On January 6, 2026, a team led by Prof. QIAN Youcun at the Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences, published a paper titled "TheIL17RELgene encodes a decoy receptor of IL‑17 family cytokines to control gut inflammation" in Nature Immunology. This study identified IL‑17REL as a new member of the human IL‑17 receptor family with a protective role in inflammatory bowel disease (IBD), and showed that genetic variants in IL17REL critically affect IBD.

IBD is a group of chronic inflammatory disorders of the intestine, primarily including Crohn’s disease (CD) and ulcerative colitis (UC). The incidence of IBD is steadily increasing worldwide and has gradually become a serious public‑health threat. Epidemiological and genetic studies suggest that genetic susceptibility together with various environmental factors provides an important basis for IBD onset and progression. 

To systematically dissect the role of genetic factors in IBD, numerous genetic studies based on genome‑wide association studies (GWAS) and exome sequencing have identified more than 240 single‑nucleotide polymorphism (SNP) loci associated with IBD. However, the functions of the vast majority of IBD‑associated loci remain unclear, and whether these variants directly contribute to IBD pathology and their precise molecular mechanisms require further systematic study.

IL17REL was identified by GWAS as an IBD‑associated gene and was predicted to encode a protein similar to IL‑17RE, but whether it is transcribed and translated was previously unknown. The researchers performed systematic analyses of tissues from IBD patients, and using RNA in situ hybridization and immunohistochemistry, for the first time confirmed that IL17REL can beinducibly expressed in immune cells including macrophages, T cells and B cells, and they established that transforming growth factor‑β (TGF‑β) plays a key role in its induction.

Although the IL‑17REL protein lacks a canonical signal peptide, the researchers found it can be released extracellularly via an ATP–P2RX7–GSDMD pathway. As a specific endogenous “decoy receptor”, extracellular IL‑17REL binds competitively and in a concentration‑dependent manner to several IL‑17 ligands recognized by IL‑17RA, including IL‑17A, IL‑17C and IL‑17F, markedly suppressing expression of downstream inflammatory genes (such as IL1B, IL6, CXCL1 and CXCL2). Human IL‑17REL also shows strong cross‑binding to mouse IL‑17A, IL‑17C and IL‑17F. In vivo, knock‑in of the human IL17REL gene in mice substantially ameliorated TNBS‑induced colitis.

Previous genetic studies had identified two IL17REL SNPs significantly associated with IBD; the researchers carried out functional experiments to validate the pathogenic mechanisms of these variants. In vitro, the mutant IL‑17REL proteins largely lost their ability to bind IL‑17A, IL‑17C and IL‑17F and lost antagonistic activity against IL‑17 signaling. In vivo, mice carrying the mutant IL17REL knock‑in (hIL17REL^G70R/L333P‑KI) completely lost the protective effect of wild‑type IL‑17REL in TNBS‑induced colitis. Building on this, the researchers evaluated the therapeutic potential of recombinant IL‑17REL protein: systemic administration of wild‑type IL‑17REL markedly improved TNBS‑induced colitis in mice, whereas the mutant protein had no therapeutic effect.

The research team has long been engaged in studies of IL‑17 family cytokines and their receptors, producing a series of related findings (Nat. Immunol. 2011; Nat. Med. 2012; Immunity 2014, 2015, 2019). This research is the first to identify and systematically characterize IL‑17REL as a decoy receptor within the IL‑17 family, elucidate its expression regulation and immune functions, and demonstrate that its functional mutations are important genetic contributors to IBD. These findings offer a new concept for understanding IBD pathogenesis and provide a potential target for therapies aimed at the IL 17 signaling pathway.

Prof. QIAN Youcun and Assoc. Prof. YANG Tao from the SINH are the co-corresponding authors of the article.  Postdoc. LI Qi from SINH is the first authors of the paper. The work was supported by contributions from Prof. LIU Zhanju (The Tenth People’s Hospital affiliated to Tongji University) and Prof. SONG Xinyang (Center for Excellence in Molecular Cell Science, CAS). This research was granted by the National Natural Science Foundation of China and the National Key R&D Program.

The wild-type, rather than mutated IL-17REL protein exerted therapeutic effects against inflammatory bowel disease by competitively binding IL-17 family ligands and suppressing downstream gene expression. (Image provided by Prof. QIAN’s group)

 Paper link: https://www.nature.com/articles/s41590-025-02368-4

Scientific Contact:
Prof. QIAN Youcun
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: ycqian@sinh.ac.cn 

Media Contact:
WANG Jin
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: wangjin01@sinh.ac.cn