Matrix metalloproteases (MMPs) are often associated with extracellular matrix (ECM) remodeling and tissue invasion by cells such as macrophages and cancer cells. Shimizu-Hirota et al. report that MT1-MMP, a membrane-anchored MMP that enables invasion of collagen-rich tissues by various cell types, is required in macrophages as a regulator of gene expression. Despite showing reduced protease activity in vitro, macrophages from MT1-MMP–/– mice had normal migratory, chemotactic, and invasive activities in both 2D and 3D culture and invaded tissues normally in vivo, indicating that MT1-MMP was not solely responsible for ECM remodeling by macrophages. After treatment with bacterial lipopolysaccharide in vitro or in mice, MT1-MMP–/– macrophages showed a proinflammatory phenotype characterized by increased expression of proinflammatory genes that are normally repressed by the chromatin remodeling complex Mi-2/NuRD and decreased expression of IL-10 (which encodes an anti-inflammatory cytokine) relative to wild-type (WT) macrophages. Expression of transcripts encoding components of the Mi-2/NuRD complex was reduced in MT1-MMP–/– macrophages, and Mi-2 was detected at the promoter of the gene encoding the proinflammatory cytokine IL-12b. Phosphoinositide 3-kinase (PI3K)–Akt signaling is also an important modulator of inflammatory responses, and expression of p110δ, which encodes the catalytic subunit of PI3Kδ, was reduced in MT1-MMP–/– macrophages. Pharmacological inhibition of PI3K signaling in WT macrophages phenocopied the MT1-MMP–/– proinflammatory phenotype. The protease activity of MT1-MMP was dispensable for gene regulation because an MMP inhibitor had no effect on p110δ expression in WT macrophages, and expression of catalytically inactive forms of MT1-MMP rescued the proinflammatory phenotype of MT1-MMP–/– macrophages. Full-length and various mutant forms of MT1-MMP rescued transcriptional responses in MT1-MMP–/– macrophages, and each form translocated to the nucleus in both WT and MT1-MMP–/– macrophages. In contrast, a secreted form of MT1-MMP did not rescue the transcriptional response or translocate to nuclei. MT1-MMP was detected at the p110δ promoter and stimulated expression of a p110δ reporter, suggesting that it acted as a transcriptional coactivator. Thus, in addition to participating in ECM remodeling, MT1-MMP stimulates expression of a PI3K signaling component to modulate expression of immune response genes under control of the Mi-2/NuRD complex.
R. Shimizu-Hirota, W. Xiong, B. T. Baxter, S. L. Kunkel, I. Maillard, X.-W. Chen, F. Sabeh, R. Liu, X.-Y. Li, S. J. Weiss, MT1-MMP regulates the PI3Kδ·Mi-2/NuRD-dependent control of macrophage immune function. Genes Dev. 26, 395–413 (2012). [Abstract] [Full Text]