Cytokine-mediated regulation of antimicrobial proteins

Abstract

Antimicrobial proteins constitute a phylogenetically ancient form of innate immunity that provides host defence at skin and mucosal surfaces. Although some components of this system are constitutively expressed, new evidence reviewed in this Progress article shows that the production of certain antimicrobial proteins by epithelial cells can also be regulated by cytokines of the innate and adaptive immune systems. In particular, the effector cytokines interleukin-17 and interleukin-22, which are produced by the T-helper-17-cell subset, are emerging as crucial regulators of antimicrobial-peptide production in the gut and the lungs. This suggests that this T-cell lineage and its cytokines have important roles in skin and mucosal immunity.

Figure 1. Antimicrobial protein structure and functional domains

a | Defensins, cathelicidins and hepcidin are synthesized as pre-pro peptides that are cleaved to release mature cationic antimicrobial peptides (AMPs) that interact with negatively charged bacterial surface moieties. Hydrophobic regions in the peptide (not shown) then integrate into the bacterial membrane, leading to membrane permeabilization, cytoplasm leakage and ultimately complete membrane perforation. Based on their primary amino-acid structure, antimicrobial CXC chemokines are thought to have similar mechanisms of action. Elastase inhibitors are also synthesized in a pre-pro form with a carboxy (C)-terminal elastase inhibitor region that contains a conserved whey acidic protein (WAP) motif. The WAP motif binds bacterial peptidase and may have antibacterial activities that are independent of the elastase inhibitory activity. The pro form of the elastase inhibitor elafin has a cationic domain that probably kills bacteria by membrane permeabilization. Lactoferrin is a 75 kDa bilobed, bivalent iron-binding protein. The amino (N)- and C-lobes, which contain an iron-binding site, may be cleaved by proteolytic digestion. The cationic lactoferricin domain in the N-lobe is thought to confer its antimicrobial activity. b | These proteins bind the bacterial peptidoglycan layer and either hydrolyse the peptidoglycan or facilitate bacterial opsonization. Peptidoglycan-recognition proteins (PGLYRPs) comprise varying numbers of peptidoglycan-recognition motifs (PGR; only one is shown here) and all have a conserved C-terminal PGR that has homology with bacterial peptidase. Most vertebrate PGLYRPs are secreted and lack the transmembrane domains (TMs) that are shown in this figure. Collectins consist of polypeptides with an N-terminal cysteine-rich domain, a collagen-like region, an α-helical region and a C-type lectin domain (CTLD). Trimers of the shown polypeptide multimerize to form the collectins. Regenerating (REG) proteins have a single CTLD; their mechanism of antibacterial activity is unknown. c | S100 proteins have two helix–loop–helix calcium-binding motifs; their mechanism of antibacterial activity is unknown. Lipocalin-2 is a 25 kDa protein that binds bacterial siderophores, which are bacterial iron-scavenging proteins, and therefore deprives bacteria of their necessary nutrient, iron. β, β-strand; SP, signal peptide.

Figure 2. Cytokine networks and antimicrobial peptides at epithelial-cell surfaces

In response to bacterial infection, the interleukin-1 (IL-1) family cytokines, such as IL-1β, potently induce the expression of antimicrobial proteins by the epithelium. IL-1β, together with IL-6 and IL-23, can also induce the differentiation of T helper 17 (T_H17) cells, which produce IL-17A, IL-17F and IL-22. These cytokines further induce antimicrobial-protein expression by the epithelium. IL-17A can also induce the production of CC-chemokine ligand 20 (CCL20), which has antimicrobial activity, recruits dendritic cells and increases the production of CXC-chemokine receptor 2 (CXCR2) ligands that are important in neutrophil recruitment. This response is beneficial to the host during an acute infection. However, in autoimmune diseases (such as psoriasis) cationic antimicrobial peptides, which are present at high levels, can interact with negatively charged DNA that is released from dying cells (cell death occurs as a result of increased cell turnover during inflammation). Antimicrobial-peptide–DNA complexes can amplify inflammation in the skin by activating Toll-like receptor 9 (TLR9) signalling.