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Proteases are key effectors in macrophage function during the initiation and resolution of inflammation. Recent studies have shown that some proteases, traditionally considered extracellular, also exhibit enzymatic and non-enzymatic functions within the cell. This study explores the differential protease landscapes of macrophages based on their phenotype. Human monocytes were isolated from healthy volunteers and stimulated with M-CSF (resting macrophages), LPS/IFN-γ (inflammatory macrophages), or IL-4 (immunosuppressive macrophages). IL-4-stimulated macrophages secreted higher levels of MMPs and natural protease inhibitors compared to LPS/IFN-γ-stimulated macrophages. Increased extracellular proteolytic activity was detected in LPS/IFN-γ-stimulated macrophages while IL-4 stimulation increased cell-associated proteolytic activity, particularly for MMPs. Subcellular fractionation and confocal microscopy revealed the uptake of extracellular MMP-9 and its relocation to the nucleus in IL-4-stimulated, though not in LPS/IFN-γ-stimulated macrophages. Collectively, macrophages alter the subcellular location and activity of their MMPs based on the stimuli received, suggesting another mechanism for protease regulation in macrophage biology.