Cytokines IL-17 and IL-22 in the host response to infection

Abstract

Cytokines IL-17 and IL-22 play pivotal roles in host defense against microbes and in the development of chronic inflammatory diseases. These cytokines are produced by cells that are often located in epithelial barriers, including subsets of T cells and innate lymphoid cells. In general, IL-17 and IL-22 can be characterized as important cytokines in the rapid response to infectious agents, both by recruiting neutrophils and by inducing the production of antimicrobial peptides. Although each cytokine induces an innate immune response in epithelial cells, their functional spectra are generally distinct: IL-17 mainly induces an inflammatory tissue response and is involved in the pathogenesis of several autoimmune diseases, whereas IL-22 is largely protective and regenerative. In this review, we compare IL-17 and IL-22, describing overlaps and differences in their cellular sources as well as their regulation, signaling, biological functions and roles during disease, with a focus on the contribution of these cytokines to the gut mucosal barrier during bacterial infection.

Keywords: IL-17; IL-22; mucosal immunity.

Figure 1.

Bacterium-induced signaling in antigen-presenting cells (APCs) leads to IL-23 production and subsequent activation of IL-17 and IL-22-producing cells. APCs, for instance DCs and macrophages, express PRRs on their surface, such as TLRs, and intracellular receptors in their cytosol, such as NLRs. These PRRs recognize conserved microbial-associated molecular motifs and PAMPs, including LPS, lipoproteins, and CpG oligodeoxynucleotides. When a TLR binds to its cognate PAMP, host-cell adaptor molecules such as MyD88, TIRAP and TRIF are recruited, and downstream signaling is initiated. The resulting activation of nuclear factor-κB (NF-κB) promotes transcription of a range of genes coding for proinflammatory cytokines, including IL-23, which trigger the production of IL-17 and IL-22 in cell subsets including Th17, γδ T and ILC3.

Figure 2.

Functions of IL-17 and IL-22 at epithelial surfaces. IL-17 and IL-22 are upregulated in response to infection with a variety of pathogens. These cytokines are produced by subsets of cells, including γδ T cells, ILC3 and Th17 cells, and elicit innate responses from mucosal epithelial cells. These responses include production of mucins by goblet cells, upregulation of genes involved in wound healing (e.g. Bcl-2, c-Myc, cyclin D1), the secretion of antimicrobial molecules (e.g. S100A8, S100A9, REG proteins, lipocalin-2) and the induction of proinflammatory mediators (e.g. TNF-α, IL-6, CXCL1, G-CSF) that contribute neutrophil recruitment at the site of infection. The functions of both cytokines are overlapping and in part synergistic. While IL-22 is more potent in tissue protection, repair and induction of antimicrobial peptides, IL-17 mediates stronger inflammatory responses by inducing other proinflammatory cytokines and the recruitment of neutrophils.