IL-17: overview and role in oral immunity and microbiome

Abstract

Interleukin-17 (IL-17) is a multifaceted cytokine with diverse roles in both immune protection and also immunopathology. IL-17 has a well-recognized role in immune surveillance at mucosal and barrier surfaces, but also has been increasingly implicated as a driver of immunopathology in settings of autoimmunity and chronic inflammation. The current review introduces basic aspects of IL-17 biology and examines the protective and pathogenic roles of IL-17 with a focus on oral mucosal immunity and inflammation. Specific emphasis is given to the role of the IL-17 response as a catalyst in 'shaping the microbiome at the oral barrier'.

Keywords: IL-17; Th17; oral microbiome; oral mucosal immunity.

Figure 1. The IL-17 signaling

IL-17 (IL-17A, IL-17F, IL-17A/F) engages the heteromeric IL-17R complex and recruits the adaptor protein Act1. Act1 triggers the ubiquitination of TRAF6. TRAF6 activates three major pathways namely NF-κB, MAPK and C/EBP, triggering the transcription of IL-17 target genes. This signaling cascade is regulated at multiple steps. Hsp90 acts as a positive regulator of this cascade by stabilizing Act1. TRAF2 and TRAF5 are also positive regulators that form a complex with SF2 and recruit HuR, to mediate mRNA stabilization. TRAF3 inhibits the association of the IL-17R with Act1 and TRAF4 inhibits the recruitment of TRAF6 by Act1. miR-23b negatively regulates NF-κB activation.

Figure 2. Cellular sources and targets of IL-17

(Upper panel) Main cellular sources of IL-17 are Th17 cells and other immune cells such as γδ T cells, lymphoid tissue inducer cells (LTi), innate lymphoid cells type 3 (ILC3s) and natural killer cells (NK). During inflammation IL-17 can also be produced by neutrophils and macrophages. (Lower panel) Cellular targets of IL-17 are primarily non-hematopoietic cells, including keratinocytes, fibroblasts, endothelial and osteoblasts cells. Immune cells such as T, B and NK cells can also be IL-17 targets.

Figure 3. IL-17 is critical for oral mucosal integrity and immunosurveillance

Th17 cells, largely through its effector cytokine IL-17 (but also through IL-22), have an important role in maintaining mucosal barrier integrity. Key functions in IL-17-mediated mucosal surveillance are (1) regulation of epithelial tight junction protein expression (2), induction of antimicrobial peptide production (3) and release of neutrophil chemo-attractants.

Figure 4. Th17 in inflammatory disease and their pathogenic Th17 signature

(Left) Th17 cells have been implicated in the pathogenesis of various inflammatory and autoimmune diseases. (Right) Cellular and molecular signature of pathogenic Th17 cells.

Figure 5. Concepts of how IL-17 immunity may participate in the establishment of the oral microbiome/mycobiome

Defects in the Th17 pathway are associated with an overgrowth of fungi leading to oral and mucocutaneous candidiasis. Conversely, exaggerated IL-17 responses in the context of periodontitis have been linked to bacterial overgrowth and dysbiosis.