Increased expression of M-CSF and IL-13 in vitreous of patients with proliferative diabetic retinopathy: implications for M2 macrophage-involving fibrovascular membrane formation

Kobayashi, Yoshiyuki; Nakama, Takahito; Zhou, Yedi; Ishikawa, Keijiro; Arita, Ryoichi; Nakao, Shintaro; Miyazaki, Masao; Sassa, Yukio; Oshima, Yuji; Izuhara, Kenji; Kono, Toshihiro; Ishibashi, Tatsuro

doi:10.1136/bjophthalmol-2014-305860

Cited by 39 publications

(26 citation statements)

References 25 publications

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“…A previous study has shown that Th2 cells are one of the cellular components in FVMs of PDR patients 30 . We have also reported an increase of the IL-13 level in the vitreous of patients with PDR 27, 28. Based on these findings, the IL-13 produced by CD4-positive Th2 cells may be the inducer of POSTN secreted by the retinal vascular endothelial cells in ischemic retinas.…”

Section: Discussionsupporting

confidence: 74%

“…In addition, our earlier studies have shown a strong positive correlation between M2 macrophage markers and POSTN in the vitreous of PDR patients 33 . We have subsequently shown that macrophage polarization toward M2 phenotype by IL-13 resulted in the production of POSTN 28 . Thus, αSMA-positive pericytes and M2 macrophages polarized by IL-13 may also produce POSTN in ischemic retinas.…”

Section: Discussionmentioning

confidence: 66%

“…Interleukin-6 (IL-6), IL-8, IL-13, MCP-1, and VEGF were used for stimulation 27, 28. The expression of POSTN in HRECs was significantly increased in a dose-dependent manner only by IL-13 (p < 0.01 or 0.0001, n = 4; Figure 5B).…”

Section: Resultsmentioning

confidence: 99%

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Therapeutic Effect of Novel Single-Stranded RNAi Agent Targeting Periostin in Eyes with Retinal Neovascularization

Nakama

Ishikawa

Kubo

et al. 2017

Molecular Therapy - Nucleic Acids

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Retinal neovascularization (NV) due to retinal ischemia remains one of the principal causes of vision impairment in patients with ischemic retinal diseases. We recently reported that periostin (POSTN) may play a role in the development of preretinal fibrovascular membranes, but its role in retinal NV has not been determined. The purpose of this study was to examine the expression of POSTN in the ischemic retinas of a mouse model of oxygen-induced retinal NV. We also studied the function of POSTN on retinal NV using Postn KO mice and human retinal endothelial cells (HRECs) in culture. In addition, we used a novel RNAi agent, NK0144, which targets POSTN to determine its effect on the development of retinal NV. Our results showed that the expression of POSTN was increased in the vascular endothelial cells, pericytes, and M2 macrophages in ischemic retinas. POSTN promoted the ischemia-induced retinal NV by Akt phosphorylation through integrin αvβ3. NK0144 had a greater inhibitory effect than canonical double-stranded siRNA on preretinal pathological NV in vivo and in vitro. These findings suggest a causal relationship between POSTN and retinal NV, and indicate a potential therapeutic role of intravitreal injection of NK0144 for retinal neovascular diseases.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 66%

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Therapeutic Effect of Novel Single-Stranded RNAi Agent Targeting Periostin in Eyes with Retinal Neovascularization

Nakama

Ishikawa

Kubo

et al. 2017

Molecular Therapy - Nucleic Acids

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“…In OIR mice, M-CSF is required for pathological RNV but not for the recovery of normal vasculature [12]. In line with these findings, in the retinas of diabetic rats and in the vitreous of patients with proliferative DR, M-CSF levels are significantly higher as compared with those of control subjects [59,60]. This suggests targeting M-CSF either directly or via the specific inflammatory signaling pathway as a highly promising strategy for treating ocular neovascular diseases including ROP.…”

Section: Discussionmentioning

confidence: 83%

Blockade of TREM-1 prevents vitreoretinal neovascularization in mice with oxygen-induced retinopathy

