Balancing neutrophil and macrophage infiltration with their clearance is key in the pathogenesis of inflammation. We have uncovered critical roles in the control of inflammation exerted by a family of extracellular matrix metalloproteinases (MMPs) that have been previously viewed as being detrimental for inflammation by tissue degradation. We previously found that ablation of the neutrophil-specific MMP8 increases inflammation that, in a murine model of chronic arthritis, led to worsened disease. Now we have explored the roles of the immune-modulatory MMP2 by quantifying global proteome and protease web transcript changes in mouse skin inflammation. By N-terminomics using Terminal Amine Isotopic Labeling of Substrates (TAILS1) the loss of MMP2 in the Mmp2-/- mouse markedly reduced vascular permeability and complement activation. MMP2 was shown to control these major inflammatory responses by proteolytic inactivation of plasma protease C1 inhibitor, the main regulator of bradykinin release and complement activation, so revealing new regulatory cross talks between inflammatory proteolytic signaling cascades. In exploring the role of macrophage MMP12, we found that Mmp12-/- mice display earlier and dramatic severe arthritis vs. wild-type mice characterized by massive neutrophil infiltrations. Overall, MMP12 dampens inflammation by concerted cleavages in multiple inflammation regulatory pathways. Mechanistically, we find that MMP12 facilitates macrophage invasion, but inactivates all CXCR2 chemokines responsible for neutrophil recruitment. This terminates neutrophil infiltration so accounting for the masses of neutrophils and the joint destruction in Mmp12-/- arthritis. MMP12 also promotes coagulation and squashes complement C3 activity at multiple levels. The importance of MMP12 in removing extracellular nets of actin and fibrin, identified by TAILS as new substrates, was strikingly demonstrated in vivo. Finally, we find crucial roles for MMP12 in antiviral innate immunity. Phosph-IκBαstimulates secretion of IFNα from virus-infected cells in a MMP12-dependent manner. Indeed, coxsackievirus type B3 infection of Mmp12-/- mice is lethal due to an inability to secrete IFNα. Secreted MMP12 is transported to the nucleus in virus-infected cells and we characterize its intracellular roles by new “omics” technologies. Such examples exemplify the general renaissance MMPs are enjoying from matrix remodellers to key cell regulators of extracellular homeostasis. By developing degradomics strategies to explore the roles of proteases in vivo many new substrates and hence functions in diverse processes have been revealed.