title: Tissue inhibitor of metalloproteinases-3 moderates the proinflammatory status of macrophages.
abstract: Tissue inhibitor of metalloproteinases-3 (TIMP-3) has emerged as a key mediator of inflammation. Recently, we reported that the resolution of inflammation is impaired in Timp3(-/-) mice after bleomycin-induced lung injury. Here, we demonstrate that after LPS instillation (another model of acute lung injury), Timp3(-/-) mice demonstrate enhanced and persistent neutrophilia, increased numbers of infiltrated macrophages, and delayed weight gain, compared with wild-type (WT) mice. Because macrophages possess broad immune functions and can differentiate into cells that either stimulate inflammation (M1 macrophages) or are immunosuppressive (M2 macrophages), we examined whether TIMP-3 influences macrophage polarization. Comparisons of the global gene expression of unstimulated or LPS-stimulated bone marrow-derived macrophages (BMDMs) from WT and Timp3(-/-) mice revealed that Timp3(-/-) BMDMs exhibited an increased expression of genes associated with proinflammatory (M1) macrophages, including Il6, Il12, Nos2, and Ccl2. Microarray analyses also revealed a baseline difference in gene expression between WT and Timp3(-/-) BMDMs, suggesting altered macrophage differentiation. Furthermore, the treatment of Timp3(-/-) BMDMs with recombinant TIMP-3 rescued this altered gene expression. We also examined macrophage function, and found that Timp3(-/-) M1 cells exhibit significantly more neutrophil chemotactic activity and significantly less soluble Fas ligand-induced caspase-3/7 activity, a marker of apoptosis, compared with WT M1 cells. Macrophage differentiation into immunosuppressive M2 cells is mediated by exposure to IL-4/IL-13, and we found that Timp3(-/-) M2 macrophages demonstrated a lower expression of genes associated with an anti-inflammatory phenotype, compared with WT M2 cells. Collectively, these findings indicate that TIMP-3 functions to moderate the differentiation of macrophages into proinflammatory (M1) cells.
authors.affiliation: 1 Center for Lung Biology, University of Washington, Seattle, Washington.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Gill
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.forename: Eli M
authors.initials: EM
authors.lastname: Bench
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Sussman
authors.forename: Roy T
authors.initials: RT
authors.lastname: Wang
authors.forename: Cliff
authors.initials: C
authors.lastname: Rims
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Birkland
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Anne M
authors.initials: AM
authors.lastname: Manicone
authors.forename: John K
authors.initials: JK
authors.lastname: McGuire
authors.forename: William C
authors.initials: WC
authors.lastname: Parks
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005838:Genotype; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D010641:Phenotype; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D019717:Tissue Inhibitor of Metalloproteinase-3