Lack of cathelicidin processing in Papillon-Lefèvre syndrome patients reveals essential role of LL-37 in periodontal homeostasis

Abstract

BackgroundLoss-of-function point mutations in the cathepsin C gene are the underlying genetic event in patients with Papillon-Lefèvre syndrome (PLS). PLS neutrophils lack serine protease activity essential for cathelicidin LL-37 generation from hCAP18 precursor.AimWe hypothesized that a local deficiency of LL-37 in the infected periodontium is mainly responsible for one of the clinical hallmark of PLS: severe periodontitis already in early childhood.MethodsTo confirm this effect, we compared the level of neutrophil-derived enzymes and antimicrobial peptides in gingival crevicular fluid (GCF) and saliva from PLS, aggressive and chronic periodontitis patients.ResultsAlthough neutrophil numbers in GCF were present at the same level in all periodontitis groups, LL-37 was totally absent in GCF from PLS patients despite the large amounts of its precursor, hCAP18. The absence of LL-37 in PLS patients coincided with the deficiency of both cathepsin C and protease 3 activities. The presence of other neutrophilic anti-microbial peptides in GCF from PLS patients, such as alpha-defensins, were comparable to that found in chronic periodontitis. In PLS microbial analysis revealed a high prevalence of Aggregatibacter actinomycetemcomitans infection. Most strains were susceptible to killing by LL-37.ConclusionsCollectively, these findings imply that the lack of protease 3 activation by dysfunctional cathepsin C in PLS patients leads to the deficit of antimicrobial and immunomodulatory functions of LL-37 in the gingiva, allowing for infection with A. actinomycetemcomitans and the development of severe periodontal disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0148-y) contains supplementary material, which is available to authorized users.

Antimicrobial peptides as a possible interlink between periodontal diseases and its risk factors: A systematic review

“…In light of the host‐related immunological differences between chronic and aggressive periodontitis, differences in baseline gingival LL‐37 expression are possible. An absence of LL‐37 in the gingival crevicular fluid of Papillon‐Lefèvre‐Lefevre syndrome, which is characterized by altered neutrophil activity, has been noted . Up until now, no study has explored signaling mechanisms underlying LL‐37 expression as modulated by smoking in human gingival epithelial cells/keratinocytes.…”

Immune and regulatory functions of neutrophils in inflammatory bone loss

“…Because they cannot activate proteinase-3 either, Papillon-Lefèvre neutrophils are also unable to process the cathelicidin precursor protein hCAP18 into the antibacterial peptide LL-37 [113,117]. Given the notion that neutrophil serine proteases (and hence the products dependent on their activity, such as LL-37) are dispensable for immune protection [113], the association of LL-37 with periodontal tissue homeostasis [117] could possibly be explained by the immunoregulatory properties attributed to LL-37, such as downregulation of Toll-like receptor-mediated inflammatory responses and osteoclastogenesis [118–120].…”

Neutrophil extracellular traps — the dark side of neutrophils

“…These microbes are efficiently killed by the antimicrobial peptide LL-37 (67), which is generated by proteolytic cleavage of cathelicidin (hCAP-18) from neutrophil-specific granules (68). This process is executed by proteinase 3 (PR3) (12), in which Papillon-Lefèvre neutrophils are deficient (11,69).…”