Interleukin (IL)- [26] and is a proinflammatory cytokine in CIA [14,27]. Recent studies have also shown that the IL-33/ST2 pathway plays a significant role in the amplification of M2 polarization and chemokine production, which contribute to innate and antigen-induced airway inflammation [28] and protect against obesity-related metabolic events [29].Interestingly, the highest levels of IL-33 expression in naïve mice are found in the brain and spinal cord [15], indicating that IL-33 may have CNS-specific functions in addition to its role in immune modulation. Astrocytes express both and the expression of IL-33 in the CNS was increased in response to inflammatory stimuli [31]. Recently, it was also reported that IL-33 levels were elevated in the periphery and CNS of MS patients, implicating IL-33 in the pathogenesis of MS [32]. However, the precise role of IL-33 and its receptor in CNS under healthy and inflammatory conditions remain unclear.In the present study, we show that ST2 1C). Quantitative PCR analysis confirmed the upregulation of ST2 expression in Fig. 1B as it clearly shows the enhanced expression of ST2 mRNA in the CNS of mice with EAE compared with that of the naïve mice (Fig. 1D). ST2 −/− mice developed exacerbated EAETo identify an endogenous role of IL-33 in EAE, we next investigated the development of EAE in ST2 −/− mice. EAE was induced in C57BL/6 WT and ST2 −/− mice, Fig. 2A shows that the ST2 −/− mice developed more severe EAE than that in the WT mice. In agreement with many previous reports, BALB/c mice are resistant to the induction of EAE. However ST2 −/− BALB/c mice developed a mild but clearly detectable EAE while the WT BALB/c controls did not (Fig. 2B), the observation was further confirmed by histological analysis of the CNS tissues at day 19 after immunization ( Fig. 2C). Minimal leukocyte infiltration was found in the CNS of WT BALB/c mice whereas significant leukocyte infiltration was found in the submeningeal infiltration in the CNS tissues of ST2 −/− BALB/c mice ( Fig. 2C). IL-33 treatment attenuates EAE developmentWe next investigated the effect of exogenous IL-33 in the development of EAE. C57BL/6 mice were immunized as described in was injected intraperitoneally to each mouse daily from day 12 to day 20 after immunization. Both groups of mice developed similar degree of EAE from day 10 to day 15. However, from day 15, mice treated with IL-33 recovered significantly faster than the control mice treated with PBS ( Fig. 3A). In induced experimental autoimmune diseases, disease severity could vary between experiments even with the same protocol. Analysis using multiple comparisons suggests that the effect of IL-33 treatment on the outcome of EAE mice could be time revealed marked reduction of infiltrating cells in the spinal cord tissues of IL-33-treated mice (Fig. 3B). Importantly, IL-33 had no effect on the disease development in ST2 −/− C57BL/6 mice ( Fig. 3C) demonstrating the specificity of the IL-33 effect. IL-33 alters the cytokine production of EAE miceTo investigate the i...

SummaryInterleukin-33 (IL-33) is a member of the IL-1 cytokine family. It predominantly induces type 2 immune responses and thus is protective against atherosclerosis and nematode infections but contributes to allergic airway inflammation. Interleukin-33 also plays a pivotal role in the development of many autoimmune diseases through mechanisms that are still not fully understood. In this review, we focus on the recent advances in understanding of the expression and function of IL-33 in some autoimmune disorders, aiming to provide insight into its potential role in disease development.

Interleukin-33 (IL-33) is a well-recognized immunomodulatory cytokine which plays critical roles in tissue function and immune-mediated diseases. The abundant expression of IL-33 in brain and spinal cord prompted many scientists to explore its unique role in the central nervous system (CNS) under physiological and pathological conditions. Indeed emerging evidence from over a decade's research suggests that IL-33 acts as one of the key molecular signaling cues coordinating the network between the immune and CNS systems, particularly during the development of neurological diseases. Here, we highlight the recent advances in our knowledge regarding the distribution and cellular localization of IL-33 and its receptor ST2 in specific CNS regions, and more importantly the key roles IL-33/ST2 signaling pathway play in CNS function under normal and diseased conditions.

Recent research findings have provided convincing evidence indicating a role for Interleukin-33 (IL-33) signalling pathway in a number of central nervous system (CNS) diseases including multiple sclerosis (MS) and Alzheimer’s disease. However, the exact function of IL-33 molecule within the CNS under normal and pathological conditions is currently unknown. In this study, we have mapped cellular expression of IL-33 and its receptor ST2 by immunohistochemistry in the brain tissues of MS patients and appropriate controls; and investigated the functional significance of these findings in vitro using a myelinating culture system. Our results demonstrate that IL-33 is expressed by neurons, astrocytes and microglia as well as oligodendrocytes, while ST2 is expressed in the lesions by oligodendrocytes and within and around axons. Furthermore, the expression levels and patterns of IL-33 and ST2 in the lesions of acute and chronic MS patient brain samples are enhanced compared with the healthy brain tissues. Finally, our data using rat myelinating co-cultures suggest that IL-33 may play an important role in MS development by inhibiting CNS myelination.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0344-1) contains supplementary material, which is available to authorized users.

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.

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