Antimicrobial and Attractant Roles for Chemerin in the Oral Cavity during Inflammatory Gum Disease

Abstract

Periodontal inflammation is one of the most common chronic inflammatory conditions in humans. Despite recent advances in identifying and characterizing oral microbiota dysbiosis in the pathogenesis of gum disease, just how host factors maintain a healthy homeostatic oral microbial community or prevent the development of a pathogenic oral microbiota remains poorly understood. An important determinant of microbiota fate is local antimicrobial proteins. Here, we report that chemoattractant protein chemerin, which we recently identified as a potent endogenous antimicrobial agent in body barriers such as the skin, is present in the oral cavity under homeostatic and inflammatory conditions. Chemerin and a chemerin-derived antimicrobial peptide are bactericidal against select bacteria strategically positioned in dental biofilm. Gingival crevicular samples from patients with gingivitis but not periodontitis contain abundant bioactive chemerin capable of inducing CMKLR1-dependent leukocyte migration. Gingipains secreted by the periodontopathogen P. gingivalis inactivate chemerin. Together, these data suggest that as an antimicrobial agent and leukocyte chemoattractant, chemerin likely contributes to antimicrobial immune defense in the oral cavity.

The antimicrobial activity of chemerin-derived peptide p4 requires oxidative conditions

“…An internal 20-amino acid peptide, Val 66 -Pro 85 (p4), exhibits most of the antimicrobial activity of active chemerin in vitro (15,16). Among its microbial targets are Gram-positive and Gram-negative bacteria: S. aureus and Escherichia coli, respectively.…”

“…To determine the role of p4 in restricting bacteria growth in vivo, p4, control peptides, or vehicle were topically administered to mouse skin. The control peptides included a scramble peptide 4 (scp4, Table 1), which, in contrast to p4, was found previously to be nonbactericidal against oral cavity-associated bacteria (16), and peptide p2, which originates from a different region of human chemerin (Glu 36 -Ala 55 ) and is devoid of antimicrobial activity against E. coli (15). The peptides were allowed to dry on the skin, and mice were then topically infected with S. aureus 8325-4.…”

“…Chemerin is expressed by many types of epithelial cells (11)(12)(13) and, in skin keratinocytes, is up-regulated in response to bacteria and acute-phase cytokines (14). Recombinant chemerin and chemerin-derived peptide 4 (p4), located in a central region of the chemerin protein sequence, are both active against a broad range of microorganisms, including skin-, lung-, and oral cavityassociated bacteria as well as the fungal pathogen Candida albicans (8,15,16). Inhibition of bacterial growth by conditioned medium from organ cultures of primary human keratinocytes is largely chemerin-dependent (15), and chemerin deficiency results in higher counts of viable bacteria associated with the epidermis in an experimental model of skin infection (14).…”

Rola chemeryny i jej antybakteryjnych pochodnych w utrzymaniu funkcji barierowych nabłonka

“…Największą skuteczność peptydu p4 notuje się wobec paciorkowców, takich jak Streptococcus salivarius oraz Streptococcus sanguinis. Natomiast inne przebadane gatunki: Streptococcus oralis i Streptococcus gordonii są oporne na działanie p4 [37]. Wszystkie wymienione gatunki paciorkowców są uznawane za gatunki komensalne, które utrzymują mikrobiom jamy ustnej w stanie równowagi, ograniczając wzrost gatunków chorobotwórczych.…”

Bacteria Modify Their Sensitivity to Chemerin-Derived Peptides by Hindering Peptide Association With the Cell Surface and Peptide Oxidation

“…Proteolytic cleavage at serine 157 in the carboxyl-terminus of Chem163S results in generation of Chem157S isoform that is effective in triggering chemotaxis of several types of immune cells (Yamaguchi et al, 2011). This isoform also exhibits much stronger growth inhibitory potential compared with Chem163S against bacteria (Kulig et al, 2011;Godlewska et al, 2017). However, in contrast to C-terminal region responsible for chemotactic potential, antimicrobial activity is mainly associated with a domain localized in the middle of the chemerin sequence, Val 66 -Pro 85 peptide (p4), which embodies the majority of chemerin's anti-microbial activity (Banas et al, 2013).…”