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Neutrophil collagenase (matrix metalloproteinase-8) : regulatory roles in inflammation and autoimmunity

University of British Columbia

Inflammation is an essential process in wound healing and for the elimination of invading pathogens. However, unregulated inflammation can lead to numerous pathologies including autoimmunities, tumorigenesis, and atherosclerosis. Matrix metalloproteinases (MMPs), once thought to be only extracellular matrix degrading enzymes, are now known to be key regulators of inflammatory and immune responses through proteolysis of bioactive molecules. MMP-8, a neutrophil-specific MMP, is protective in skin cancer models where MMP-8 knockout mice have an initial delay in neutrophil infiltration followed by a massive accumulation at the site of treatment. We investigated this delay in a murine air pouch model of acute inflammation, where MMP-8 deficiency caused decreased neutrophil migration in response to LPS. This was attributed to MMP-8 processing and activation of LPS-inducible CXC chemokine (LIX), a murine neutrophil chemoattractant. Indeed, MMP-8 knockout mice had normal neutrophil infiltration in response to synthetic analogs of cleaved LIX. Furthermore, homologous pathways with human chemokines CXCL5 and CXCL8 were described. In vivo, an indirect interaction between MMP-8 and LIX also occurs, whereby MMP-8 processes and inactivates cLl-proteinase inhibitor causing increased neutrophil elastase activity, which then efficiently cleaves and activates LIX. MMP-8 was protective in a model of rheumatoid arthritis where synovial tissues from MMP-8 deficient mice had an abundance of neutrophils. This prolonged neutrophil accumulation correlated with a loss of caspase-1 1 expression, consequent decreased caspase-3 activity and reduced apoptosis. MMP-8 shedding of TNF-a was also decreased in MMP-8 deficient leukocytes, potentially dampening a key apoptotic pathway in neutrophils. The role of MMPs in processing the Thi cell CXCR3-binding chemokines CXCL9, CXCL1O, and CXCL11 was investigated. The leukocytic MMPs -7, -8, -9, and -12 cleaved CXCL11 at both the amino and carboxy terminus. N-terminal cleavage resulted in the conversion of a receptor agonist to antagonist whereas C-terminal cleavage by MMP-8 caused a significant loss in glycosaminoglycan binding, demonstrating for the first time that direct chemokine proteolysis can regulate the formation of haptotactic gradients. Therefore, MMP-8 is a pivotal regulator in the onset and termination of inflammation, and has multifaceted roles in innate and acquired immunity as well as the autoimmune disorder rheumatoid arthritis.

Thesis/Dissertation

application/pdf

2009-02-27

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/5247

Biochemistry and Molecular Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/