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In vivo E-selectin upregulation correlates early with infiltration of PMN, later with PBL entry: MAbs block both
R M Binns1, S T Licence, A A Harrison
1Department of Immunology, Babraham Institute, Cambridge, United Kingdom.
Abstract:
The endothelial molecule E-selectin binds most leukocyte subsets in vitro. Yet its role in regulating the very different kinetics of inflammatory infiltration of different leukocyte subsets in vivo is unclear. The kinetics of E-selectin upregulation and polymorphonuclear leukocyte (PMN) and blood lymphocyte (PBL) localization in inflammation induced by interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha), phytohemagglutinin (PHA), and phorbol myristate acetate (PMA) were investigated in a well-established inbred pig trafficking model. They differed markedly both for these three labeled indicators of inflammation and in each of the four inflammatory processes. In each, E-selectin upregulation correlated with early PMN entry and later with PBL infiltration but was more protracted than both. The importance of E-selectin was confirmed by marked inhibition of PMN and PBL entry (up to > 60%) by F(ab')2 anti-E-selectin. Involvement of other molecules was illustrated by similar or greater inhibition with anti-CD18 F(ab')2. We conclude that, like CD18, E-selectin is necessary for most PMN and PBL infiltration but alone is insufficient, consistent with the involvement of several alternative multistep molecular mechanisms in this entry.
Insights
E-selectin is crucial for leukocyte infiltration during inflammation, binding both polymorphonuclear leukocytes (PMNs) and blood lymphocytes (PBLs). However, it works alongside other molecules like CD18, indicating complex inflammatory response mechanisms.
Area of Science:
- Immunology
- Cell Biology
- Inflammation Research
Background:
- E-selectin mediates leukocyte adhesion in vitro, but its in vivo role in inflammatory cell kinetics is not fully understood.
- Inflammatory responses involve distinct infiltration patterns for different leukocyte subsets.
Purpose of the Study:
- To investigate the kinetics of E-selectin upregulation and leukocyte (PMN and PBL) infiltration in response to various inflammatory stimuli.
- To determine the necessity of E-selectin and other molecules in leukocyte trafficking during inflammation.
Main Methods:
- Utilized an inbred pig model to study inflammation induced by IL-1α, TNF-α, PHA, and PMA.
- Monitored E-selectin expression and quantified PMN and PBL localization.
- Administered F(ab')2 anti-E-selectin and anti-CD18 antibodies to assess their inhibitory effects on leukocyte infiltration.
Main Results:
- E-selectin upregulation correlated with early PMN and later PBL infiltration, but its expression persisted longer than leukocyte entry.
- Anti-E-selectin F(ab')2 significantly inhibited both PMN and PBL infiltration (up to >60%).
- Anti-CD18 F(ab')2 demonstrated similar or greater inhibition, highlighting the involvement of multiple adhesion molecules.
Conclusions:
- E-selectin is essential for significant PMN and PBL infiltration into inflammatory sites.
- E-selectin alone is insufficient for complete leukocyte entry, indicating the involvement of alternative, multi-step molecular pathways.
- CD18 plays a critical role, comparable to or exceeding that of E-selectin, in leukocyte trafficking during inflammation.