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

Modesto Antonio Rojas, Zu T. Shen, Ruth B Caldwell, Alexander B. Sigalov

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2761-2768
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1864
Issue number9
DOIs
StatePublished - Sep 1 2018

Fingerprint

Myeloid Cells
Oxygen
Retinal Neovascularization
Pathologic Neovascularization
Macrophage Colony-Stimulating Factor
Peptides
Retina
Macrophages
Inflammation
Lipopeptides
Retinal Diseases
Retinopathy of Prematurity
Life Expectancy
Half-Life
Monocytes
Neoplasms
Leukocytes
Down-Regulation
Air
Ligands

Keywords

  • Neovascularization
  • Retinopathy
  • SCHOOL model of cell signaling
  • TREM-1 peptide inhibitors
  • Triggering receptor expressed on myeloid cells 1

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

Blockade of TREM-1 prevents vitreoretinal neovascularization in mice with oxygen-induced retinopathy. / Rojas, Modesto Antonio; Shen, Zu T.; Caldwell, Ruth B; Sigalov, Alexander B.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1864, No. 9, 01.09.2018, p. 2761-2768.

Research output: Contribution to journalArticle

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