Mast-cell-dependent secretion of CXC chemokines regulates ischemia-reperfusion-induced leukocyte recruitment in the colon

Abstract

Recruitment of leukocytes in the tissue microvasculature is considered to be a rate-limiting step in ischemia-reperfusion (I/R)-induced inflammation. The objective of this study was to examine the role of mast cells in CXC-chemokine- and I/R-provoked leukocyte recruitment in the colon. Balb/c- and mast-cell-deficient mice were challenged with the CXC chemokines macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC) for 3 h. Leukocyte-endothelium interactions in the colonic microvascular bed were analyzed using an inverted intravital fluorescence microscopy technique. In separate experiments, mice were subjected to I/R by clamping of the superior mesenteric artery for 30 min followed by 120 min of reperfusion. MIP-2 and KC induced a clear-cut increase in the number of rolling and adherent leukocytes in the colon. I/R increased the expression of MIP-2 and KC as well as leukocyte rolling and adhesion in the large bowel. Interestingly, leukocyte rolling and adhesion was reduced by more than 91% in mast-cell-deficient mice in response to CXC chemokine challenge. Moreover, I/R-induced leukocyte rolling and adhesion was decreased by more than 57% in mast-cell-deficient animals. Administration of MIP-2 increased the colonic expression of E-selectin mRNA in wild type but not in mast-cell-deficient mice. Our data demonstrate that CXC chemokine-induced leukocyte rolling and adhesion is regulated by mast cells. Moreover, these findings also show that mast cells play a crucial role in supporting I/R-induced leukocyte rolling and adhesion in the colonic microvascular bed via secretion of CXC chemokines.