European Journal of Immunology.  2014 Nov;44(11):3320-9. doi: 10.1002/eji.201444671.

IL-33 attenuates the development of experimental autoimmune uveitis.

Barbour M1, Allan D1, Xu H2, Pei C1, Chen M2, Niedbala W3, Fukada SY3, Besnard AG3, Alves-Filho JC3, Tong X1, Forrester JV4,5,6, Liew FY3,7,8, Jiang HR1

1 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
2 Centre for Experimental Medicine, Queen’s University Belfast, Belfast, UK
3 Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
4 Institute of Medical Science, University of Aberdeen, UK
5 Centre for Ophthalmology and Visual Science, The University of Western Australia, Australia
6 Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Australia
7 CEGMR, King Abdulaziz University, Jeddah, Saudi Arabia
8 Institute of Biology and Medical Sciences, Soochow University, Suzhou, China



Interleukin-33 (IL-33) is associated with several important immune-mediated disorders. However, its role in uveitis, an important eye inflammatory disease, is unknown. Here, we investigated the function of IL-33 in the development of experimental autoimmune uveitis (EAU). IL-33 and IL-33 receptor (ST2) were expressed in murine retinal pigment epithelial (RPE) cells in culture, and IL-33 increased the expression of Il33 and Mcp1 mRNA in RPE cells. In situ, IL-33 was highly expressed in the inner nuclear cells of the retina of naïve mice, and its expression was elevated in EAU mice. ST2-deficient mice developed exacerbated EAU compared with WT mice, and administration of IL-33 to WT mice significantly reduced EAU severity. The attenuated EAU in IL-33-treated mice was accompanied by decreased frequency of IFN-γ+ and IL-17(+) CD4+ T cells and reduced IFN-γ and IL-17 production but with increased frequency of IL-5(+) and IL-4(+) CD4 T cells and IL-5 production in the draining lymph node and spleen. Macrophages from the IL-33-treated mice show a significantly higher polarization toward an alternatively activated macrophage phenotype. Our results therefore demonstrate that the endogenous IL-33/ST2 pathway plays an important role in EAU, and suggest that IL-33 represents a potential option for treatment of uveitis.

PMID: 25116404



Since its discovery in 2005, emerging research evidence has shown that IL-33, a member of the IL-1 family, is a cytokine with pleiotropic immune responses in various immune mediated diseases. While it predominantly induces type 2 immune responses and thus is involved in allergic inflammation, parasite infection and atherosclerosis, IL-33 is also a pro-inflammatory cytokine which exacerbates joint inflammation in rheumatoid arthritis disease models.

In this study we have demonstrated that IL-33 attenuates retinal inflammation in an animal model of uveoretinitis, and the attenuation is associated with a shift toward type 2 immune responses. Furthermore, our data show that both IL-33 and its receptor ST2 are highly expressed by RPE cells, an important component of blood retina barrier. IL-33 activates RPE cells to up-regulate various chemokines and cytokines (e.g. IL-6, Figure 1). Interestingly, IL-33 is also constitutively expressed by Müller cells in normal mouse retina, and the expression level is dramatically increased in the EAU tissue. Data from other studies have suggested that IL-33 is expressed by tissue resident cells such as astrocytes and neurons in the central nervous system, and has organ specific functions in addition to its immune-modulatory role in diseases. Therefore findings from this study suggest that IL-33 plays an important role in the development of retinal inflammation, possibly through modulating the peripheral immune response and via its ocular specific function. However, how IL-33 influences EAU development via ocular resident cells is not yet known and requires further investigation.


HRJ Fig1Figure 1. Dose dependent secretion of IL-6 by murine RPE cell line. IL-33 was added in the RPE cell culture for 48 hours and supernatants were collected for ELISA assay. Data are shown as mean+SEM, n=5, and are representative of three independent experiments.


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