Rojas

Caldwell

Sigalov

2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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In pathological retinal neovascularization (RNV) disorders, the retina is infiltrated by activated leukocytes and macrophages. Triggering receptor expressed on myeloid cells 1 (TREM-1), an inflammation amplifier, activates monocytes and macrophages and plays an important role in cancer, autoimmune and other inflammation-associated disorders. Hypoxia-inducible TREM-1 is involved in cancer angiogenesis but its role in RNV remains unclear. Here, to close this gap, we evaluated the role of TREM-1 in RNV using a mouse model of oxygen-induced retinopathy (OIR). We found that hypoxia induced overexpression of TREM-1 in the OIR retinas compared to that of the room air group. TREM-1 was observed specifically in areas of pathological RNV, largely colocalizing with macrophage colony-stimulating factor (M-CSF) and CD45- and Iba-1-positive cells. TREM-1 blockade using systemically administered first-in-class ligand-independent TREM-1 inhibitory peptides rationally designed using the signaling chain homooligomerization (SCHOOL) strategy significantly (up to 95%) reduced vitreoretinal neovascularization. The peptides were well-tolerated when formulated into lipopeptide complexes for peptide half-life extension and targeted delivery. TREM-1 inhibition substantially downregulated retinal protein levels of TREM-1 and M-CSF suggesting that TREM-1-dependent suppression of pathological angiogenesis involves M-CSF. Targeting TREM-1 using TREM-1-specific SCHOOL peptide inhibitors represents a novel strategy to treat retinal diseases that are accompanied by neovascularization including retinopathy of prematurity.

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“…In the OIR mice, M-CSF is required for pathological RNV but not for the recovery of normal vasculature (Kubota et al, 2009). In the retinas of diabetic rats and in the vitreous of patients with proliferative DR, M-CSF levels are significantly higher compared to control subjects (Liu, Xu, Jiang, & Da, 2009;Yoshida et al, 2015). This suggests targeting M-CSF either directly or via the specific inflammatory signaling pathway as a highly promising strategy for treating ocular neovascular diseases including ROP.…”

Section: Retinopathymentioning

confidence: 99%

Targeting Intramembrane Protein–Protein Interactions: Novel Therapeutic Strategy of Millions Years Old

Sigalov

2018

Advances in Protein Chemistry and Structural Biology

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Intramembrane protein-protein interactions (PPIs) are involved in transmembrane signal transduction mediated by cell surface receptors and play an important role in health and disease. Recently, receptor-specific modulatory peptides rationally designed using a general platform of transmembrane signaling, the signaling chain homooligomerization (SCHOOL) model, have been proposed to therapeutically target these interactions in a variety of serious diseases with unmet needs including cancer, sepsis, arthritis, retinopathy, and thrombosis. These peptide drug candidates use ligand-independent mechanisms of action (SCHOOL mechanisms) and demonstrate potent efficacy in vitro and in vivo. Recent studies surprisingly revealed that in order to modify and/or escape the host immune response, human viruses use similar mechanisms and modulate cell surface receptors by targeting intramembrane PPIs in a ligand-independent manner. Here, I review these intriguing mechanistic similarities and discuss how the viral strategies optimized over a billion years of the coevolution of viruses and their hosts can help to revolutionize drug discovery science and develop new, disruptive therapies. Examples are given.

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Increased expression of M-CSF and IL-13 in vitreous of patients with proliferative diabetic retinopathy: implications for M2 macrophage-involving fibrovascular membrane formation

Abstract: These findings indicate that the M2 polarisation of macrophages is induced by M-CSF and IL-13 in diabetic retinas. The presence of M-CSF and IL-13 would then promote FVM formation by periostin production.

Cited by 39 publications

References 25 publications

Therapeutic Effect of Novel Single-Stranded RNAi Agent Targeting Periostin in Eyes with Retinal Neovascularization

Therapeutic Effect of Novel Single-Stranded RNAi Agent Targeting Periostin in Eyes with Retinal Neovascularization

Blockade of TREM-1 prevents vitreoretinal neovascularization in mice with oxygen-induced retinopathy

Targeting Intramembrane Protein–Protein Interactions: Novel Therapeutic Strategy of Millions Years Old

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