Research

Currently the research focuses on how leukocyte adhesion and integrin activity are regulated. Leukocyte integrins are expressed on leukocyte surfaces but are normally not active. They can be activated for example through the T lymphocyte receptor ( TCR ) or by chemokines. The activation through the TCR involves signalling through several molecules such as the Lck tyrosine kinase and  protein kinase C family members resulting in phosphorylation of threonine-758 in the beta-chain of the Leukocyte function associated antigen-1( LFA-1 ). This is followed by binding of intracellular 14-3-3 proteins, the exchange factor Tiam1 and activation of the small G-protein Rac-1. This results in remodeling of the actin cytoskeleton. The group has also shown that phosphorylation of the alfa-chains of LFA-1, the myeloid integrin Mac-1 and the monocyte/macrophage integrin alfa-X/beta2 is essential. It is still poorly understood how the different protein kinases and phosphatases involved are regulated. In addition to these molecules, several cytosolic proteins such as filamin, talin, kindlin family members and alfa-actinin are important. They all bind to the cytoplasmic domain of the LFA-1 beta-chain. Recent work has shown that LFA-1 can cross talk to the alfa4/beta1 integrin by phosphorylation based signalling. This can occur by ligand binding ( ICAM ) but also by antibodies to LFA-1. Although much is known about the signalling, there still remains a number of poorly understood events.

Upon activation of glutamate receptors in the brain, the integrin ligand ICAM-5, which is confined to neurons, is cleaved and a large extracellular fragment( s ) is released. ICAM-5 is localized to dendritic spines and interacts with axonal beta1-integrins, but also with LFA-1 expressed on brain T cells and microglia. We focus on what happens with the shedded ICAM-5 fragment, does it bind to the brain leukocytes and affect their function. ICAM-5 could regulate interactions between central leukocytes and neurons and this could be physiologically important but also involved in inflammation in the brain.

Many tissues have to live under relatively low oxygen pressure and this certainly is the case for developing blood cells. We are interested in how low oxygen affects integrin expression and activity in leukocyte precursors. We anticipate that integrins must be important in early precursor cells to keep the cells in the lymph nodes and bone marrow. When cells mature they must be released to enter the circulation. This field of research is still poorly developed.