On the role of mast cells in chemokine-induced leukocyte recruitment

Sammanfattning: Leukocyte recruitment is considered to playa key role in numerous inflammatory diseases. Tissue accumulation of Jeukocytes is a multi-steps process comprising rolling, adhesion and transmigration. This process depends on the function of several different cells, including leukocytes, endothelial cells, mast cells and macrophages as well as a wide spectrum of inflammatory mediators, such as TNF-alpha and chemokines. Chemokines are effective leukocyte attractants and according to structural properties, chemokines are divided into two major subfamilies, CC and CXC. In general, CC chemokines exert chemotactic influence on monocytes and lymphocytes while CXC chemokine mainly attract neutrophils. However, the mechanisms of chemokine-induced leukocyte recruitment in vivo remain elusive. Mast cells are tissue resident cells exerting multi-functional roles. Upon activation, mast cells release potent mediators, such as histamine, leukotrienes, chemokines and TNF-alpha. The aim of this study was to investigate the role of mast cells in regulating chemokine-provoked tissue infiltration ofleukocytes. It was found that TNF-alpha can activate endothelial cells to express P-selectin and CXC chemokine (MIP-2) and cause leukocyte adhesion in vitro in a glucocorticoid-sensitive manner. Interestingly, chemokines, both MIP-Ialpha, MCP-I and MIP-2, KC, were found to provoke a dose-dependent increase in P-selectin-dependent leukocyte roUing, adhesion and recruitment in vivo. It was demonstrated that chemokine-induced neutrophil recruitment in vivo was abolished in mast cell-deficient mice. TNF-alpha activated endothelial cells (increased E-selectin mRNA expression) in both wild-type and mast cell-deficient animals. In contrast, MIP-Ialpha, MCP-I and MIP-2 increased gene expression of E-selectin only in wild-type mice but not in mast cell-deficient mice, suggesting that chemokine-induced activation of endothelial cells is indeed dependent on mast cells. Moreover, it was observed that mast cell-derived TNF-alpha, but not histamine and leukotrienes, mediated chemokine-induced extravasation ofneutrophils. Considered together, this work elucidates important mechanisms regulating chemokine-induced leukocyte recruitment, which may help understand the pathophysiology of inflammatory diseases and serve as a basis for development of anti-inflammatory treatment strategies.