Abstract
M2 macrophage (Mφ) promotes pathologic angiogenesis through a release of pro-angiogenic mediators or the direct cell–cell interaction with endothelium in the micromilieu of several chronic inflammatory diseases, including rheumatoid arthritis and cancer, where interleukin (IL)-18 also contributes to excessive angiogenesis. However, the detailed mechanism remains unclear. The aim of this study is to investigate the mechanism by which M2 Mφs in the micromilieu containing IL-18 induce excessive angiogenesis in the in vitro experimental model using mouse Mφ-like cell line, RAW264.7 cells, and mouse endothelial cell line, b.End5 cells. We discovered that IL-18 acts synergistically with IL-10 to amplify the production of Mφ-derived mediators like osteopontin (OPN) and thrombin, yielding thrombin-cleaved form of OPN generation, which acts through integrins α4/α9, thereby augmenting M2 polarization of Mφ with characteristics of increasing surface CD163 expression in association with morphological alteration. Furthermore, the results of visualizing temporal behavior and morphological alteration of Mφs during angiogenesis demonstrated that M2-like Mφs induced excessive angiogenesis through the direct cell–cell interaction with endothelial cells, possibly mediated by CD163.
Highlights
Macrophages (Mφs) play essential roles in tissue homeostasis and immunity [1], and exist along with a continuum of functional states between two major subpopulation s of M1 and M2 phenotypes with different functions dependent upon environmental cues [2, 3]
According to the recent proposal of nomenclature for Mφ subsets linked to the stimulation scenarios [41], Mφs treated with medium, tumor necrosis factor (TNF)-α, IL-10, IL-18, TNF-α + IL-18, or IL-10 + IL-18 were described as Mφ (–), Mφ (TNF-α), Mφ (IL-10), Mφ (IL-18), Mφ (TNF-α + IL-18) or Mφ (IL-10 + IL-18), respectively
To explore the mechanism by which IL-18 augments IL-10-induced Mφ M2 polarization and angiogenic potency, we focused on OPN, a pleiotropic cytokine produced by various cells including Mφ [11], according to the results of comprehensive protein analysis showing that OPN levels were obviously increased in Mφ (IL-10), which was further enhanced in Mφ (IL-10 + IL-18) (Figure 5A)
Summary
Macrophages (Mφs) play essential roles in tissue homeostasis and immunity [1], and exist along with a continuum of functional states between two major subpopulation s of M1 and M2 phenotypes with different functions dependent upon environmental cues [2, 3]. M1 Mφs are typically triggered by Th1 cytokines, such as interferon-γ and tumor necrosis factor (TNF)-α, or by bacterial lipopolysaccharide, or by stimulation of granulocyte Mφ colony-stimulating factor (GM-CSF) [2,3,4,5]. These Mφs produce a large amount of pro-inflammatory cytokines, along with higher expressions of cell surface proteins, such as cluster of differentiation (CD) 54, CD80, CD86, and CD197 [2,3,4,5]. The detailed mechanism remains largely unknown how Mφ induces excessive angiogenesis through the release of pro-angiogenic mediators or the cell–cell interaction with endothelium
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