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The CD11/CD18 (beta2) integrins modulate neutrophil caspase activation and survival following TNF-alpha or endotoxin

Sen Rong Yan1, Kusum Sapru, Andrew C Issekutz

  • 1Department of Pediatrics, The Dalhousie Inflammation Group, Dalhousie University, Halifax, Nova Scotia, Canada.

Immunology and Cell Biology
|July 31, 2004
PubMed

Insights

Beta2 integrins (CD11/CD18) on neutrophils delay apoptosis by binding to extracellular matrix and endothelium ligands. Blocking these integrins accelerates neutrophil clearance from inflamed tissues.

Area of Science:

  • Immunology
  • Cell Biology
  • Inflammation Research

Background:

  • Neutrophils (PMN) are crucial immune cells with short lifespans, yet their survival is extended during inflammation.
  • The role of beta2 integrins in regulating PMN survival and apoptosis remains incompletely understood.

Purpose of the Study:

  • To investigate the function of beta2 integrins in modulating neutrophil (PMN) caspase activation and apoptosis.
  • To determine if beta2 integrin engagement with extracellular matrix and endothelial ligands influences PMN survival during inflammatory responses.

Main Methods:

  • Western blotting was used to assess caspase activation in PMNs cultured on different substrates (fibrinogen, fibronectin, albumin).
  • Monoclonal antibodies (mAbs) were employed to block beta2 integrin (CD18) function.
  • PMN migration through endothelium in vitro was analyzed, with caspase activation assessed in migrated versus non-migrated cells.

Main Results:

  • Culturing PMNs on fibrinogen, a ligand for Mac-1 (CD11b/CD18), significantly decreased caspase activation.
  • Blocking CD18 function in the presence of TNF-alpha or LPS markedly increased caspase activation on fibrinogen.
  • Migrated PMNs exhibited significantly lower caspase activation compared to non-migrated cells.
  • Blocking beta2 integrins (CD18 or LFA-1/Mac-1) on migrated PMNs led to a 2-4 fold increase in active caspases, accelerating apoptosis and cell death.

Conclusions:

  • Engagement of beta2 integrins (Mac-1, LFA-1) with extracellular matrix and endothelial ligands delays apoptosis in neutrophils recruited during inflammatory responses (e.g., LPS, TNF-alpha).
  • Inhibiting beta2 integrin function could potentially enhance PMN clearance from inflamed tissues, in addition to reducing infiltration.

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