tPA regulates proinflammatory macrophage activation. In a yin-yang manner, LRP1 mediates both proinflammatory and anti-inflammatory effects on macrophage cytokine expression, through ligand-specific cell signaling. In an anti-inflammatory mechanism, tPA interacts with both NMDA-R and LRP1 to block the sustained IκBα phosphorylation induced when LPS interacts with Toll-like receptor 4 (TLR4). This results in blockade of the LPS-induced expression of TNFα, IL-1β, IL-6, and CCL3. In a proinflammatory mechanism, RAP interacts with LRP1 to induce expression of TNFα, IL-6, and CCL3.