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

Abstract

ABSTRACTObjectiveMMP‐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.MethodsSurface 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.ResultsLipopolysaccharides 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.ConclusionsMMP‐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.