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 Table of Contents  
Year : 2014  |  Volume : 17  |  Issue : 2  |  Page : 69-75

Cathelicidin expression and role in oral health and diseases: A short review

1 Department of Oral and Maxillofacial Pathology, Vipula Care Hospital, Vijayawada, Andhra Pradesh, India
2 Department of Oral and Maxillofacial Pathology, Amrita School of Dentistry, Kerala, India
3 Department of Oral and Maxillofacial Pathology, Azeezia Dental College and Research, Kollam, Kerala, India
4 Department of Oral Medicine and Radiology, Azeezia Dental College and Research, Kollam, Kerala, India

Date of Web Publication9-Sep-2014

Correspondence Address:
Prem Anand Prabhakaran
Department of Oral and Maxillofacial Pathology, Amrita School of Dentistry, Kerala
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DOI: 10.4103/1119-0388.140414

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The oral cavity is a unique environment in which antimicrobial peptides play a key role in maintaining health. Cathelicidins are small cationic antimicrobial host defense peptides that possess broad-spectrum antimicrobial activity. Humans possess a single cathelicidin, which was first cloned from human bone marrow cDNA. Its mature form is known as LL-37. Various immune and epithelial cells secrete LL-37, and its level varies in response to caries, periodontal, congenital, inflammatory, and malignant diseases in the oral region. Human cathelicidin peptide LL-37 exhibits antimicrobial activity against bacteria that cause oral pathological conditions, including cariogenic disease and periodontitis. Further research on LL-37 is needed as its usefulness as a new class of antimicrobial drugs still remains to be proven and may have future therapeutic applications.

Keywords: Antimicrobial peptides, cathelicidins, defense peptides, innate immunity, LL-37

How to cite this article:
Potturu M, Prabhakaran PA, Oommen N, Sarojini DM, Sunil SN. Cathelicidin expression and role in oral health and diseases: A short review. Trop J Med Res 2014;17:69-75

How to cite this URL:
Potturu M, Prabhakaran PA, Oommen N, Sarojini DM, Sunil SN. Cathelicidin expression and role in oral health and diseases: A short review. Trop J Med Res [serial online] 2014 [cited 2020 Feb 29];17:69-75. Available from: http://www.tjmrjournal.org/text.asp?2014/17/2/69/140414

  Introduction Top

The human oral cavity is a harbor to a variety of microorganisms that can colonize and cause disease. Oral mucous membrane acts as the first barrier of resistance to oral infections. In order to provide an efficient defense the oral mucosa is equipped with various innate mechanisms against invading microbial pathogens. Most do not require the specific recognition of the invading pathogen and within oral innate immunity three distinct barriers can be identified: A chemical, a physical, and a mechanical barrier. The flow of saliva has a mechanical effect, flushing microorganisms from mucosal and tooth surfaces. [1] While a neutral pH and antimicrobial peptides in saliva contribute to the chemical shield on the surface of the oral mucosa, the intact stratified squamous epithelium supported by the lamina propria presents a physical barrier to oral microorganisms. The continuous shedding by exfoliation of epithelial squames limits microbial colonization of the surface and forms a mechanical cellular barrier. These cells, together with professional antigen presenting cells such as dendritic cells and oral epithelial macrophages, form the first line of cellular innate immunity in the oral cavity. All these cells are equipped with sensors and communicate with each other upon microbial challenge or a danger signal. Subsequently, further immune or pro-inflammatory cascades are triggered providing an adequate and coordinated immune response.

One of the most important contributors in maintaining the balance between health and disease in this complex oral environment is antimicrobial peptides. These include several salivary antimicrobial peptides, the β-defensins expressed in the epithelium, the α-defensins expressed in neutrophils, and the cathelicidin, LL-37, expressed in both epithelium and neutrophils. [2] These peptides are part of the host innate immune response. In addition to antimicrobial, antifungal, and antiviral activities, some of these peptides also possess antitumor or immune modulatory properties.

This review focuses mainly on human cathelicidin in the oral cavity and discusses its importance in oral health and its potential in the clinical therapy of oral diseases.

