Antimicrobial peptides in the pathogenesis of psoriasis

Abstract

One characteristic abnormality of lesional skin in psoriasis is the excessive production of antimicrobial peptides and proteins (AMPs). AMPs typically are small (12-50 amino acids), have positive charge and amphipathic structure, and are found in all living organisms including mammals, insects, plants and invertebrates. These peptides are best known for their integral role in killing pathogenic microorganisms; however, in vertebrates, they are also capable of modifying host inflammatory responses by a variety of mechanisms. In psoriatic lesions, many AMPs are highly expressed, and especially the associations between psoriasis and cathelicidin, β-defensins or S100 proteins have been well studied. Among them, a cathelicidin peptide, LL-37, has been highlighted as a modulator of psoriasis development in recent years. AMPs had been thought to worsen psoriatic lesions but recent evidence has also suggested the possibility that the induction of AMPs expression might improve aspects of the disease. Further investigations are needed to uncover a previously underappreciated role for AMPs in modulating the immune response in psoriasis, and to improve disease without the risks of systemic immunosuppressive approaches.

Figure 1

Structure of human cathelicidin. Human cathelicidin precursor protein hCAP18 contains a signal peptide domain on its N-terminus. LL-37 is the C-terminal peptide fragment derived from hCAP18, and needs to be released by enzymatic cleavage such as kallikreins in keratinocytes and protease 3 in neutrophils. LL-37 is further cleaved into smaller peptides such as RK-31, KS-30, LL-29, KS-22 and KR-20.

Figure 2

Proposed role for LL-37 in the pathogenesis of psoriasis. Stressed cells stimulated by trauma or bacterial products release LL-37, self-RNA and self-DNA. Self-RNA and self-DNA form complexes with LL-37 and the complexes are then recognized by Toll-like receptor (TLR)7 or TLR9 in plasmacytoid dendritic cells (pDCs) or TLR8 in myeloid dendritic cells (mDCs). On the other hand, LL-37 induces TLR9 expression in keratinocytes (KCs) and greatly enhances type I IFN production induced by TLR9 signaling. Stimulated mDCs induce the differentiation of naïve T cells into Th1 cells or Th17 cells. Interleukin (IL)-17A, IL-17F and IL-22 are produced by Th17 cells and IFN-γ and tumor necrosis factor (TNF)-α are produced by Th1 cells. These mediators act on keratinocytes, leading to the activation, proliferation and production of antimicrobial peptides and proteins (AMPs) or chemokines.

Figure 3

Different interactions between LL-37 and DNA in keratinocytes. In keratinocytes, extracellular or endosomal LL-37 enhances DNA recognition by Toll-like receptor (TLR)9, leading to type I interferon (IFN) production. The mechanism of TLR9 induction by LL-37 is unclear. Another mechanism may enhance TLR9 sensitivity rather than the upregulation of TLR9 expression and complex formation in keratinocytes. Intracellular or cytosolic LL-37 binds to DNA and inhibits interleukin (IL)-1β production through AIM2 inflammasome.