T-helper 17 (Th17) inflammatory signaling pathway (Th17 pathway)

The T-helper 17 (Th17) inflammatory signaling pathway, primarily defined by the IL-23/IL-17 axis, is a specialized immune cascade that coordinates host defense against extracellular pathogens and drives the pathogenesis of various chronic inflammatory diseases. The pathway is initiated when naive CD4+ T cells differentiate into Th17 cells under the influence of cytokines like IL-6, TGF-β, and IL-23, a process governed by the master transcription factor RORγt. Activated Th17 cells produce effector cytokines, including IL-17A, IL-17F, and IL-22, which bind to receptor complexes like IL-17RA/RC on epithelial and mesenchymal cells. This interaction triggers downstream signaling through the adapter protein Act1 and the NF-κB and MAPK pathways, leading to the production of pro-inflammatory chemokines, antimicrobial peptides, and matrix metalloproteinases. While essential for mucosal immunity, dysregulation of this pathway is a major driver of conditions such as psoriasis, psoriatic arthritis, and ankylosing spondylitis. Therapeutic strategies targeting this pathway include monoclonal antibodies against IL-17A (e.g., secukinumab), the IL-17 receptor (e.g., brodalumab), and the p19 subunit of IL-23 (e.g., guselkumab).

Other names

IL-23/IL-17 axisIL-17 signaling pathwayTh17 axisT-helper 17 pathwayIL-23/Th17 signaling pathway

Drugs targeting the Th17 pathway act by neutralizing key pro-inflammatory cytokines (such as IL-17A, IL-17F, or the p19/p40 subunits of IL-23) or by blocking their respective receptors (such as IL-17RA), thereby preventing the activation of downstream signaling cascades involving the adapter protein Act1 and the transcription factor NF-κB, which reduces the production of inflammatory mediators and the recruitment of neutrophils to tissues.