251 - Acute, but not chronic, leukocyte recruitment in vascular inflammation requires endothelial CD40L (ID 303)
Abstract
Background and Aims
The co-stimulatory immune molecule CD40L (CD154) is critically required for host defense by inducing B cell maturation via its classical receptor CD40. In addition, we and others have previously shown that endothelial CD40L promotes leukocyte accumulation in various cardiovascular conditions, such as atherosclerosis, by binding to its alternative receptor Mac-1. The unspecific inhibition of CD40L, however, causes severe immune deficiency. Here, we have tested the cell-type specific role of CD40L in inflamed endothelial cells (EC).
Methods
We created a tamoxifen inducible EC-specific CD40L-knockout mouse on an ApoE-deficient background. To induce atherogenesis, 8-week-old male CD40Lfl/flBMX-Cre+ApoE-/- (CD40L-EC) or CD40Lfl/flBMX-Cre-ApoE-/- (control) mice were fed a chow diet for 20 weeks. Furthermore, we used a model of acute TNFα-induced mesenteric inflammation in intravital microscopy and a model of thioglycolate induced sterile peritonitis to assess the role of endothelial CD40L in acute inflammation.
Results
Surprisingly, CD40L-deficiency on endothelial cells did not modulate the extend of atherosclerotic lesions, features of plaque stability, or levels of dyslipidemia. However, intravital microscopy in TNFα-stimulated mesenteric vessels showed significantly reduced leukocyte adhesion in CD40L-EC mice compared with control mice (1.8 vs. 4.6 adhering leukocytes/field, respectively). Furthermore, in a model of thioglycolate induced sterile peritonitis, we found significantly less cells in the peritoneal cavity after 72 hours in CD40L-EC mice.
Conclusions
Our data implicate that endothelial CD40L is critically required for direct EC-leukocyte interaction, leukocyte adhesion to the inflamed vasculature, and leukocyte recruitment in the setting of acute, but not chronic, inflammation. These findings hold great promise for the future development of novel anti-inflammatory strategies.
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