TY - JOUR
T1 - Blockade of TREM-1 prevents vitreoretinal neovascularization in mice with oxygen-induced retinopathy
AU - Rojas, Modesto A.
AU - Shen, Zu T.
AU - Caldwell, Ruth B.
AU - Sigalov, Alexander B.
N1 - Funding Information:
This work was partly supported by the National Cancer Institute of the National Institutes of Health grant R43CA195684 (ZTS, ABS; Alexander B. Sigalov, Principal Ie nvestigator) and the National Eye Institute of the National Institutes of Health grant R43EY028779 (ZTS, ABS; Alexander B. Sigalov, Principal Investigator), the National Eye Institute of the National Institutes of Health grant R01EY11766 (Ruth B. Caldwell, Principal Investigator), and the Vision Discovery Institute grant 70000-15000-04340046-12100-11200 (Modesto A. Rojas, Principal Investigator). Ruth B. Caldwell is the recipient of a Research Career Scientist Award from the Department of Veterans Affairs. The additional funding (ABS, MAR, ZTS) has come from SignaBlok, Inc. The sponsors were not involved in the study design, data collection, analysis and interpretation and the writing of the report.
Funding Information:
This work was partly supported by the National Cancer Institute of the National Institutes of Health grant R43CA195684 (ZTS, ABS; Alexander B. Sigalov, Principal Investigator) and the National Eye Institute of the National Institutes of Health grant R43EY028779 (ZTS, ABS; Alexander B. Sigalov, Principal Investigator), the National Eye Institute of the National Institutes of Health grant R01EY11766 (Ruth B. Caldwell, Principal Investigator), and the Vision Discovery Institute grant 70000-15000-04340046-12100-11200 (Modesto A. Rojas, Principal Investigator). Ruth B. Caldwell is the recipient of a Research Career Scientist Award from the Department of Veterans Affairs. The additional funding (ABS, MAR, ZTS) has come from SignaBlok, Inc. The sponsors were not involved in the study design, data collection, analysis and interpretation and the writing of the report.
Funding Information:
This work was partly supported by the National Cancer Institute of the National Institutes of Health grant R43CA195684 (ZTS, ABS; Alexander B. Sigalov, Principal Ie nvestigator) and the National Eye Institute of the National Institutes of Health grant R43EY028779 (ZTS, ABS; Alexander B. Sigalov, Principal Investigator), the National Eye Institute of the National Institutes of Health grant R01EY11766 (Ruth B. Caldwell, Principal Investigator), and the Vision Discovery Institute grant 70000-15000-04340046-12100-11200 (Modesto A. Rojas, Principal Investigator). Ruth B. Caldwell is the recipient of a Research Career Scientist Award from the Department of Veterans Affairs. The additional funding (ABS, MAR, ZTS) has come from SignaBlok, Inc. The sponsors were not involved in the study design, data collection, analysis and interpretation and the writing of the report.
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
KW - Neovascularization
KW - Retinopathy
KW - SCHOOL model of cell signaling
KW - TREM-1 peptide inhibitors
KW - Triggering receptor expressed on myeloid cells 1
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U2 - 10.1016/j.bbadis.2018.05.001
DO - 10.1016/j.bbadis.2018.05.001
M3 - Article
C2 - 29730341
AN - SCOPUS:85046693707
SN - 0925-4439
VL - 1864
SP - 2761
EP - 2768
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 9
ER -