Antimicrobial peptides: Essential players in oral innate immunity

Antimicrobial peptides (AMPs); also called host defense peptides (HDPs) are an evolutionarily conserved component of the innate immune response and are found among all classes of life. AMPs are short (less than 100 amino acids), amphipathic molecules with hydrophobic and cationic amino acids arranged spatially. [3] AMPs form predominantly two different secondary structures; disulfide-rich peptides form β-sheets while linear peptides form α-helices. [4] Their amphipathic structure not only allows those peptides to be soluble in aqueous environments but also to interact with lipid membranes. [5] Initially, the modes of action by which AMPs kill bacteria are varied and include disrupting membranes, interfering with metabolism, and targeting cytoplasmic components. [6] They have broad spectrum antimicrobial activity and are able to kill gram-positive and gram-negative bacteria, viruses, and fungi. Oral keratinocytes, gingiva, tongue, salivary glands, and mucosa express AMPs. In addition, invading immune cells (e.g. neutrophils, natural killer cells) contribute to the pool of AMPs in the oral cavity. [2]

Oral AMPs provide a first line of defense against a wide spectrum of pathogens. Members of the three main AMP families are found in the oral cavity. These are defined by biochemical and structural characteristics: 1) α-helical peptides without cysteine (the cathelicidin, LL-37); 2) peptides with three disulfide bonds (α- and β- defensins); and 3) peptides with an unusually high proportion of specific amino acids; for example, the histatins. [5] The role of these natural antibiotics is only just beginning to be appreciated, with potential applications for enhanced natural expression or as new therapeutic agents. Especially, their function in the oral cavity is important as there is constant exposure to microbial challenges. [7],[8],[9] Recent research suggests the importance of the defensins and the cathelicidin LL-37 as antibacterial agents in the oral cavity, [10] while histatins are primarily antifungal agents. [2]

Basic structure of cathelicidins

Cathelicidins are small (12/100 amino acids), cationic and amphipathic in nature, features they share with other major classes of mammalian antimicrobial peptides such as the defensins. Cathelicidins were first discovered in mammals but have been recently found in chickens and three species of fish (rainbow trout, Atlantic salmon, and hagfish). In particular, hagfish remarkably lacks essential components of adaptive immunity. The presence of cathelicidins in this very ancient species may indicate the fact that cathelicidin genes developed early in vertebrate phylogeny. [7]

While humans and mice possess a single cathelicidin each, other species such as cattle and pigs express many different cathelicidins. It was first cloned from human bone marrow cDNA. Its mature form is known as LL-37 as it begins with 2 leucines and is 37 residues in length. An alternative designation assigned to this gene product is hCAP18. This terminology was applied after identification of a human cationic antimicrobial peptide found to have a mass of 18 kDa before processing. [8]

All cathelicidins are produced as a precursor consisting of an N-terminal signal peptide, a highly conserved prosequence and a structurally variable C-terminal mature peptide. It is the presence of the evolutionarily conserved prosequence which assigns an antimicrobial function to the cathelicidin class. The prosequence is termed the "cathelin" domain for its homology to cathelin, a protein from porcine neutrophils that inhibits the protease cathepsin L. In contrast, the mature C-terminal cathelicidin antimicrobial peptides share little sequence homology, but can be divided into three general groups: Those forming amphipathic α-helices (e.g. human LL-37), those with intramolecular disulfide bonds adopting β-sheet structure (e.g. porcine protegrins), and those heavily enriched in one or two amino acids such as proline or arginine (e.g. bovine Bac7). [9] Cathelicidin genes consist of four exons and three introns: The first three exons comprise the signal sequence and cathelin prodomain, while the fourth exon encodes the processing site and variable C-terminal antimicrobial peptide (3). Proteolytic cleavage of the inactive precursor molecule to release the mature C-terminal antimicrobial peptide from the cathelin prodomain is accomplished by elastase or proteinase-3 upon degranulation of activated neutrophils; processing of epithelial cell-derived cathelicidin precursors is less understood. These basic features of cathelicidins are illustrated in [Figure 1]. [8]
Figure 1: Photograph depicting the basic features of cathelicidins

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Expression and mechanism of action of antimicrobial activity of LL-37

The human cathelicidin LL-37 is produced within secondary granules of 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. [11] LL-37 is consistently expressed at both the mRNA and protein levels in the squamous epithelia of the airways, esophagus, intestine, cervix, and vagina. In oral cavity its secretion (or that of its precursor hCAP18) has been detected in the epithelium of tongue and buccal mucosa. [12],[13],[14] However, LL-37 detected in gingival epithelium by immunohistochemistry appears to be the product of neutrophil migration through the tissue rather than the epithelial cells per se. LL-37 is also detected in the saliva and salivary glands, specifically in the acinar cells of the submandibular gland and palatine minor glands as well as in the lingual epithelium and palatal mucosa. Additionally, it is also detected in a number of other body fluids, including sweat, gastric juices, semen, plasma, airway surface fluid, and breast milk. [15]

