期刊
JOURNAL OF IMMUNOLOGY
卷 202, 期 11, 页码 3267-3281出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1801466
关键词
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类别
资金
- Public Health Service, National Heart, Lung, and Blood Institute [HL063137, HL086814, HL111835, AI111475-01]
- Flight Attendants Medical Research Institute [CIA123046]
- Department of Defense (Congressionally Directed Medical Research Programs) [PR152060]
- CDMRP [PR152060, 893843] Funding Source: Federal RePORTER
Matrix metalloproteinase (MMP)-8 and -9 released by degranulating polymorphonuclear cells (PMNs) promote pericellular proteolysis by binding to PMN surfaces in a catalytically active tissue inhibitor of metalloproteinases (TIMP)-resistant forms. The PMN receptor(s) to which MMP-8 and MMP-9 bind(s) is not known. Competitive binding experiments showed that Mmp-8 and Mmp-9 share binding sites on murine PMN surfaces. A novel form of TIMP-1 (an inhibitor of soluble MMPs) is rapidly expressed on PMN surfaces when human PMNs are activated. Membrane-bound TIMP-1 is the PMN receptor for pro- and active MMP-8 and -9 as shown by the following: 1) TIMP-1 is strikingly colocalized with MMP-8 and -9 on activated human PMN surfaces and in PMN extracellular traps; 2) minimal immunoreactive and active Mmp-8 or Mmp-9 are detected on the surface of activated Timp-1(-/-) murine PMNs; and 3) binding of exogenous Timp-1 (but not Timp-2) to Timp-1(-/-) murine PMNs reconstitutes the binding of exogenous pro-Mmp-8 and pro-Mmp-9 to the surface of Timp-1(-/-) PMNs. Unlike full-length pro-Mmp-8 and pro- Mmp-9, mutant pro-Mmp proteins lacking the COOH-terminal hemopexin domain fail to bind to Mmp-8(-/-)x Mmp-9(-/-) murine PMNs. Soluble hemopexin inhibits the binding of pro-Mmp-8 and pro-Mmp-9 to Mmp-8(-/-)x Mmp-9(-/-) murine PMNs. Thus, the COOH-terminal hemopexin domains of pro-Mmp-8 and pro-Mmp-9 are required for their binding to membrane-bound Timp-1 on murine PMNs. Exposing nonhuman primates to cigarette smoke upregulates colocalized expression of TIMP-1 with MMP-8 and MMP-9 on peripheral blood PMN surfaces. By anchoring MMP-8 and MMP-9 to PMN surfaces, membrane-bound TIMP-1 plays a counterintuitive role in promoting PMN pericellular proteolysis occurring in chronic obstructive pulmonary disease and other diseases.
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