Human cathelicidin LL-37-derived peptide IG-19 confers protection in a murine model of collagen-induced arthritis

Abstract

Current therapies for autoimmune chronic inflammatory diseases e.g. rheumatoid arthritis (RA) include inhibitors of inflammatory cytokines. However, these therapies can result in increased risk of infections. There is a need to explore alternate strategies that can control inflammation without compromising the innate ability to resolve infections. In this study, we examined the effect of small peptides derived from endogenous cathelicidin peptides in a murine model of collagen-induced arthritis (CIA). Cathelicidins are immunomodulatory peptides known to control infections. We demonstrate that the administration of the peptide IG-19, which represents an internal segment of the human cathelicidin LL-37, decreased disease severity and significantly reduced the serum levels of antibodies against collagen type II in the CIA model. IG-19 peptide reduced cellular infiltration in joints, prevented cartilage degradation and suppressed pro-inflammatory cytokines in the CIA mice. We also showed that not all cathelicidin-derived peptides exhibit similar functions. A bovine cathelicidin-derived peptide IDR-1018 did not exhibit the beneficial effects observed with the human cathelicidin LL-37-derived peptide IG-19, in the same murine model of CIA. This is the first study to provide evidence demonstrating the ability of a peptide derived from the human cathelicidin LL-37 to alleviate the arthritic disease process in a murine model of RA. Our results has lead us to propose a new approach for controlling autoimmune chronic inflammatory disorders such as RA, by using specific synthetic derivatives of endogenous host defence peptides. Cathelicidin-derived peptides are particularly attractive for their dual antimicrobial and anti-inflammatory actions.

LL-37-Derived Peptides Eradicate Multidrug-Resistant Staphylococcus aureus from Thermally Wounded Human Skin Equivalents

“…In agreement with these findings, others have demonstrated that a bovine cathelicidin-derived peptide, IDR1018, can aid in wound healing in S. aureus-infected murine wounds (48). In addition, another LL-37-derived synthetic peptide, named IG-19, decreased disease severity and significantly reduced the serum levels of antibodies against collagen type II in a collagen-induced arthritis model (49). Besides allowing for an assessment of the antibacterial activities of peptides on infected tissues, the advantage of using an in vitro infection model that mimics the human skin is that the possible effects of the peptides on inflammation (as exemplified by IL-8 release), cell viability, and wound healing can be monitored in the same model.…”

Inactivation of the Antifungal and Immunomodulatory Properties of Human Cathelicidin LL-37 by Aspartic Proteases Produced by the Pathogenic Yeast Candida albicans

“…Very recent studies report the antibacterial peptide cathelicidin LL-37 and its fragments as a promising antifungal drug (38,39). Once secreted at the site of candidal infection, LL-37 may be actively localized on the Candida cell wall (40), thereby reducing cell wall thickness and affecting the functionality of the cytoplasmic membrane (41, 42).…”

Human cathelicidin antimicrobial protein 18 (hCAP18/LL-37) is increased in foetal membranes and myometrium after spontaneous labour and delivery

“…Indeed, both pro-and antiinflammatory functions have been assigned to LL-37 and this may be modulated by the microenvironment and disease background. Anti-inflammatory actions have been reported in arthritic animal models, where a synthetically derived LL-37 peptide suppressed pro-inflammatory cytokine levels (Chow et al, 2014). LL-37 attenuates LPS-stimulated IL-6 and MCP-1 expression in periodontal ligament cells (Jonsson and Nilsson, 2012) and LPSstimulated IL-8 production in monocytes (Scott et al, 2011).…”