AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense

Abstract

Antimicrobial peptides (AMPs) are widely expressed and rapidly induced at epithelial surfaces to repel assault from diverse infectious agents including bacteria, viruses, fungi and parasites. Much information suggests that AMPs act by mechanisms that extend beyond their capacity to serve as gene-encoded antibiotics. For example, some AMPs alter the properties of the mammalian membrane or interact with its receptors to influence diverse cellular processes including cytokine release, chemotaxis, antigen presentation, angiogenesis and wound healing. These functions complement their antimicrobial action and favor resolution of infection and repair of damaged epithelia. Opposing this, some microbes have evolved mechanisms to inactivate or avoid AMPs and subsequently become pathogens. Thus, AMPs are multifunctional molecules that have a central role in infection and inflammation.

Figure 1

Structure of selected antimicrobial peptides (AMPs). AMPs are present in a wide variety of structural conformation, such as peptides with α-helix structures, peptides with β-sheet structures stabilized by disulfide bridges or peptides with extended or loop structures. (a) α-helix. NMR-structure of the LL-37 core peptide of cathelicidin bound to detergent micelles [PDB ID: 2FBS). (b) β-sheet Solution structure of the defensin hBD2 by two-dimensional proton nuclear magnetic resonance spectroscopy (PDB ID: 1FQQ). (c) extended structure, NMR structure of the bovine antimicrobial peptide indolicidin bound to dedecytphosphocholine (OPC) micelles (PDB ID: 1G89). (d) loop structure. 3D structure of a cyclic defensin from the leukocytes of rhesus macaques (PDB ID: 1HVZ). PDB ID: ID of peptide structure in Research Collaboratory for Structural Bioinformatics (RCSB) protein data bank (http://www.rcsb.org/pdb/home/home.do). The style of LL37 in (a) is shown as secondary coloring shortcuts, whereas the styles of peptides in (b-d) are shown in rainbow coloring shortcuts.

Figure 2

Multiple functions of antimicrobial peptides in host defense. AMPs induce a variety of responses in host Innate immune cells such as monocytes, macrophages, neutrophils and epithelial cells. They alter gene expression of host cells, induce production of chemokines and cytokins, promote leukocyte recruitment to the site of infection, influence cell differentiation and activation and block or activate TLR signaling. The outcome of the selective Immunomodulation by AMPs results in innate Immune responses, leading to protection against infection, selective control of inflammation, promotion of wound healing and initiation of adaptive immune responses. Abbrevations: AMP, anti-microbial peptide; DC, dendritic cell; LPS, lipopolysaccharide; pDC, plasmacytold dendritic cell; PMN, polymorphonucleocyte; TLR, Toll-like receptor.

Figure 3

Alternative models for host activation by antimicrobial peptides. Three mechanisms have been proposed to explain how AMPs activate mammalian cells. Alternate ligand model; some AMPs, such as defensins and cathelicidin, might directly bind to a specific receptor, resulting in initiation of receptor signaling. This has been proposed for CCR6 and FPRL-1. Membrane disruption model in this model AMPs associate with and modify the membrane containing the receptor. This membrane activity indirectly results in a change in receptor function such that it can signal without a ligand or becomes insensitive to binding by its specific ligand. This has been proposed for inactivation of TLR4. Trans-activation model: AMPs stimulate the release of a membrane-bound growth factor, which then binds to its high affinity receptor and activates it. This has been proposed for HB-EGF (heparin binding epidermal growth factor) and the EGF receptor.

Figure 4

Model of the initiation and maintenance of autoimmune skin inflammation by LL37 in psoriasis. Skin injury and infections induce a rapid expression of the cathelicidin hCAPl8 in keratinocytes or infiltrated neutrophils. The mature peptide LL37 is cleaved from the precursor hCAP18 by Kalllikreins or proteinese 3. Subsequently LL37 combines with self-DNA released by damagad cells to form a complex. which triggers TLR9 in pDC to produce type 1 Interferons (IFNα and β). Type 1 IFNs trigger local maturation of myeloid dendritic cell to activate autoreactive Th1 or Th17 cells, resulting in the production of INF-γ,.IL-22 and IL-17. The sustained production of IL-22 and IL-17 leads to the expression of LL37 that forms a feedback loop to maintain inflammation in psoriasis.