CCL3 Production by Microglial Cells Modulates Disease Severity in Murine Models of Retinal Degeneration

Kohno, Hideo; Maeda, Tadao; Perusek, Lindsay; Pearlman, Eric; Maeda, Akiko

doi:10.4049/jimmunol.1301738

Cited by 67 publications

(83 citation statements)

References 46 publications

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“…Retinal CD11b+ microglial cells are the major inflammatory cells interacting with CD4+ effector T cells during retinal injury3233. Immunofluorescent staining showed abundant CD11b+ cells surrounding the involved RGCs at day 7 of reperfusion (Fig.…”

Section: Resultsmentioning

confidence: 94%

mTOR regulates neuroprotective effect of immunized CD4+Foxp3+ T cells in optic nerve ischemia

Chen

Tang

Wei

et al. 2016

Sci Rep

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The therapeutic potential of targeting CD4+Foxp3+ regulatory T cells (Tregs) remains controversial under the condition of neuroinflammation. This study aims to explore the neuroprotective role of Tregs in optic nerve ischemia (ONI) and evaluate the therapeutic strategy of Tregs transfer with a focus on targeting the mammalian target of rapamycin (mTOR) pathway. Intraocular pressure was transiently increased in adult C57BL/6 mice to induce ONI. Mucosal tolerance of myelin basic protein (MBP) markedly increased retinal ganglion cell (RGC) survival after ONI through enhanced Tregs suppression. mTOR inhibition significantly promoted the frequency of MBP-immunized Tregs in vitro with increased production of anti-inflammatory cytokines. Transient rapamycin treatment highly promoted the immunosuppressive capacity of Tregs and inhibited retinal inflammation in ONI animals. Intravenous infusion of MBP-immunized Tregs, instead of regular Tregs, beneficially modulated immune activities of host retinal CD11b+ cells and CD4+ effector T cells, leading to significant improvement of RGC survival. Importantly, rapamycin treatment further enhanced the neuroprotective effect of Tregs transfer. Taken together, these findings reveal a fine regulation of mTOR signaling on immunized Tregs after acute retinal injury. Adoptive transfer with targeting-mTOR strategy markedly improves neuronal recovery after ONI, supporting the therapeutic potentials of Tregs in acute and chronic neurological disorder.

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Section: Resultsmentioning

confidence: 94%

mTOR regulates neuroprotective effect of immunized CD4+Foxp3+ T cells in optic nerve ischemia

Chen

Tang

Wei

et al. 2016

Sci Rep

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“…Similarly, inactivation of microglia/macrophages by pharmacological approaches attenuated retinal degeneration in a mouse model of RP with impaired retinal pigment epithelium phagocytosis (Kohno et al, 2013). Moreover, an interesting correlation was found between severity of retinal inflammatory response, assessed by measuring the levels of CCl3, and severity of the retinal degeneration phenotype in the Mertk(À/À) mouse model of RP (Kohno et al, 2014).…”

Section: Targeting Inflammation In Rpmentioning

confidence: 92%

“…Recent studies highlight the occurrence of microglial activation and consequent inflammatory cytokines production in the outer retinas of rodent models of RP at the time of photoreceptor death (Kohno et al, 2014). Among cytokines, the Chemokine ligand 3 (CCl3), directly produced by activated microglial cells, appears to have a primary role in the development of the pathological phenotype.…”

Section: Targeting Inflammation In Rpmentioning

confidence: 99%

Pharmacological approaches to retinitis pigmentosa: A laboratory perspective

Guadagni

Novelli

Piano

et al. 2015

Progress in Retinal and Eye Research

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“…In turn, the neurotoxic effect of microglia has been demonstrated by a study that used minocycline, in which the inhibition of microglia activation resulted in decreased photoreceptor apoptosis [75]. Moreover, a deficiency of CCL3 promoted photoreceptor survival in a murine model of RP, which suggests that CCL3 plays an important role in the pathogenesis of RP [76] via the mediation of the microglia reaction [75]. In conclusion, resident microglia play a dual role in the retina of RP, whereas the detrimental effects appear to be substantially more powerful.…”

Section: Dual Role Of Resident Microglia In the Retina Of Rpmentioning

confidence: 96%

Friend or Foe? Resident Microglia vs Bone Marrow-Derived Microglia and Their Roles in the Retinal Degeneration

et al. 2016

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Microglia are immune cells in the central nervous system (CNS) that originate from the yolk sac in an embryo. The renewal of the microglia pool in the adult eye consists of two components. In addition to the self-proliferation of resident cells, microglia in the CNS also derive from the bone marrow (BM). BM-derived cells pass through the blood-brain barrier (BBB) or blood-retina barrier (BRB) and differentiate into microglia under specific conditions which involves a complex mechanism. Recent studies have widely investigated the role of resident microglia and BM-derived microglia in the retinal degenerative disease. Both two cell types play dual roles and share many similar functions. However, resident microglia tend to polarize to the M1 phenotype which is pro-inflammatory and neurotoxic, whereas BM-derived microglia mainly polarize to the neuroprotective M2 phenotype in retinal degeneration. The molecular mechanism that underlines the invasion of peripheral cells has led to extensive discussions. In addition to the BBB and BRB disruption, many signaling pathways are involved in this process. Based on these studies, we discuss the roles of these two types of microglia in retinal degeneration disease and the potential clinical application of BM-derived microglia, which may benefit future therapies.

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CCL3 Production by Microglial Cells Modulates Disease Severity in Murine Models of Retinal Degeneration

Cited by 67 publications

References 46 publications

mTOR regulates neuroprotective effect of immunized CD4+Foxp3+ T cells in optic nerve ischemia

mTOR regulates neuroprotective effect of immunized CD4+Foxp3+ T cells in optic nerve ischemia

Pharmacological approaches to retinitis pigmentosa: A laboratory perspective

Friend or Foe? Resident Microglia vs Bone Marrow-Derived Microglia and Their Roles in the Retinal Degeneration

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