LL-37 exhibits broad antimicrobial activity against gram-negative and gram-positive bacteria and is effective against oral microorganisms such as Streptococcus mutans, Porphyromonas gingivalis, and Actinobacillus actinomycetemcomitan. [16],[17],[18] LL-37 can disrupt the cell wall and cell membrane of Candida albicans and inhibit the growth of C. albicans. It can also inhibit virus replication against vaccinia (smallpox) virus. In addition, LL-37 exhibits antiviral activity against HSV-1 in corneal and conjunctival epithelia. LL-37 peptide usually acts synergistically with other AMPs as many of these peptides are produced in the same environment. For example, LL-37, lysosome, and lactoferrin were shown to act synergistically in killing bacteria in the airways. A recent study showed that LL-37, combined with β defensin-2, acts synergistically to kill S. aureus. [15]

The primary function of LL-37 is antibacterial and usually it acts along with other AMPs. The modes of action by which antimicrobial peptides kill bacteria are varied and include disrupting membranes, interfering with metabolism, and targeting cytoplasmic components. The initial contact between the peptide and the target organism is electrostatic, as most bacterial surfaces are anionic or hydrophobic. Their amino acid composition, amphipathicity, cationic charge, and size allow them to attach to and insert into membrane bilayers to form pores. Alternately, they may penetrate into the cell to bind intracellular molecules that are crucial to cell living. Intracellular binding models include inhibition of cell wall synthesis, alteration of the cytoplasmic membrane, activation of autolysin, inhibition of DNA, RNA, and protein synthesis, and inhibition of certain enzymes. However, in many cases, the exact mechanism of killing is not known.

There are several mechanisms of membrane disruption proposed to explain the activity of AMPs [Table 1]. Some of the models used to identify the membrane-disrupting process are carpet model, barrel-stave model, toroidal-pore wormhole model, and detergent-type membrane lytic mechanism. [16] In the carpet model, the peptides accumulate on the bilayer surface. They are electrostatically attracted to the anionic phospholipid head groups at numerous sites covering the surface of the membrane in a carpet-like manner. At high concentrations, the peptides are believed to disrupt the bilayer acting like a detergent, resulting in the formation of micelles. This type of transmembrane pore is induced by LL-37. [15]
Table 1: Antimicrobial peptides expressed in the oral cavity[2]

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In the barrel-stave model, peptide helices form a bundle in the membrane with a central lumen, very similar to a barrel, with the helical peptides as the staves. The toroidal pore model combines the action of the two previous models and begins with aggregation on the membrane surface. The peptides insert into the membrane perpendicularly as barrel-stave model and at some critical concentration of peptide curvature strain induces the membranes to curve inward, resulting in the formation of a pore that is lined by both peptide and lipid head groups. Repulsive interactions between the positively charged residues of the peptide are minimized due to the presence of the negatively charged phospholipids in the pore-lining. While the formation of these pores depends on the lipid and peptide ratio and the ionic selectivity depends on the membrane composition, the lifetime of these pores seems to vary.

In the detergent-type mechanism, the peptides first carpet the surface of the lipid bilayer like the beginning stages of the toroidal-pore model. Following this step, the peptide aggregation leads to a sufficient high local concentration where the amphipathic nature of the peptide allows them to behave like detergents and break the lipid membrane into small fragments. These fragments can be like bicelles or micelles. [16] There are other models such as the sinking raft model or the molecular electroporation, which have not received much attention in the field, but could be useful to explain the antimicrobial activity of certain AMPs. [17]

Additional functions of cathelicidins

Apart from the antimicrobial activity, LL-37 has additional functions in the activation and the control of immune responses. LL-37 protects against endotoxin shock by binding to lipopolysaccharide in the cell membrane component of gram-negative bacteria and neutralizes its biological activity, thus preventing production and release of potent pro-inflammatory cytokines.

