The CD11/CD18 (β2) integrins modulate neutrophil caspase activation and survival following TNF‐α or endotoxin induced transendothelial migration

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Abstract
Neutrophils (PMN) are short‐lived cells but their survival is often prolonged in inflammation. The β2 (CD11/CD18) integrins are involved in PMN migration into inflammation but their role in PMN survival is not well understood. We investigated the role of β2 integrins in PMN caspase activation, a key enzyme cascade in apoptosis. After 20 h, caspase activation (Western blotting) was markedly decreased in PMN cultured on fibrinogen, a ligand for Mac‐1 (CD11b/CD18), but not on fibronectin or albumin. In the presence of TNF‐α or endotoxin (LPS), blockade of CD18 (β2 chain) with mAb markedly increased caspase activation in PMN on fibrinogen. PMN which migrated through endothelium in vitro in response to TNF‐α, LPS, IL‐1α, IL‐8 or C5a contained 58% fewer active caspase positive PMN after 20 h than non‐migrated PMN remaining on the endothelium. When β2 (CD18) integrin or lymphocyte function antigen (LFA)‐1 (CD11a) plus Mac1 (CD11b) were blocked by mAb (intact or Fab′), the proportion of migrated PMN (but not of non‐migrated PMN) with active caspases was significantly increased (2−4‐fold) and this was associated with accelerated PMN apoptosis and death. Thus, engagement of ligands on extracellular matrix and endothelium by the β2 integrins Mac‐1 and LFA‐1 plays a role in delaying apoptosis in PMN recruited in response to LPS and TNF‐α. Inhibition of β2 integrin function may not only inhibit PMN infiltration, but also accelerate PMN clearance from inflamed tissue.
Funding Information
  • Canadian Institutes of Health Research (MT‐7684)

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