| First Author | Augustine J | Year | 2019 |
| Journal | J Neuroinflammation | Volume | 16 |
| Issue | 1 | Pages | 251 |
| PubMed ID | 31796062 | Mgi Jnum | J:284919 |
| Mgi Id | MGI:6392486 | Doi | 10.1186/s12974-019-1625-y |
| Citation | Augustine J, et al. (2019) IL-33 deficiency causes persistent inflammation and severe neurodegeneration in retinal detachment. J Neuroinflammation 16(1):251 |
| abstractText | BACKGROUND: Interleukin-33 (IL-33) belongs to the IL-1 cytokine family and resides in the nuclei of various cell types. In the neural retina, IL-33 is predominately expressed in Muller cells although its role in health and disease is ill-defined. Muller cell gliosis is a critical response during the acute phase of retinal detachment (RD), and in this study, we investigated if IL-33 was modulatory in the inflammatory and neurodegenerative pathology which is characteristic of this important clinical condition. METHODS: RD was induced by subretinal injection of sodium hyaluronate into C57BL/6 J (WT) and IL-33(-/-) mice and confirmed by fundus imaging and optical coherence tomography (OCT). The expression of inflammatory cytokines, complement components and growth factors was examined by RT-PCR. Retinal neurodegeneration, Muller cell activation and immune cell infiltration were assessed using immunohistochemistry. The expression of inflammatory cytokines in primary Muller cells and bone marrow-derived macrophages (BM-DMs) was assessed by RT-PCR and Cytometric Bead Array. RESULTS: RD persisted for at least 28 days after the injection of sodium hyaluronate, accompanied by significant cone photoreceptor degeneration. The mRNA levels of CCL2, C1ra, C1s, IL-18, IL-1beta, TNFalpha, IL-33 and glial fibrillary acidic protein (GFAP) were significantly increased at day 1 post-RD, reduced gradually and, with the exception of GFAP and C1ra, returned to the basal levels by day 28 in WT mice. In IL-33(-/-) mice, RD induced an exacerbated inflammatory response with significantly higher levels of CCL2, IL-1beta and GFAP when compared to WT. Sustained GFAP activation and immune cell infiltration was detected at day 28 post-RD in IL-33(-/-) mice. Electroretinography revealed a lower A-wave amplitude at day 28 post-RD in IL-33(-/-) mice compared to that in WT RD mice. IL-33(-/-) mice subjected to RD also had significantly more severe cone photoreceptor degeneration compared to WT counterparts. Surprisingly, Muller cells from IL-33(-/-) mice expressed significantly lower levels of CCL2 and IL-6 compared with those from WT mice, particularly under hypoxic conditions, whereas IL-33(-/-) bone marrow-derived macrophages expressed higher levels of inducible nitric oxide synthase, TNFalpha, IL-1beta and CCL2 after LPS + IFNgamma stimulation compared to WT macrophages. CONCLUSION: IL-33 deficiency enhanced retinal degeneration and gliosis following RD which was related to sustained subretinal inflammation from infiltrating macrophages. IL-33 may provide a previously unrecognised protective response by negatively regulating macrophage activation following retinal detachment. |
