title: LPS responsiveness and neutrophil chemotaxis in vivo require PMN MMP-8 activity.
abstract: 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.
authors: University of British Columbia Centre for Blood Research, Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Angus M
authors: AM
authors: Tester
authors: Jennifer H
authors: JH
authors: Cox
authors: Andrea R
authors: AR
authors: Connor
authors: Amanda E
authors: AE
authors: Starr
authors: Richard A
authors: RA
authors: Dean
authors: Xose S
authors: XS
authors: Puente
authors: Carlos
authors: C
authors: López-Otín
authors: Christopher M
authors: CM
authors: Overall
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D019743:Chemokines, CXC / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020784:Matrix Metalloproteinase 8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009503:Neutropenia / Q000503:physiopathology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D014945:Wound Healing
chemical_list: D019743:Chemokines, CXC; D008070:Lipopolysaccharides; D020784:Matrix Metalloproteinase 8