Directing traffic: IL-17 and IL-22 coordinate pulmonary immune defense

Abstract

Respiratory infections and diseases are among the leading causes of death worldwide, and effective treatments probably require manipulating the inflammatory response to pathogenic microbes or allergens. Here, we review mechanisms controlling the production and functions of interleukin-17 (IL-17) and IL-22, cytokines that direct several aspects of lung immunity. Innate lymphocytes (γδ T cells, natural killer cells, innate lymphoid cells) are the major source of IL-17 and IL-22 during acute infections, while CD4(+) T-helper 17 (Th17) cells contribute to vaccine-induced immunity. The characterization of dendritic cell (DC) subsets has revealed their central roles in T-cell activation. CD11b(+) DCs stimulated with bacteria or fungi secrete IL-1β and IL-23, potent inducers of IL-17 and IL-22. On the other hand, recognition of viruses by plasmacytoid DCs inhibits IL-1β and IL-23 release, increasing susceptibility to bacterial superinfections. IL-17 and IL-22 primarily act on the lung epithelium, inducing antimicrobial proteins and neutrophil chemoattractants. Recent studies found that stimulation of macrophages and DCs with IL-17 also contributes to antibacterial immunity, while IL-22 promotes epithelial proliferation and repair following injury. Chronic diseases such as asthma and chronic obstructive pulmonary disease have been associated with IL-17 and IL-22 responses directed against innocuous antigens. Future studies will evaluate the therapeutic efficacy of targeting the IL-17/IL-22 pathway in pulmonary inflammation.

Keywords: IL-17; IL-22; T cell; immunity; lung.

Fig. 1. Regulation of IL-17 and IL-22 production by dendritic cell subsets

Dendritic cells (DCs) and alveolar macrophages identify pathogens through PRRs. Bacterial cell walls, viral nucleic acids, and fungal cell walls are detected by cell surface TLRs, intracellular TLRs, and Dectin-1, respectively. Alveolar macrophages produce IL-1β in response to bacteria, stimulating IL-17 secretion from innate lymphocytes. Other stimuli that activate NLRP3 also contribute to IL-1β production. DCs influence effector CD4⁺ T-cell polarization by providing antigens, costimulatory molecules, and cytokines. IL-1β and IL-23 produced by CD11b⁺ DCs in response to bacteria or fungi induces Th17 differentiation. The activation of NK-κB and STAT3 transcription factors in lymphocytes favors RORγt expression and IL-17/IL-22 production. Viruses stimulate plasmacytoid DCs to secrete type I IFNs, inhibiting the expression of Th17 polarizing cytokines. In this way, viruses suppress anti-bacterial Th17 immunity. Other cytokines that activate STAT1 and suppress IL-17/IL-22 production include IFN-γ and IL-27.

Fig. 2. Roles of IL-17 and IL-22 in host defense

Infections and inflammatory diseases increase the accumulation of IL-17 producing cells in lung tissue. Airway epithelium responds to IL-17 by producing antimicrobial proteins and neutrophil chemoattractants, helping to eradicate bacteria and fungi. In response to viruses, IL-17RA signaling contributes to acute lung injury through neutrophil recruitment, increasing levels of oxidized phospholipids. IL-22 is important for epithelial repair following injury. The major sources of IL-17 and IL-22 include innate lymphocytes during primary responses and antigen-specific CD4⁺ T cells during secondary responses. Vaccines that prime Th17 immunity have demonstrated protection against bacteria and fungi. Interleukin-17 stimulates DCs to produce IL-12 while inhibiting IL-10, augmenting Th1 differentiation. Further, lung-resident Th17 cells induce the secretion of CXCR3 ligands, recruiting Th1 cells during infections. Direct stimulation of macrophages with IL-17 also increases their bactericidal activity. The pleiotropic functions of IL-17 and IL-22 are protective against infections but contribute to chronic inflammation in the presence of allergens.