PMID- 31796062 OWN - NLM STAT- MEDLINE DCOM- 20200514 LR - 20200514 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 16 IP - 1 DP - 2019 Dec 3 TI - IL-33 deficiency causes persistent inflammation and severe neurodegeneration in retinal detachment. PG - 251 LID - 10.1186/s12974-019-1625-y [doi] LID - 251 AB - 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. FAU - Augustine, Josy AU - Augustine J AD - Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast, Northern Ireland, UK. FAU - Pavlou, Sofia AU - Pavlou S AD - Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast, Northern Ireland, UK. FAU - Ali, Imran AU - Ali I AD - Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast, Northern Ireland, UK. FAU - Harkin, Kevin AU - Harkin K AD - Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast, Northern Ireland, UK. FAU - Ozaki, Ema AU - Ozaki E AD - Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland. FAU - Campbell, Matthew AU - Campbell M AD - Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland. FAU - Stitt, Alan W AU - Stitt AW AD - Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast, Northern Ireland, UK. FAU - Xu, Heping AU - Xu H AD - Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast, Northern Ireland, UK. FAU - Chen, Mei AU - Chen M AUID- ORCID: 0000-0001-5661-1386 AD - Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast, Northern Ireland, UK. m.chen@qub.ac.uk. LA - eng GR - N/A/Department of Education ( Northern Ireland)/ GR - 1574/75/Fight for Sight UK/ GR - SCIAD 076/National Eye Research Centre (UK)/ GR - 12/YI/B2514/SFI_/Science Foundation Ireland/Ireland GR - POR-2015-1077/the Health Research Board of Ireland/ PT - Journal Article DEP - 20191203 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Il33 protein, mouse) RN - 0 (Inflammation Mediators) RN - 0 (Interleukin-33) SB - IM MH - Animals MH - Cells, Cultured MH - Inflammation Mediators/*metabolism MH - Interleukin-33/*deficiency MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Retinal Degeneration/*metabolism/pathology MH - Retinal Detachment/*metabolism/pathology MH - *Severity of Illness Index PMC - PMC6889479 OTO - NOTNLM OT - IL-33 OT - Macrophages OT - Muller cells OT - Neurodegeneration OT - Retinal detachment COIS- The authors declare that they have no competing interests. EDAT- 2019/12/05 06:00 MHDA- 2020/05/15 06:00 PMCR- 2019/12/03 CRDT- 2019/12/05 06:00 PHST- 2019/06/21 00:00 [received] PHST- 2019/10/28 00:00 [accepted] PHST- 2019/12/05 06:00 [entrez] PHST- 2019/12/05 06:00 [pubmed] PHST- 2020/05/15 06:00 [medline] PHST- 2019/12/03 00:00 [pmc-release] AID - 10.1186/s12974-019-1625-y [pii] AID - 1625 [pii] AID - 10.1186/s12974-019-1625-y [doi] PST - epublish SO - J Neuroinflammation. 2019 Dec 3;16(1):251. doi: 10.1186/s12974-019-1625-y.