Autoimmune uveitis is a vision-threatening disorder characterized by chronic intraocular inflammation and progressive damage to the uveal tract and retina, often leading to irreversible visual impairment. Emerging evidence suggests that both adaptive immune responses and innate inflammatory signaling contribute to disease progression.
In this recent Genes & Diseases study, researchers from The First Affiliated Hospital of Chongqing Medical University, Third Military Medical University (Army Medical University), and The First Affiliated Hospital of Zhengzhou University investigated the immunomodulatory role of type III interferons (IFN-λ) in autoimmune uveitis, focusing on their capacity to regulate pathogenic T-cell responses and retinal pigment epithelium (RPE) cell function through the NLRP1/NLRP3 inflammasome signaling axis.
Clinical analysis of patients with active Vogt-Koyanagi-Harada syndrome and Behçet’s disease revealed significantly elevated serum IFN-λ levels compared to healthy controls, suggesting an immunoregulatory role for these cytokines during autoimmune uveitis.
To further elucidate this mechanism, the researchers utilized an experimental autoimmune uveitis (EAU) model in IFNLR1-deficient mice. These mice exhibited increased disease severity, characterized by an exacerbated Th1/Th17 response, a reduction in regulatory T-cell frequency, and substantial disruption of the blood-retinal barrier, as evidenced by the decreased expression of critical tight junction proteins such as ZO-1, Claudin-5, and Occludin.
Furthermore, IFNLR1 deficiency promoted hyper-activation of dendritic cells, characterized by increased expression of costimulatory molecules, including CD40, CD80, CD86, and MHC II, and the overproduction of pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and IL-12. The study further identified the RPE as a key target for IFN-λ signaling. In the absence of functional IFNLR1, RPE cells displayed increased secretion of pro-inflammatory cytokines, including IL-6, IL-8, IL-1β, and MCP-1. Conversely, treatment with recombinant IFN-λ1 and IFN-λ2 effectively suppressed these inflammatory mediators in human primary RPE cells.
RNA sequencing and bioinformatic analyses revealed that the NLRP1/NLRP3 signaling axis mediates the therapeutic effects of IFN-λ. IFNLR1 deficiency resulted in elevated expression of NLRP1 and NLRP3 in RPE cells, both in vitro and in vivo . Under inflammatory conditions, activation of the NLRP1 and NLRP3 inflammasomes induces inflammatory cytokine release and promotes retinal tissue injury. IFN-λ markedly inhibited activation of both inflammasome complexes, thereby suppressing downstream inflammatory signaling and protecting RPE cells from inflammation-induced dysfunction, thus limiting the reciprocal amplification of innate and adaptive immune responses. Together, these findings demonstrate that IFN-λ coordinately regulates adaptive and innate immune responses through suppression of pathogenic Th1/Th17 cell activity and NLRP1/NLRP3-mediated RPE inflammation.
Overall, this study identifies type III interferons as promising immunomodulatory agents for autoimmune uveitis by demonstrating their ability to attenuate pathogenic Th1 and Th17 cell responses, preserve RPE function, and suppress NLRP1/NLRP3 inflammasome activation. These findings provide important mechanistic insights into the coordinated regulation of adaptive and innate immunity in ocular inflammation and establish the IFN-λ–NLRP1/NLRP3 signaling axis as a potential therapeutic target for the development of more selective and effective treatments for autoimmune uveitis.
Reference
Title of the original paper: Type III interferons attenuates Th1/Th17 cell pathogenicity and regulates retinal pigment epithelium cells via NLRP1/NLRP3 signaling axis in autoimmune uveitis
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101957
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