LPS responsiveness and neutrophil chemotaxis in vivo require PMN MMP-8 activity

• Published in: PloS one 2007-03, Vol.2 (3), p.e312-e312
• Main Authors: Tester, Angus M, Cox, Jennifer H, Connor, Andrea R, Starr, Amanda E, Dean, Richard A, Puente, Xose S, López-Otín, Carlos, Overall, Christopher M
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biochemistry; Biological activity; Calcium; Calcium (intracellular); Calcium mobilization; Cancer; Cell migration; Cell Movement - drug effects; Cell Movement - physiology; Chemokines; Chemokines, CXC - drug effects; Chemokines, CXC - genetics; Chemokines, CXC - physiology; Chemotactic factors; Chemotaxis; Chemotaxis - drug effects; Chemotaxis - physiology; Collagen; Collagenase; CXC chemokines; CXCR2 protein; Departments; Encephalitis; Extracellular matrix; Extravasation; Humans; Immunity; Immunology/Immune Response; Immunology/Innate Immunity; Infections; Infiltration; Inflammation; Inflammatory response; Innate immunity; Interleukin 8; Legionella; Leukocyte migration; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Matrix metalloproteinase; Matrix Metalloproteinase 8 - deficiency; Matrix Metalloproteinase 8 - genetics; Matrix Metalloproteinase 8 - metabolism; Metalloproteinase; Metastasis; Mice; Mice, Knockout; Mitogens; Molecular biology; Neurodegeneration; Neutropenia - physiopathology; Neutrophil collagenase; Neutrophils; Neutrophils - drug effects; Neutrophils - physiology; Physiological aspects; Physiology; Pneumonia; Proteins; Redundancy; Rodents; Substrates; Tumorigenesis; Tumors; Wound Healing
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0000312

We identify matrix metalloproteinase (MMP)-8, the polymorphonuclear (PMN) leukocyte collagenase, as a critical mediator initiating lipopolysaccharide (LPS)-responsiveness in vivo. PMN infiltration towards LPS is abrogated in Mmp8-null mice. MMP-8 cleaves LPS-induced CXC chemokine (LIX) at Ser(4)-Val(5) and Lys(79)-Arg(80). LIX bioactivity is increased upon N-terminal cleavage, enhancing intracellular calcium mobilization and chemotaxis upon binding its cognate receptor, CXCR2. As there is no difference in PMN chemotaxis in Mmp8-null mice compared with wild-type mice towards synthetic analogues of MMP-8-cleaved LIX, MMP-8 is not essential for extravasation or cell migration in collagenous matrices in vivo. However, with biochemical redundancy between MMPs 1, 2, 9, and 13, which also cleave LIX at position 4 approximately 5, it was surprising to observe such a markedly reduced PMN infiltration towards LPS and LIX in Mmp8-/- mice. This lack of physiological redundancy in vivo identifies MMP-8 as a key mediator in the regulation of innate immunity. Comparable results were found with CXCL8/IL-8 and CXCL5/ENA-78, the human orthologues of LIX. MMP-8 cleaves CXCL8 at Arg(5)-Ser(6) and at Val(7)-Leu(8) in CXCL5 to activate respective chemokines. Hence, rather than collagen, these PMN chemoattractants are important MMP-8 substrates in vivo; PMN-derived MMP-8 cleaves and activates LIX to execute an in cis PMN-controlled feed-forward mechanism to orchestrate the initial inflammatory response and promote LPS responsiveness in tissue.