Blockade of α6 integrin inhibits IL-1β- but not TNF-α-induced neutrophil transmigration in vivo

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Abstract
In vitro and in vivo evidence supports a functional role for the integrin α6β1 in neutrophil migration through the perivascular basement membrane, a response that in vivo appears to be associated with platelet/endothelial cell adhesion molecule-1 (PECAM-1)-mediated up-regulation of α6β1 on the cell surface of transmigrating leukocytes. As the involvement of PECAM-1 in leukocyte migration is cytokine-specific, the aim of the present study was to investigate whether α6β1 exhibited a similar profile of stimulus specificity in this context. The cytokines interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) were used to elicit neutrophil migration in two murine models of inflammation, migration through cremasteric venules, as observed by intravital microscopy, and migration into the peritoneal cavity. The role of α6β1 was investigated using an α6 integrin-blocking monoclonal antibody GoH3. In both models, GoH3 significantly inhibited neutrophil transmigration induced by IL-1β but not TNF-α. This cytokine-specific role of α6 integrin was associated with enhanced cell-surface expression of α6β1 on transmigrated neutrophils (as compared with blood cells) in response to IL-1β but not TNF-α. Using lipopolysaccharide as an inflammatory stimulus in the cremaster muscle model, the study also provides evidence for the involvement of α6 integrin in leukocyte transmigration as mediated by endogenously generated IL-1β. Collectively, the findings demonstrate that α6β1 blockade inhibits neutrophil migration induced by exogenous and endogenous IL-1β but not TNF-α, observations that are associated with increased expression of the integrin on transmigrated leukocytes.
Funding Information
  • Wellcome Trust, UK (064920)