster infection resistance, promoting and modulating to mitigate in agricultural settings.

Clinical and Therapeutic Relevance

Role in Diseases

Cathelicidin dysregulation plays a significant role in various infectious diseases. In tuberculosis, vitamin D deficiency impairs cathelicidin expression, thereby increasing susceptibility to Mycobacterium tuberculosis infection by weakening the innate immune response in macrophages. This deficiency hinders the peptide's antimicrobial activity against the pathogen, as demonstrated in studies showing that low 25-hydroxyvitamin D levels correlate with reduced LL-37 production and higher risk of active disease. Conversely, in rosacea, elevated cathelicidin levels in facial skin contribute to abnormal inflammation and vascular changes, with abnormally high expression of the peptide promoting serine protease activity and disease pathogenesis. In sepsis, overexpression of cathelicidin LL-37 exacerbates systemic inflammation by inducing neutrophil extracellular trap (NET) formation and modulating pyroptosis in macrophages, potentially worsening organ dysfunction during polymicrobial infections. In inflammatory skin diseases, cathelicidin levels exhibit contrasting patterns that influence disease severity. is characterized by elevated LL-37 expression, where the peptide acts as a T-cell autoantigen, driving autoreactive immune responses and sustaining chronic inflammation through complex formation with self-DNA that activates plasmacytoid dendritic cells. This overexpression correlates with lesional skin activity and contributes to the recruitment of pathogenic T cells. In , however, cathelicidin expression is markedly reduced in lesional skin, leading to impaired defense and heightened susceptibility to bacterial and viral skin infections such as colonization and . This downregulation is partly attributed to the Th2-dominant cytokine milieu, including IL-4 and IL-13, which suppress LL-37 induction via STAT6 signaling. In chronic rhinosinusitis (CRS), elevated endogenous levels of LL-37 in the nasal mucosa are associated with chronic nasal inflammation. Studies have demonstrated upregulation of LL-37 in chronic nasal inflammatory disease and in patients with CRS, contributing to disease pathogenesis. Furthermore, topical application of LL-37 in mouse models induces acute inflammation of the olfactory epithelium in a dose-dependent manner, characterized by increased inflammatory cell infiltrate (including neutrophils and mast cells), edema, and secretory cell hyperplasia with associated mucus changes. Beyond infections and skin disorders, cathelicidin influences other pathologies through pro-tumorigenic and prothrombotic effects. In , LL-37 promotes tumor progression by stimulating and local invasion; the activates both melanoma cells and tumor-associated macrophages to upregulate pro-angiogenic factors, enhancing vascularization and metastatic potential. In cardiovascular conditions, cathelicidin LL-37 augments by directly activating platelets, increasing aggregation, and promoting formation on surfaces, as evidenced in both and murine models. Recent analyses confirm this role in thrombo-inflammation, where elevated LL-37 levels during vascular contribute to arterial clot stability and ischemic events. Genetic variations in the CAMP gene, which encodes cathelicidin, are linked to altered susceptibility. Polymorphisms such as rs9844812 in the CAMP promoter region disrupt hypoxia-inducible factor binding, leading to reduced LL-37 expression and increased risk of pulmonary in certain populations. Additionally, exacerbates low cathelicidin expression across multiple contexts, including tuberculosis and , by limiting the ligand-dependent induction of CAMP transcription via the .

Therapeutic Applications and Challenges

Cathelicidins and their synthetic analogs have emerged as promising candidates for therapies, particularly against antibiotic-resistant infections. For instance, TC-14, a 14-amino acid derivative of the tree cathelicidin TC-33, demonstrates broad-spectrum activity against such as MRSA and , with minimum inhibitory concentrations ranging from 1.17 to 18.75 μg/mL, and reduces bacterial loads by 57.9–93.1% in murine models without significant at doses up to 10 mg/kg. Topical applications of the cathelicidin LL-37 have been explored for , showing efficacy in promoting closure of chronic venous leg ulcers in subgroup analyses of phase IIb clinical trials, where 0.5–1.6 mg/mL formulations accelerated healing in ulcers ≥10 cm² when combined with compression therapy, though overall cohort benefits were not statistically significant. Similarly, LL-37 cream enhanced healing rates, particularly formation, in a 2023 randomized double-blind controlled trial. In , engineered cathelicidin variants offer potential for managing autoimmune diseases by mitigating excessive . The murine ortholog attenuates colitis severity in dextran sulfate sodium-induced models by decreasing pro-inflammatory cytokines and enhancing mucosal barrier integrity, suggesting therapeutic utility in inflammatory bowel diseases. Likewise, the synthetic LLKKK18, a cathelicidin derivative, improves β-cell function and regeneration in rat models when delivered via nanoparticles, restoring insulin production and glycemic control. For , while endogenous LL-37 exacerbates , modified cathelicidins could target dysregulated immune responses, and LL-37 has been investigated as a adjuvant to enhance antigen-specific immunity without overstimulating plasmacytoid dendritic cells. In 2025, studies have highlighted LL-37's potential in promoting for ischemic conditions, such as lower limb ischemia, via activation of the VEGFA-PI3K/AKT/ pathway. Emerging applications in peptide therapy involve subcutaneous injections of LL-37, which is reported to provide benefits including broad-spectrum antimicrobial activity against bacteria, viruses, and fungi; promotion of wound healing and skin regeneration; immune modulation with both pro- and anti-inflammatory effects; and support for gut health and infection resistance. In such therapeutic contexts, LL-37 is generally well-tolerated, with mild side effects including injection site reactions, transient flu-like symptoms (low-grade fever, body aches), fatigue, and occasionally headache. Runny nose is not commonly reported as a side effect of systemic LL-37 administration; however, elevated endogenous LL-37 is associated with chronic rhinosinusitis and nasal inflammation, and topical application in animal models induces acute olfactory epithelium inflammation with edema and mucus changes. Despite these prospects, therapeutic development faces significant challenges, including dose-dependent to host cells due to membrane disruption, rapid proteolytic degradation that limits , and high production costs estimated at $50–400 per gram compared to conventional antibiotics. Stability issues, such as aggregation or loss of activity in physiological conditions, further complicate . Recent advances from 2023–2025 address these hurdles through encapsulation, such as nanocapsules for LL-37 delivery in infections, which improve targeted release and reduce , and hybrid peptides combining cathelicidin motifs with other like BF-30 for enhanced antitumor and anti-inflammatory effects in models. As of late 2024, most clinical trials involving LL-37-based drugs are in phase II, either ongoing or completed, underscoring continued progress toward practical translation in applications such as skin infections and .

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