IL-33 deficiency causes persistent inflammation and severe neurodegeneration in retinal detachment

Josy Augustine, Sofia Pavlou, Imran Ali, Kevin Harkin, Ema Ozaki, Matthew Campbell, Alan W Stitt, Heping Xu, Mei Chen

Research output: Contribution to journalArticle

3 Citations (Scopus)
59 Downloads (Pure)

Abstract

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 Müller cells although its role in health and disease is ill-defined. Müller 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, Müller cell activation and immune cell infiltration were assessed using immunohistochemistry. The expression of inflammatory cytokines in primary Müller 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-1β, TNFα, 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-1β 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, Müller 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, TNFα, IL-1β and CCL2 after LPS + IFNγ 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.

Original languageEnglish
Article number251
Number of pages15
JournalJournal of neuroinflammation
Volume16
DOIs
Publication statusPublished - 03 Dec 2019

Fingerprint Dive into the research topics of 'IL-33 deficiency causes persistent inflammation and severe neurodegeneration in retinal detachment'. Together they form a unique fingerprint.

  • Student Theses

    The role of Interleukin-33 in Retinal degenerative diseases

    Author: Augustine, J., Jul 2020

    Supervisor: Chen, M. (Supervisor) & Stitt, A. (Supervisor)

    Student thesis: Doctoral ThesisDoctor of Philosophy

    Cite this