The Complex Role of Neuroinflammation in Glaucoma

Soto, Ileana; Howell, Gareth R.

doi:10.1101/cshperspect.a017269

Cited by 177 publications

(142 citation statements)

References 95 publications

(162 reference statements)

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“…The source of pro-inflammatory signaling molecules like TNFα is expected to be from retinal macro- and microglia (Almasieh et al, 2012; Tezel, 2008), cells which change their physiology and become “activated” in response to retinal damage. Studies suggest that inflammatory cytokine production by glia is most likely a characteristic of the activated phenotype (Mac Nair and Nickells, 2015; Soto and Howell, 2014; Suzuki et al, 2004). Interestingly, the process of activation of both classes of glia is dramatically muted in Bax-deficient retinas after optic nerve damage (Mac Nair et al, 2016) (Fig.…”

Section: Discoveries Made Possible Using Bax-deficient Micementioning

confidence: 99%

BAX to basics: How the BCL2 gene family controls the death of retinal ganglion cells

Maes

Schlamp

Nickells

2017

Progress in Retinal and Eye Research

152

109

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Retinal ganglion cell (RGC) death is the principal consequence of injury to the optic nerve. For several decades, we have understood that the RGC death process was executed by apoptosis, suggesting that there may be ways to therapeutically intervene in this cell death program and provide a more direct treatment to the cells and tissues affected in diseases like glaucoma. A major part of this endeavor has been to elucidate the molecular biological pathways active in RGCs from the point of axonal injury to the point of irreversible cell death. A major component of this process is the complex interaction of members of the BCL2 gene family. Three distinct family members of proteins orchestrate the most critical junction in the apoptotic program of RGCs, culminating in the activation of pro-apoptotic BAX. Once active, BAX causes irreparable damage to mitochondria, while precipitating downstream events that finish off a dying ganglion cell. This review is divided into two major parts. First, we summarize the extent of knowledge of how BCL2 gene family proteins interact to facilitate the activation and function of BAX. This area of investigation has rapidly changed over the last few years and has yielded a dramatically different mechanistic understanding of how the intrinsic apoptotic program is run in mammalian cells. Second, we provided a comprehensive analysis of nearly two decades of investigation of the role of BAX in the process of RGC death, much of which has provided many important insights into the overall pathophysiology of diseases like glaucoma.

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Section: Discoveries Made Possible Using Bax-deficient Micementioning

confidence: 99%

BAX to basics: How the BCL2 gene family controls the death of retinal ganglion cells

Maes

Schlamp

Nickells

2017

Progress in Retinal and Eye Research

152

109

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“…Classic inflammatory responses are triggered via pattern recognition receptors such as two important classes: Toll-like receptors (TLRs) and nucleotide-binding oligomerization-domain protein (NOD)-like receptors (NLRs) [3]. These signalings lead to the secretion of potent inflammatory mediators, such as cytokines and chemokines.…”

Section: Introductionmentioning

confidence: 99%

The mutual regulation between miR-214 and A2AR signaling plays an important role in inflammatory response

Zhao

Liu

Yang

et al. 2015

Cellular Signalling

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“…In addition, multiple studies in human and experimental glaucoma suggest a link between the progressive deterioration of RGCs and alterations of glial cell types (Yuan and Neufeld, 2001; Naskar et al, 2002; Neufeld and Liu, 2003; Nakazawa et al, 2006; Inman and Horner, 2007; Bosco et al, 2011, 2015b; Lye-Barthel et al, 2013; Chong and Martin, 2015). Microglia are the resident innate immune cells of the central nervous system, and in both glaucoma patients and in animal models of glaucoma, they display increased reactivity and cluster at the optic nerve head, which is a site of early damage (Bosco et al, 2011; Yuan and Neufeld, 2001; Roh et al, 2012; Soto and Howell, 2014). It has also been demonstrated that peripheral macrophages infiltrate the retina in animal models of glaucoma (Howell et al, 2012) suggesting that different myeloid cell types may participate in glaucoma progression.…”

Section: Introductionmentioning

confidence: 99%

Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma

et al. 2016

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Neurodegeneration in glaucoma results in decline and loss of retinal ganglion cells (RGCs), and is associated with activation of myeloid cells such as microglia and macrophages. The chemokine fractalkine (FKN or Cx3cl1) mediates communication from neurons to myeloid cells. Signaling through its receptor Cx3cr1 has been implicated in multiple neurodegenerative diseases, but the effects on neuronal pathology are variable. Since it is unknown how FKN-mediated crosstalk influences RGC degeneration in glaucoma, we assessed this in a chronic mouse model, DBA/2J. We analyzed a DBA/2J substrain deficient in Cx3cr1, and compared compartmentalized RGC degeneration and myeloid cell responses to those in standard DBA/2J mice. We found that loss of FKN signaling exacerbates axon transport dysfunction, an early event in neurodegeneration, with a significant increase in RGCs with somal accumulation of the axonal protein phosphorylated neurofilament, and reduced retinal expression of genes involved in axon transport, Kif1b, and Atp8a2. There was no change in the loss of Brn3-positive RGCs, and no difference in the extent of damage to the proximal optic nerve, suggesting that the loss of fractalkine signaling primarily affects axon transport. Since Cx3cr1 is specifically expressed in myeloid cells, we assessed changes in retinal microglial number and activation, changes in gene expression, and the extent of macrophage infiltration. We found that loss of fractalkine signaling led to innate immune changes within the retina, including increased infiltration of peripheral macrophages and upregulated nitric oxide synthase-2 (Nos-2) expression in myeloid cells, which contributes to the production of NO and can promote axon transport deficits. In contrast, resident retinal microglia appeared unchanged either in number, morphology, or expression of the myeloid activation marker ionized calcium binding adaptor molecule 1 (Iba1). There was also no significant increase in the proinflammatory gene interleukin 1 beta (Il1β). We conclude that loss of fractalkine signaling causes a selective worsening of axon transport dysfunction in RGCs, which is linked to enhanced Nos-2 expression in myeloid cells. Our findings suggest that distinct mechanisms may contribute to different aspects of RGC decline in glaucoma, with axonal transport selectively altered after loss of Cx3cr1 in microglia and/or macrophages.

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The Complex Role of Neuroinflammation in Glaucoma

Cited by 177 publications

References 95 publications

BAX to basics: How the BCL2 gene family controls the death of retinal ganglion cells

BAX to basics: How the BCL2 gene family controls the death of retinal ganglion cells

The mutual regulation between miR-214 and A2AR signaling plays an important role in inflammatory response

Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma

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