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Deficiency in Retinal TGFβ Signaling Aggravates Neurodegeneration by Modulating Pro-Apoptotic and MAP Kinase Pathways.

ABSTRACT: Transforming growth factor β (TGFβ) signaling has manifold functions such as regulation of cell growth, differentiation, migration, and apoptosis. Moreover, there is increasing evidence that it also acts in a neuroprotective manner. We recently showed that TGFβ receptor type 2 (Tgfbr2) is upregulated in retinal neurons and Müller cells during retinal degeneration. In this study we investigated if this upregulation of TGFβ signaling would have functional consequences in protecting retinal neurons. To this end, we analyzed the impact of TGFβ signaling on photoreceptor viability using mice with cell type-specific deletion of Tgfbr2 in retinal neurons and Müller cells (Tgfbr2ΔOC) in combination with a genetic model of photoreceptor degeneration (VPP). We examined retinal morphology and the degree of photoreceptor degeneration, as well as alterations of the retinal transcriptome. In summary, retinal morphology was not altered due to TGFβ signaling deficiency. In contrast, VPP-induced photoreceptor degeneration was drastically exacerbated in double mutant mice (Tgfbr2ΔOC; VPP) by induction of pro-apoptotic genes and dysregulation of the MAP kinase pathway. Therefore, TGFβ signaling in retinal neurons and Müller cells exhibits a neuroprotective effect and might pose promising therapeutic options to attenuate photoreceptor degeneration in humans.

SUBMITTER: Bielmeier CB

PROVIDER: S-EPMC8910086 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Deficiency in Retinal TGFβ Signaling Aggravates Neurodegeneration by Modulating Pro-Apoptotic and MAP Kinase Pathways.

Bielmeier Christina B CB Schmitt Sabrina I SI Kleefeldt Nikolai N Boneva Stefaniya K SK Schlecht Anja A Vallon Mario M Tamm Ernst R ER Hillenkamp Jost J Ergün Süleyman S Neueder Andreas A Braunger Barbara M BM

International journal of molecular sciences 20220227 5

Transforming growth factor β (TGFβ) signaling has manifold functions such as regulation of cell growth, differentiation, migration, and apoptosis. Moreover, there is increasing evidence that it also acts in a neuroprotective manner. We recently showed that TGFβ receptor type 2 (<i>Tgfbr2</i>) is upregulated in retinal neurons and Müller cells during retinal degeneration. In this study we investigated if this upregulation of TGFβ signaling would have functional consequences in protecting retinal ...[more]

PMID: 35269767

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Project description:BackgroundMaintenance of the retina, part of the central nervous system, and other structures in the eye is critical for vision preservation. Aging increases the prevalence of vision impairment, including glaucoma, macular degeneration, and diabetic retinopathy. The retina is primarily maintained by glial cells; however, recent literature suggests that lymphocytes may play a role in the homeostasis of central nervous system tissues. Natural antibodies are produced by B cells without infection or immunization and maintain tissue homeostasis. Here, we explored the potential role of natural immunoglobulin M (IgM) produced by B lymphocytes in maintaining retinal health during aging in mice.ResultsOur results indicate that the vitreous humor of both mice and humans contains IgM and IgG, suggesting that these immunoglobulins may play a role in ocular function. Furthermore, we observed that aged mice lacking secreted IgM (µs-/-) exhibited pronounced retinal degeneration, accompanied by reactive gliosis, and a proinflammatory cytokine environment. This contrasts with the aged wild-type counterparts, which retain their ability to secrete IgM and maintain a better retinal structure and anti-inflammatory environment. In addition to these findings, the absence of secreted IgM was associated with significant alterations in the retinal pigment epithelium, including disruptions to its morphology and signs of increased stress. This was further observed in changes to the blood-retinal-barrier, which is critical for regulation of retinal homeostasis.ConclusionsThese data suggest a previously unrecognized association between a lack of secreted IgM and alterations in the retinal microenvironment, leading to enhanced retinal degeneration during aging. Although the precise mechanism remains unclear, these findings highlight the potential importance of secreted IgM in processes that support retinal health over time. By increasing our understanding of ocular aging, these results show that there is a broader role for the immune system in retinal function and integrity in advanced age, opening new areas for the exploration of immune-related interventions in age-associated retinal conditions.

Project description: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.

Dataset Information

Deficiency in Retinal TGFβ Signaling Aggravates Neurodegeneration by Modulating Pro-Apoptotic and MAP Kinase Pathways.

Publications

Deficiency in Retinal TGFβ Signaling Aggravates Neurodegeneration by Modulating Pro-Apoptotic and MAP Kinase Pathways.

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