Surface-bound matrix metalloproteinase-8 on macrophages: Contributions to macrophage pericellular proteolysis and migration through tissue barriers

Objective: MMP-8 binds to surface-bound tissue inhibitor of metalloproteinase-1 (TIMP-1) on PMNs to promote pericellular proteolysis during the development of inflammatory diseases associated with tissue destruction. Little is known about the biology of MMP-8 in macrophages. We tested the hypotheses that: (1) MMP-8 and TIMP-1 are also expressed on the surface of activated macrophages, (2) surface-bound MMP-8 on macrophages promotes TIMP-resistant pericellular proteolysis and macrophage migration through tissue barriers, and (3) MMP-8 binds to surface-bound TIMP-1 on macrophages.

Methods: Surface MMP-8 and TIMP-1 levels were measured on human monocyte-derived macrophages (MDM) and/or murine macrophages using immunostaining, biotin-labeling, and substrate cleavage methods. The susceptibility of membrane-bound Mmp-8 on activated macrophages from wild-type (WT) mice to TIMPs was measured. Migration of WT and Mmp-8^-/- macrophages through models of tissue barriers in vitro and the accumulation of peritoneal macrophages in WT versus Mmp-8^-/- mice with sterile peritonitis was compared. Surface levels of Mmp-8 were compared on activated macrophages from WT and Timp-1^-/- mice.

Results: Lipopolysaccharides and a cluster of differentiation 40 ligand increased surface MMP-8 and/or TIMP-1 staining and surface type I collagenase activity on MDM and/or murine macrophages. Activated Mmp-8^-/- macrophages degraded less type I collagen than activated WT macrophages. The surface type-I collagenase activity on WT macrophages was resistant to inhibition by Timp-1. Peritoneal macrophage accumulation was similar in WT and Mmp-8^-/- mice with sterile acute peritonitis. However, Mmp-8^-/- macrophages migrated less efficiently through models of tissue barriers (especially those containing type I collagen) than WT cells. Activated WT and Timp-1^-/- macrophages had similar surface-bound Mmp-8 levels.

Conclusions: MMP-8 and TIMP-1 are expressed on the surface of activated human MDM and murine macrophages, but Mmp-8 is unlikely to bind to surface-bound Timp-1 on these cells. Surface-bound MMP-8 contributes to TIMP-resistant monocyte/macrophage pericellular proteolysis and macrophage migration through collagen-containing tissue barriers.