Plasmin has a central role in the regulation of the inflammatory response via MMP9 activation. Administration of CpG/DG activates TLR-9 in different cell populations, which stimulates the secretion of urokinase-type plasminogen activator that will modify plasminogen into its active form, plasmin. The activation of TLR-9 in monocyte/macrophages will activate production of a cytokine storm, which involves the production of transmembrane TNFα, chemokine ligand 2 (CCL2), and interleukin-1 (IL-1) and IL-6. Notably, the generation of plasmin promotes the activation of MMP9, which will cleave mTNFα into its soluble form (sTNFα), increasing the inflammatory response. The transient inhibition of plasmin with YO-2 decreases the inflammatory response, increasing the viability of treated mice; however, it did not affect the increase in blood coagulation markers, suggesting that CpG/DG activates the coagulation cascade in a plasmin-independent manner. This response might be mediated by the activation in endothelial cells of the NFκB pathway, which has been described as being activated by CpG and being involved in the inflammatory and coagulation responses mediated by endothelial cells. mTNFα, membrane TNF-α; uPA, urokinase-type plasminogen activator. Professional illustration by Somersault18:24.