LL-37 (Cathelicidin): Antimicrobial Peptide Biology and Clinical Research Landscape

Overview

LL-37 (hCAP-18) is the C-terminal peptide derived from the human cathelicidin antimicrobial peptide (CAMP) gene product. It is expressed by epithelial tissues, neutrophils, and macrophages, and represents the sole cathelicidin in humans. LL-37 exhibits broad-spectrum antimicrobial activity against bacteria, fungi, and enveloped viruses, while also functioning as an immunomodulator with effects on chemotaxis, angiogenesis, and inflammatory signaling.

Biological Mechanism

LL-37 exerts antimicrobial activity through disruption of microbial membranes, facilitated by its amphipathic alpha-helical structure in physiological environments. Beyond direct killing, it acts as a chemoattractant for immune cells (neutrophils, monocytes, T cells) via formyl peptide receptor-like 1 (FPRL1) and other G-protein-coupled receptors. It also modulates TLR signaling, potentially dampening excessive inflammatory responses.

Clinical Research

Psoriasis

In psoriatic skin, LL-37 forms complexes with self-DNA and RNA, triggering plasmacytoid dendritic cell activation via TLR9 and TLR7/8. This autoinflammatory loop is considered a key initiating event in psoriasis pathogenesis. Anti-LL-37 strategies are under investigation.

Rosacea

In rosacea, elevated cathelicidin processing by kallikrein proteases generates pro-inflammatory LL-37 fragments, contributing to the characteristic inflammation. This pathway has informed therapeutic approaches targeting protease activity.

Wound Healing

LL-37 promotes angiogenesis and re-epithelialization in preclinical wound models. Clinical investigation of topical LL-37 and synthetic cathelicidin analogues for chronic wounds and diabetic ulcers has been reported in the peer-reviewed literature, with evidence supporting accelerated healing in limited-cohort studies.

Infectious Disease

LL-37 and synthetic derivatives (e.g., Pexiganan, an LL-37-inspired peptide) have been evaluated in clinical trials for topical antibacterial applications. Pexiganan reached Phase 3 trials for diabetic foot ulcer infections.

Evidence Assessment

LL-37 is among the most extensively studied human antimicrobial peptides, with a robust body of peer-reviewed literature spanning in vitro mechanistic studies, in vivo models, and clinical investigation. Clinical evidence is strongest for its role in dermatological disease pathogenesis and moderate for therapeutic applications in wound healing and topical antimicrobial therapy.