Type III interferons attenuate autoimmune uveitis

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

Funding Information:
National Natural Science Foundation Key Program (China) (No. 82230032)
National Natural Science Foundation Project (No. 82371046)
Chongqing Natural Science Foundation Project (China) (No. CSTB2023NSCQ-MSX0306)
Chongqing Science and Technology Bureau Mountaineering Project (China) (No.cyyy-xkdfjhjcyj-202301,cyyy-xkdfjh-lcyj-202303, cyyy-xkdfjhcgzh202302)
Science and Technology Research Program of Chongqing Municipal Education Commission (China) (No. KJZD-K202300405)
Chongqing graduate research innovation project (China) (No. CYS21220)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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Attached files

(A, B) Representative clinical slit-lamp (A) and hematoxylin and eosin (H&E) staining section (B) images of EAU mice on day 14 after immunization. Scale bar: 50 μm. (C) Clinical scores were measured from day 8 to day 14 after immunization (the P value was evaluated on day 14 after immunization, ∗P < 0.05, ∗∗P < 0.01). (D) Histological scores were assessed by H&E staining on day 14 after immunization. (E–H) Flow cytometric analysis was performed on splenic cells from the two groups using antibodies against IFN-γ, IL-17, Foxp3, MHC-II and CD11c. (E, G) Representative flow cytometry dot plots. (F, H) Histograms of CD4+IFN-γ+, CD4+IL-17+, CD25+Foxp3+ and CD11c+MHCII+ (n = 4–5 per group). Data are shown as mean ± SEM from two independent experiments. ∗P < 0.05, ∗∗P < 0.01; P value was corrected by Bonferroni. EAU, experimental autoimmune uveitis; WT, wild-type.
(A, B) The primary RPE cells from IFNLR1−/− EAU mice and WT EAU mice were harvested for the detection of NLRP3 and NLRP1. (A) The mRNA expression of NLRP3 and NLRP1 was detected by RT-qPCR. (B) The representative Western blotting images and histogram (n = 4). (C, D) Primary hRPE cells were transfected with siIFNLR1, and then the cells were assayed for NLRP1 and NLRP3 expression by RT-qPCR and Western blotting (n = 4). (E) Primary RPE cells from IFNLR1−/− EAU mice and hRPE cells with siIFNLR1 were treated with or without MCC950 (a potent, selective and small-molecule inhibitor of NLRP3) or DPP9 (a direct inhibitor of NLRP1) in the presence of LPS stimulation, and the supernatants were harvested for the expression of inflammatory cytokines including IL-6, IL-8, MCP-1, IL-1β and TNF-α by ELISA (n = 5). ∗∗P < 0.01, ∗∗∗P < 0.001; P value was corrected by Bonferroni. EAU, experimental autoimmune uveitis; ELISA, enzyme-linked immunosorbent assay; LPS, lipopolysaccharide; RPE, retinal pigment epithelium; RT-qPCR, real-time quantitative PCR.
(A) Representative images of Evans blue staining in retinas from WT EAU mice and IFNLR1−/− EAU mice. Scale bar: 50 μm. (B) Representative Western blotting images and quantitative analysis of ZO-1, Claudin-5 and Occludin in retinas from the two groups (n = 4 per group). (C) Primary RPE cells were harvested from the two groups and cultured with LPS for 24 h, then the supernatants were collected for the detection of IL-6, IL-8, IL-1β, and MCP-1 by ELISA (n = 8 per group). (D) Primary RPE cells were co-treated with recombinant IFN-λ2 and LPS. The secreted levels of the pro-inflammatory cytokines IL-6, IL-8, IL-1β, and MCP-1 in the supernatants were measured by ELISA (n = 5 per group). ∗∗P < 0.01, ∗∗∗P < 0.001; P value was corrected by Bonferroni. EAU, experimental autoimmune uveitis; ELISA, enzyme-linked immunosorbent assay; LPS, lipopolysaccharide; RPE, retinal pigment epithelium; WT, wild-type.

27/07/2026 Compuscript Ltd

Regions: Europe, Ireland, Asia, China

Keywords: Science, Life Sciences

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