Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease

Abstract

The innate immune system utilizes many approaches for defense against invading microorganisms, including complement-mediated lysis, engulfment, formation of neutrophil extracellular traps, and release of antimicrobial peptides. Although classically thought to be driven by adaptive immunity, the development of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus is increasingly associated with dysregulated innate immune pathways. An emerging theme within this literature is the contribution of antimicrobial peptides to the development of autoimmune disorders. This is best exemplified in atopic dermatitis and psoriasis where the defensins and the single human cathelicidin, LL-37, may contribute to disease. Furthermore, in the past few years, a role for LL-37 has emerged in the pathogenesis of systemic lupus erythematosus, rheumatoid arthritis, atherosclerosis, and possibly other diseases. In this review, we discuss the role of LL-37 and its murine ortholog, mCRAMP, in the modulation of immune and inflammatory pathways and their effects on autoimmune and inflammatory diseases.

Figure 1. L-37 is generated via cleavage of full-length hCAP18 and has numerous immunomodulatory functions depending on environmental and cellular context

The 18 kDa pro-peptide, hCAP18, is synthesized and stored in granules and lamellar bodies. Following stimulation by pro-inflammatory signals, hCAP18 is released into the extracellular environment and cleaved by proteinase 3 in neutrophils and kallikrein in keratinocytes (green dots) and the N-terminal 37 amino acids form the alpha-helical LL-37 peptide which then dimerizes and trimerizes in solution. Exposure to LL-37 results in recruitment of inflammatory cells, induction of M1 macrophages and stimulation of inflammatory responses such as inflammasome activation and type I IFN production. Type I IFN production is promoted via LL-37 protection of both RNA and DNA, allowing for activation of endosomal TLR7 and TLR9 respectively. LL-37, expressed on the surface of neutrophils is recognized by anti-LL-37 autoantibodies, which promotes NETosis, generating a source of additional LL-37 DNA complexes. However, LL-37 has strong anti-inflammatory effects such as neutralization of TLR4 activation by LPS, downmodulation of inflammatory cytokine responses and preventing invasion and inflammatory responses to pathogenic bacteria.