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

Abstract

BackgroundInterleukin-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.MethodsRD 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.ResultsRD 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.ConclusionIL-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.

The role of interleukin-33 in patients with mild cognitive impairment and Alzheimer’s disease

“…The aMCI and AD patients lacking IL-33 expression revealed significantly cognitive decline, while the patients with IL-33 expression preserved their cognitive function over 1-year period. This finding was consistent with the bidirectional relationship between IL-33 deficiency and neurodegeneration in several studies, including the following: (1) mice lacking IL-33 had persistent inflammation and severe neurodegeneration in retinal detachment [30]; (2) IL-33 deficiency mice failed to repair deoxyribonucleic acid damage of aged neuron, resulting in neurodegeneration and tau abnormality [19];…”

The Role of Interleukin-33 in Patients with Mild Cognitive Impairment and Alzheimer's Disease

“…The aMCI and AD patients lacking IL-33 expression revealed signi cantly cognitive decline, while the patients with IL-33 expression preserved their cognitive function over 1-year period. This nding was consistent with the bidirectional relationship between IL-33 de ciency and neurodegeneration in several studies, including : (1) mice lacking IL-33 had persistent in ammation and severe neurodegeneration in retinal detachment [27]; (2) IL-33 de ciency mice failed to repair deoxyribonucleic acid damage of aged neuron, resulting in neurodegeneration and tau abnormality [16]; (3) mice lacking IL-33 were found to impaired recovery after CNS injury [11]; and (4) IL-33 treatment rescued contextual memory de cits in AD mouse models [15]. Collectively, our study provided the rst human evidence that linking IL-33 to neurodegeneration in the aMCI and AD patients.…”

The role of Interleukin-33 in patients with mild cognitive impairment and Alzheimer’s disease

“…The aMCI and AD patients lacking IL-33 expression revealed signi cantly cognitive decline, while the patients with IL-33 expression preserved their cognitive function over 1-year period. This nding was consistent with the bidirectional relationship between IL-33 de ciency and neurodegeneration in several studies, including : (1) mice lacking IL-33 had persistent in ammation and severe neurodegeneration in retinal detachment [30]; (2) IL-33 de ciency mice failed to repair deoxyribonucleic acid damage of aged neuron, resulting in neurodegeneration and tau abnormality [19]; (3) mice lacking IL-33 were found to have impaired recovery after CNS injury [16]; and (4) IL-33 treatment rescued contextual memory de cits in AD mouse models [18]. Collectively, our study provided the rst human evidence that linking IL-33 to neurodegeneration in the aMCI and AD patients.…”