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

Angus M Tester1, Jennifer H Cox, Andrea R Connor

  • 1University of British Columbia Centre for Blood Research, Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Plos One
|March 22, 2007
PubMed

Insights

Matrix metalloproteinase-8 (MMP-8) is crucial for initiating lipopolysaccharide (LPS) responsiveness by activating immune cell-attracting chemokines. This study reveals MMP-8

Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • Lipopolysaccharide (LPS) triggers innate immune responses, involving polymorphonuclear (PMN) leukocytes.
  • Matrix metalloproteinases (MMPs) are enzymes with diverse roles, including extracellular matrix degradation.
  • The specific role of MMP-8 in initiating LPS responsiveness and PMN recruitment is not fully understood.

Purpose of the Study:

  • To elucidate the role of matrix metalloproteinase-8 (MMP-8) in initiating lipopolysaccharide (LPS)-induced innate immune responses.
  • To investigate the mechanism by which MMP-8 regulates polymorphonuclear (PMN) leukocyte infiltration.
  • To identify MMP-8's substrates involved in chemokine activation and PMN chemotaxis.

Main Methods:

  • Utilized Mmp8-null mice and wild-type littermates to assess PMN infiltration in response to LPS.
  • Analyzed the cleavage sites and bioactivity of chemokines, specifically LPS-induced CXC chemokine (LIX), CXCL8, and CXCL5, upon MMP-8 treatment.
  • Investigated PMN chemotaxis towards synthetic chemokine analogues in vitro.

Main Results:

  • PMN infiltration towards LPS was significantly abrogated in Mmp8-null mice, indicating MMP-8's critical role.
  • MMP-8 cleaves and activates LIX, CXCL8, and CXCL5, enhancing their ability to mobilize intracellular calcium and promote chemotaxis via CXCR2.
  • Despite redundancy in collagenolytic activity, MMP-8 demonstrated a unique physiological role in activating chemoattractants for innate immunity.

Conclusions:

  • Matrix metalloproteinase-8 is a key initiator of LPS responsiveness by cleaving and activating PMN chemoattractants.
  • PMN-derived MMP-8 orchestrates an in cis feed-forward mechanism to amplify the initial inflammatory response.
  • MMP-8's non-collagenolytic function in activating chemokines is essential for regulating innate immunity and LPS responsiveness in vivo.

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