LL-37 increases cytokine and chemokine liberation from local cells and leucocytes and has chemotactic effects on a large number of immune cells. [4] In addition, chemokine and cytokine release is induced by LL-37 in mast cells or keratinocytes. [19] In cooperation with the cytokines LL-37 enhances innate immune responses by multiple pathways. [4] Furthermore, LL-37 enhances the proliferation of endothelial cells and influences angiogenesis. These attributes complement the antimicrobial functions of LL-37 and have led to the perception of LL-37 as not only an antimicrobial but also an "alarmin" peptide. [20]

On a molecular level LL-37 mediates its "alarmin" functions on immune or resident cells in a ligand-receptor-mediated or a receptor-independent manner resulting in increased host responses. In doing so, LL-37 influences adenosine triphosphate-receptor P2X7 and Toll-like receptor signaling in immune cells, epidermal growth factor receptor transactivation and intracellular Ca 2+ mobilization.

The dual role of cathelicidin-the antimicrobial and the alarmin function-suggests a central role for this peptide in innate immunity. Consequently, dysfunction of the "alarmin" function of cathelicidin LL-37 could play a role in the pathogenesis of inflammatory diseases to the same extent as impaired antimicrobial activity. [21]

The role of cathelicidins in the oral diseases

The expression of AMPs in saliva and throughout the oral cavity suggests that they may have a role in protecting tooth structure from caries as well as protecting oral mucosa. Several reasons for this proposal are as follows: 1) AMPs have broad antimicrobial activity; 2) their action is synergistic with other antimicrobials in saliva; co-expression of cathelicidins and defensins with peptides, such as histatins, and proline-rich proteins may enhance antimicrobial function; 3) they stimulate the acquired immune system and could function to enhance IgA production as well as IgG production; 4) these AMPs may function to keep overall bacteria in check and to help prevent biofilm formation. Thus, oral AMPs may provide a natural antibiotic barrier. [22],[23]

The role of LL-37 in oral immune competency has been further investigated, and high LL-37 levels in saliva have been correlated with resistance to caries. LL-37 is present in gingival crevicular fluid, where it may contribute as a marker for oral health status. Data from children show that the LL-37 saliva concentration is higher in girls versus boys, increases with age, and is higher in those with mixed or permanent dentition, whereas levels are diminished in individuals with high caries activity. [24]

The expression of LL-37 is upregulated in the inflamed gingival tissue in comparison with healthy gingival tissue and is correlated positively with the depth of the gingival crevice, indicating that LL-37 expression in the gingival tissue is associated with the severity of periodontal disease. Certain strains of pathogenic bacteria exhibit intrinsic resistance to cathelicidins and related antimicrobial peptides. [23] Studies have shown that the three well-known causative pathogens in chronic periodontitis, Porphyromonas gingivalis, Tanerella forsythia, and Treponema denticola, which fall under red-complex periodontal pathogens downregulate hBD-3 mRNA expression, as well as IL-8 production and secretion in an oral epithelial cell line. Moreover, they are more resistant to LL-37 and phagocytosis by neutrophils, indicating their strong implication with chronic periodontal infection. [24]

An important alternative source, other than salivary gland secretion, for HNP1-3 and LL-37 is the neutrophils that migrate into the oral cavity through gingival crevicular fluid. In normal individuals it has been estimated that neutrophils enter the oral cavity at the rate of 30,000 per minute through this route and the junctional epithelium surrounding the teeth. Studies have shown that flow of neutrophils is required for periodontal health and for protection against caries. Subsequently, the defects in neutrophil function and chemotaxis are associated with early-onset periodontal disease and caries in children. [18]

Swedish pediatrician Rolf Kostmann (1909-1982) was the first to report on infantile genetic agranulocytosis, now known as Morbus Kostmann, in a 1956 article in Acta Paediatrica Scandinavia. While the mechanism underlying this recessive genetic disorder was still unknown, Kostmann speculated on a missing serum factor. [25] The disease renders patients more susceptible to pathogens consequent to abnormal myelopoiesis, and clinical findings are characterized by chronic skin and mucous membrane infections that necessitate repeated treatment with antibiotics. Overall life-quality for patients was improved after introduction of recombinant human granulocyte colony-stimulating factor (G-CSF) in the late 1980s. While G-CSF works to restore neutrophil levels, problems with chronic infections, particularly severe periodontitis and chronic gingivitis, persisted despite treatment. In the decades to follow, research in immunology focused increasingly on effector molecules of innate immunity, leading also to evaluation of HDPs in this patient category. In 2002, Hans Boman's group reported that human cathelicidin is absent in plasma and saliva in Morbus Kostmann patients, while individuals subjected to bone marrow transplantation have essentially normal LL-37 concentrations. [22] The study as such established the fact that the occurrence of severe periodontal disease in Morbus Kostmann patients is in accordance with deficient LL-37 production. Several of the original index cases in the Kostmann family were recently shown to harbor mutations in the neutrophil elastase gene, suggesting a mechanism for a lack of cathelicidin processing and activation.

