Abstract
The role of pro-inflammatory macrophage activation in cardiovascular disease (CVD) is a complex one amenable to network approaches. While an indispensible tool for elucidating the molecular underpinnings of complex diseases including CVD, the interactome is limited in its utility as it is not specific to any cell type, experimental condition or disease state. We introduced context-specificity to the interactome by combining it with co-abundance networks derived from unbiased proteomics measurements from activated macrophage-like cells. Each macrophage phenotype contributed to certain regions of the interactome. Using a network proximity-based prioritization method on the combined network, we predicted potential regulators of macrophage activation. Prediction performance significantly increased with the addition of co-abundance edges, and the prioritized candidates captured inflammation, immunity and CVD signatures. Integrating the novel network topology with transcriptomics and proteomics revealed top candidate drivers of inflammation. In vitro loss-of-function experiments demonstrated the regulatory role of these proteins in pro-inflammatory signaling.
Highlights
Pro-inflammatory macrophage activation plays a prominent role in a large number of disorders including cardiovascular disease (CVD) (Aikawa and Libby, 2004; Glass and Olefsky, 2012; Glass and Witztum, 2001; Gregor and Hotamisligil, 2011; Liang et al, 2007; Randolph, 2014; Ridker and Luscher, 2014; Tabas, 2010)
Our results revealed that edges derived from macrophage-specific proteomics contributed to the less characterized parts of the interactome, reflected the respective macrophage stimulation condition in terms of pathways and biological processes, and increased the prediction performance of CVD therapeutic targets
The literature-curated human interactome, or protein-protein interactions (PPIs) network, hosts invaluable information about potential protein subnetworks related to diseases
Summary
Pro-inflammatory macrophage activation plays a prominent role in a large number of disorders including cardiovascular disease (CVD) (Aikawa and Libby, 2004; Glass and Olefsky, 2012; Glass and Witztum, 2001; Gregor and Hotamisligil, 2011; Liang et al, 2007; Randolph, 2014; Ridker and Luscher, 2014; Tabas, 2010). Characterizing the mechanisms underlying macrophage activation itself proves to be a challenging task, given the functional heterogeneity of macrophages and the complex interplay between the pro- and anti-inflammatory phenotypes (Biswas and Mantovani, 2012; Gordon and Mantovani, 2011; Koltsova et al, 2013; Lawrence and Natoli, 2011; Ley et al, 2011; Moore et al, 2013; Murray et al, 2014; Swirski and Nahrendorf, 2013). It is increasingly recognized that macrophage activation has many distinct types and follows a spectrum model defined by specific stimuli rather than the bipolar model of pro- and anti-inflammatory polarization that once prevailed (Murray et al, 2014; Nahrendorf and Swirski, 2016; Xue et al, 2014).
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