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| Title | On the role of mast cells in chemokine-induced leukocyte recruitment |
| Author/s | Yusheng Wang |
| Department/s |
Surgery Research Unit
|
| Full-text | Available as PDF |
| Defence date | 2006-10-26 |
| Defence time | 13:00 |
| Defence place | CRC, Clinical Research Centre, Public Forum, Entrance 72, Malmö University Hospital, Malmö, Sweden |
| Opponent | Associate professor, MD, PhD Johan D Söderholm |
| Publishing year | 2006 |
| Pages | 100 |
| Document type | Dissertation |
| Language | English |
| Publisher | Dept of Clinical Sciences, Surgery Research Unit, Malmö University Hospital, Lund University. |
| Popular science abstract Swedish | Inflammation är vävnadens svar på yttre störning och syftar till att eliminera främmade ämnen såsom bakterier men under vissa omständigheter initieras den inflammatoriska reaktionen av ofarliga substanser eller för starkt mot patogener och kan därmed orsaka vävnadsskada och är en underliggande mekanism vid många vanliga sjukdomar inkluderande allergier, blodförgiftning och inflammatorisk tarmsjukdom. Den viktigaste komponenten i den inflammatoriska reaktionen är vävnadsinfiltrationen av leukocyter. Rekryteringen av leukocyter är en flerstegsprocess som medieras av specifika adhesionsmolekyler som är uttryckta på kärlväggen och leukocyterna i samband med inflammation. En relativt ny grupp av kemotaktiska cytokiner, s.k. kemokiner stimulerar vävnadsmigration av leukocyter. Avhandlingen har studerat mekanismerna bakom kemokin-inducerad leukocytrekrytering. En central del i rekryteringen av leukocyter är aktivering av endotelceller som i sin tur uppreglerar P-selectin som medierar leukocytrullning i blodkärlen vilket är nödvändigt för den senare adhesionen och vävnadsackumulationen av leukocyter. Avhandlingen har visat att kemokiner kan aktivera endotelceller in vivo (men inte in vitro eftersom receptorerna saknas på endotelceller) via aktivering av mast celler i vävnaden, vilka uttrycker kemokin receptorerna. Avhandlingen har också kunnat visa att det är mast cell deriverat TNF-? som medierar kemokin-inducerad endotelcells aktivering och P-selektin uttryck in vivo. Tidigare har man ansett, baserat på in vitro försök med endast endotelceller och leukocyter, att CC kemokiner stimulerar rekrytering av mononukleära leukocyter men inte neutrofiler. På samma sett har man ansett att CXC kemokiner huvudsakligen stimulerar neutrofiler men inte mononukleära celler. Dessa slutsatser har baserats på in vitro metoder som uteslutit andra vävnadsceller som bidrar till komplexiteten in vivo. Den här avhandlingen har visat att det inte är så enkelt och polariserat in vivo utan att både CC och CXC kemokiner effektivt stimulerar rekryteringen av neutrofiler. Anledningen är att mast celler i vävnaden uttrycker receptor för både CC och CXC kemokiner vilket leder till endotelcells aktivering och därmed leukocytrekrytering. Dessa fynd bidrar inte bara till en fördjupad förståelse för inflammatoriska processer utan kan också vara viktiga för framtagandet av mer specifika och effektiva substanser riktade mot patologisk inflammation där kemokiner spelar en roll i patofysiologin. |
| Abstract English | 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. |
| Subject |
Medicine and Health Sciences |
| Keywords | mast cells, chemokines, TNF-alpha, dexamethasone, P-selectin, E-selectin, activation, Medicine (human and vertebrates), endothelial cells, adhesion, Neutrophil, Medicin (människa och djur), recruitment |
| ISBN/ISSN/Other |
ISSN: 1652-8220 ISBN: 91-85559-37-7 |
| Supervisor | Henrik Thorlacius |
| Additional info |
Qing Liu, Yusheng Wang and Henrik Thorlacius. 2000. Dexamethasone inhibits tumor necrosis factor-?-induced expression of macro-phage inflammatory protein-2 and adhesion of neutrophils to endothelial cells. Biochemical and Biophysical Research Communications, vol 271 pp 364-367. Department of Surgery, Malmö University Hospital, Lund University, 205 02 Malmö, Sweden
Xiao Wei Zhang, Qing Liu, Yusheng Wang and Henrik Thorlacius. 2001. CXC chemokines, MIP-2 and KC, induce P-selectin-dependent neutrophil rolling and extravascular migration in vivo. British Journal of Pharmacology, vol 133 pp 413-421. Department of Surgery, Malmö Unviersity Hospital, Lund University, 205 02 Malmö, Sweden
Ming Xiu Wan, Yusheng Wang, Qing Liu, Rene Schramm and Henrik Thorlacius. 2003. CC chemokines induce P-selectin-dependent neutrophil rolling and recruitment in vivo: intermediary role of mast cells. British Journal of Pharmacology, vol 138 pp 698-706. Department of Surgery, Malmö Univeristy Hospital, Lund University, 20502 Malmö, Sweden
Yusheng Wang and Henrik Thorlacius. 2005. Mast cell-derived tumor necrosis factor-? mediates macrophage inflammatory protein-2-induced recruitment of neutrophils in mice. British Journal of Pharmacology, vol 145 pp 1062-1068. Department of Surgery, Malmö University Hospital, Lund University, 20502 Malmö, Sweden
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