The human cathelicidin LL-37 — A pore-forming antibacterial peptide and host-cell modulator

• Cathelicidins are a conserved component of innate immunity in vertebrates.
• LL-37, the human CATHELICIDIN peptide, has multiple roles in host defence.
• It inactivates bacteria by forming discreet membrane lesions (pore-forming).
• It modulates host cell responses via membrane-mediated receptor interactions.
• These capacities depend on its adoption of a helical oligomeric structure.
• Orthologues from other eutherian species have evolved different modes of action.

The human cathelicidin hCAP18/LL-37 has become a paradigm for the pleiotropic roles of peptides in host defence. It has a remarkably wide functional repertoire that includes direct antimicrobial activities against various types of microorganisms, the role of ‘alarmin’ that helps to orchestrate the immune response to infection, the capacity to locally modulate inflammation both enhancing it to aid in combating infection and limiting it to prevent damage to infected tissues, the promotion of angiogenesis and wound healing, and possibly also the elimination of abnormal cells. LL-37 manages to carry out all its reported activities with a small and simple, amphipathic, helical structure. In this review we consider how different aspects of its primary and secondary structures, as well as its marked tendency to form oligomers under physiological solution conditions and then bind to molecular surfaces as such, explain some of its cytotoxic and immunomodulatory effects. We consider its modes of interaction with bacterial membranes and capacity to act as a pore-forming toxin directed by our organism against bacterial cells, contrasting this with the mode of action of related peptides from other species. We also consider its different membrane-dependent effects on our own cells, which underlie many of its other activities in host defence. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale.