A new cytokine IL-17 was discovered in 1995 generated by CD4+ helper T cell (now recognized as type 17 T helper cell). IL-17 stimulated the production of IL-6 and IL-8, while also increasing the surface expression of ICAM-1 in human fibroblasts[1]. Subsequent exploration found additional family members: IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25), and IL-17F.

IL-17 exerts its effects through various immune cell subsets in response to inflammatory stimuli (The IL-17 mentioned in the text, unless specifically stated, refers to IL-17A). Studies had been discovering IL-17 pathophysiology in immunity context due to the promising efficacy of anti-IL-17 therapy in several autoimmune diseases, such as rheumatoid arthritis (RA), where it instigates inflammation and tissue destruction[2]. The development of anti-IL-17 therapy has revolutionized the treatment landscape for IMIDs. While IL-17A inhibitors like secukinumab have shown success in trials for different arthritis types, the emergence of adverse reactions prompts a strategic shift towards dual antibodies targeting IL-17A and specific factors[3]. Besides common adverse events, the cardiovascular events in anti-IL-17 therapies underscores the importance of vigilant pharmacovigilance, especially when the relationship between IL-17 and cardiovascular system remains uncertain.

The discovery of IL-17D in 2002 marked a significant advancement in our understanding of the IL-17 family. IL-17D was found preferential expression in various tissues, including the brain, skeletal muscle, adipose tissue, pancreas, lung, colon, and heart. Like its counterparts, IL-17D demonstrated pro-inflammatory properties, stimulating cytokine production such as IL-6, IL-8, and GM-CSF by endothelial cells[4]. In a groundbreaking development in 2021, Huang et al. identified CD93 as the functional receptor for IL-17D. This revelation showcased IL-17D's role in regulating ILC3 and maintaining intestinal homeostasis through binding to CD93[5]. This discovery not only expanded our understanding of the IL-17 receptor family but also opened new avenues for potential treatments of inflammatory diseases. Subsequent research by Ni et al. in 2022 uncovered the IL-17D-triggered CD93-p38 MAPK-AKT-SMAD2/3 signaling pathway, highlighting its involvement in enhancing skin inflammation. IL-17D-/- and CD93-/- mice exhibited similar skin lesions, emphasizing the significance of this pathway in inflammatory responses[6].

This review explores the immunological context of IL-17, its signaling pathways, and its contributions to immune responses, inflammation, and autoimmunity. Furthermore, it discusses the development and clinical application of anti-IL-17 therapy, addressing emerging concerns and future directions in this rapidly evolving field. We also discuss the evolving landscape of IL-17-related research but also offer valuable insights for future pharmacological interventions targeting the IL-17D-CD93 pathway.