The balance between antioxidants and reactive oxygen species (ROS) critically regulates tumor initiation and progression. However, whether and how the tumor-favoring redox status is controlled by cytokine networks remain poorly defined. Here, it is shown that IL-36 and IL-36Ra reciprocally regulate the progression of non-small cell lung cancer (NSCLC) by modulating glutathione metabolism and ROS resolution. Knockout, inhibition, or neutralization of IL-36 significantly inhibits NSCLC progression and prolongs survival of the Kras LSL-G12D/+ Tp53 fl/fl and Kras LSL-G12D/+ Lkb1 fl/fl mice after tumor induction, whereas knockout of IL-36Ra exacerbates tumorigenesis in these NSCLC mouse models and accelerates death of mice. Mechanistically, IL-36 directly upregulates an array of genes involved in glutathione homeostasis to reduce ROS and prevent oxidative stress-induced cell death, which is mitigated by IL-36Ra or IL-36 neutralizing antibody. Consistently, IL-36 staining is positively and negatively correlated with glutathione biosynthesis and ROS in human NSCLC tumor biopsies, respectively. These findings highlight essential roles of cytokine networks in redox for tumorigenesis and provide potential therapeutic strategy for NSCLC.

The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) plays a critical role in antiviral immunity and autoimmunity. The activity and stability of cGAS are fine-tuned by post-translational modifications. Here, we show that ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1) catalyzes the mono-ISGylation and induces the oligomerization of cGAS, thereby promoting antiviral immunity and autoimmunity. Knockdown or knockout of ARIH1 significantly inhibits herpes simplex virus 1 (HSV-1)- or cytoplasmic DNA-induced expression of type I interferons (IFNs) and proinflammatory cytokines. Consistently, tamoxifen-treated ER-Cre;Arih1fl/fl mice and Lyz2-Cre; Arih1fl/fl mice are hypersensitive to HSV-1 infection compared with the controls. In addition, deletion of ARIH1 in myeloid cells alleviates the autoimmune phenotypes and completely rescues the autoimmune lethality caused by TREX1 deficiency. Mechanistically, HSV-1- or cytosolic DNA-induced oligomerization and activation of cGAS are potentiated by ISGylation at its K187 residue, which is catalyzed by ARIH1. Our findings thus reveal an important role of ARIH1 in innate antiviral and autoimmune responses and provide insight into the post-translational regulation of cGAS.

Inflammatory bowel disease and colorectal cancer are associated with dysregulation of cytokine networks. However, it is challenging to target cytokines for effective intervention because of the overlapping functions and unpredictable interactions of cytokines in such diverse networks. Here, it is shown that IL-36𝜸 and IL-36Ra, an agonist and an antagonist for IL-36R signaling respectively, reciprocally regulate the experimental colitis and the colon cancer development in mice. Knockout or neutralization of IL-36𝜸 alleviates dextran sulfate sodium (DSS)-induced colitis and inhibits colon cancer development, whereas knockout of IL-36Ra exacerbates DSS-induced colitis and promotes colonic tumorigenesis in multiple colon cancer models in mice. Mechanistically, IL-36𝜸 upregulates extracellular matrix and cell-matrix adhesion molecules and facilitates Wnt signaling, which is mitigated by IL-36Ra or IL-36𝜸 neutralizing antibody. Consistently, IL-36𝜸 levels are positively correlated with extracellular matrix levels and 𝜷-catenin levels in human colorectal tumor biopsies. These findings suggest the critical role of IL-36𝜸 and IL-36Ra in gut inflammation and tumorigenesis and indicate that targeting the IL-36𝜸/IL-36Ra signal balance provides potential therapeutic strategy for inflammatory bowel disease and gastrointestinal cancers.