LPS responsiveness and neutrophil chemotaxis in vivo require PMN MMP-8 activity.
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.
Tester
Angus M
AM
University of British Columbia Centre for Blood Research, Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Cox
Jennifer H
JH
Connor
Andrea R
AR
Starr
Amanda E
AE
Dean
Richard A
RA
Puente
Xose S
XS
López-Otín
Carlos
C
Overall
Christopher M
CM
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
D019743:Chemokines, CXC; D008070:Lipopolysaccharides; D020784:Matrix Metalloproteinase 8