Severe periodontitis is found in the Papillon-Lefevre syndrome (PLS), an inheritable disease caused by loss-of-function mutations in the cathepsin C gene. Cathepsin C is the activator of serine proteinases, elastase, cathepsin G, and proteinase 3. These patients have been recently found to lack active neutrophil-derived serine proteases. The neutrophils from patients with PLS release reduced levels of mature LL-37 because serine proteinases are needed to convert the neutrophil-derived LL-37 into the mature peptide that possesses antimicrobial activity. These studies suggest that hCAP18/LL-37 plays an important role in innate immunity against periodontal pathogens. [15]

Cathelicidin is produced in high levels in skin post wounding and is strongly expressed in healing skin epithelium, and an antibody against this antimicrobial peptide inhibits re-epithelialization in a dose-dependent manner. [26] In chronic ulcers, LL-37 levels are low and absent in the ulcer edge epithelium. Thus, it appears that cathelicidins are important for successful wound closure and defects in their production can be correlated with the development of chronic ulcers on skin and this theory may imply oral mucositis also. [8]

It has been demonstrated that the expression of hCAP18/LL-37 mRNA is undetected in 16 cell lines from human oral SCC (Squamous cell carcinoma). A similar result is obtained in that LL-37 peptide expression is decreased in colonic epithelial cancer cells than in the normal colonic tissue. In addition, it is demonstrated by using an in vitro model of colon epithelial cell differentiation that the expression of LL-37 mRNA and its protein are increased during differentiation. [14] These results indicate that cell differentiation may be a determinant for the up-regulation of epithelial hCAP18/LL-37 expression. Conversely, LL-37 is highly expressed in human breast cancer cells, ovarian cancer cells, and lung cancer cells. However, the involvement of hCAP18/LL-37 in human oral SCC remains to be elucidated. Further study is needed to clearly understand this phenomenon. [15]

Antimicrobial peptides as therapeutic agents in oral cavity

Cationic antimicrobial peptides, including human cathelicidin LL-37, possess qualities that make them excellent candidates for antimicrobial therapeutics, including a broad spectrum of antimicrobial activity, ease of synthesis, and a novel mechanism of action. [27] In the oral cavity, HDPs, including the LL-37 peptide, play important roles in maintaining oral health. Therapeutic use of HDPs in oral care requires clinical studies with defined end points due to the complexity of the etiology and pathogenesis of oral complications. Human trials failed to support the use of Iseganan (a protegrin variant) as cathelicidin family peptide to reduce the severity of oral mucositis although microbial limit testing and safety studies clearly indicated the efficacy of histatins in animals. [28],[29]

The expression of CD69 and IFN-γ from NK cells stimulated by CpG-ODNs can be enhanced by treatment with the LL-37 peptide, thus leading to the activation of NK cells. NK cells play a critical role in the antitumor effects against murine ovarian tumor. Although HDPs, including LL-37, indicate antimicrobial and antitumor activity, it is currently difficult to develop peptide-based drugs due to poor pharmacokinetics and potential systemic toxicity. [30]

  Conclusion Top

The oral cavity is a unique environment in which antimicrobial peptides play a key role in maintaining health. Present evidence suggests that α-defensins, β-defensins, LL-37, histatins, and other antimicrobial peptides and proteins have distinct but overlapping roles in maintaining oral health. Diverse biological functions have been documented for cathelicidins in microbial killing and augmentation of innate immune functions. Clinical studies are now identifying associations between changes in cathelicidin production or function and human infectious diseases, inflammatory syndromes, or immune deficiencies. A thorough understanding of these associations will pave the way for new treatment strategies involving administration of exogenous cathelicidin or modulation of endogenous cathelicidin production.

  References Top

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  [Figure 1]

  [Table 1]

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