The CD11/CD18 (beta2) integrins modulate neutrophil caspase activation and survival following TNF-alpha or endotoxin induced transendothelial migration.
Neutrophils (PMN) are short-lived cells but their survival is often prolonged in inflammation. The beta2 (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 beta2 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-alpha or endotoxin (LPS), blockade of CD18 (beta2 chain) with mAb markedly increased caspase activation in PMN on fibrinogen. PMN which migrated through endothelium in vitro in response to TNF-alpha, LPS, IL-1alpha, IL-8 or C5a contained 58% fewer active caspase positive PMN after 20 h than non-migrated PMN remaining on the endothelium. When beta2 (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 beta2 integrins Mac-1 and LFA-1 plays a role in delaying apoptosis in PMN recruited in response to LPS and TNF-alpha. Inhibition of beta2 integrin function may not only inhibit PMN infiltration, but also accelerate PMN clearance from inflamed tissue.
Department of Pediatrics, The Dalhousie Inflammation Group, Dalhousie University, Halifax, Nova Scotia, Canada.
Sen Rong
SR
Yan
Kusum
K
Sapru
Andrew C
AC
Issekutz
D017209:Apoptosis; D018845:CD11 Antigens / Q000276:immunology / Q000502:physiology*; D018821:CD18 Antigens / Q000276:immunology / Q000502:physiology*; D020169:Caspases / Q000378:metabolism*; D018929:Cell Culture Techniques; D002465:Cell Movement; D002470:Cell Survival; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation; D005340:Fibrinogen / Q000502:physiology; D006801:Humans; D007375:Interleukin-1 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018845:CD11 Antigens; D018821:CD18 Antigens; D007375:Interleukin-1; D016209:Interleukin-8; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D005340:Fibrinogen; D020169:Caspases