Figure 7.

Schematic showing proposed macrophage and fibroblast phenotype responses to high glucose conditions in the absence of SP (upper panel) and high glucose conditions with replacement SP (lower panel). Under conditions of high glucose in the absence of SP, macrophages take on a pro-inflammatory M1 phenotype that releases pro-inflammatory cytokines (TNF-α, CCL2, IL-6), which can act on fibroblasts to promote a pro-fibrotic phenotype by overwhelming reparative M2 macrophages. High glucose in the absence of SP also acts directly at the fibroblast to promote a pro-fibrotic phenotype mediated by increased RAGE, oxidative stress, and inflammatory cytokines (TNF-α). Conversely, when SP is present in addition to high glucose, M1 macrophages are reduced and M2 macrophages become the dominant macrophage phenotype. M2 macrophages release the anti-fibrotic cytokine IL-10. Additionally, the presence of SP opposes the pro-fibrotic fibroblast phenotype by reducing RAGE and oxidative stress, as well as increasing NO production. In response to SP, cardiac fibroblasts also produce IL-4, which can act as an additional stimulus for M2 macrophage development.