What has the lipid metabolism of the human body got to do with inflammation? Scientists in Dr. Petra May’s group at the Centre for Neuroscience at the University of Freiburg recently found that molecules which normally regulate the availability of cholesterol and other water-insoluble substances, also interact with the signalling networks of the immune system. According to their findings, a receptor which mediates the uptake of certain lipoproteins into liver cells, helps to control the chaotic situations that can occur after inflammation.
The members of the lipoprotein family are transporters; they enclose water-insoluble substances such as fats, cholesterol or vitamin A and transport them in the bloodstream to peripheral tissues where required. The membranes of the target cells contain proteins that recognise these lipoproteins, for example the low-density lipoprotein (LDL) receptor. These receptors mediate the uptake of the lipids into the cell. Scientists long assumed that the lipid metabolism is the only domain where such lipoprotein receptors are found, and therefore concentrated on molecules that were thought to be associated with atherosclerosis, a disease caused by high blood cholesterol levels that can lead to cardiac infarction or stroke. "However, it has now been known for quite a few years that the LDL receptors have close relatives," said Dr. Petra May of the Centre for Neuroscience at the University of Freiburg. "And these receptors have interesting additional functions."
May came into contact with LDL-receptor-related proteins during her postdoctoral period in Dallas. The head of the Dallas team, Prof. Dr. Joachim Herz, had previously discovered a representative of this family, and further representatives were discovered soon after. The scientists now know that apolipoprotein E (ApoE), which is involved in the transport of lipids, plays a role in the development of Alzheimer’s disease. However, the ApoE receptors also regulate the synaptic transmission in certain brain areas (for example in the hippocampus) and are therefore thought to affect learning and memory. Another representative of this receptor family, megalin, plays a role in the hormone-mediated signal transmission by regulating the uptake of these substances into the cells. May and her team have now found out that a third representative of this receptor family, LDL-related protein 1 (LRP1), interacts with the immune system as well as mediating the uptake of lipoproteins in liver cells. LRP1 does not exert its action like its relatives by influencing the uptake of signalling substances into the cell, instead it behaves rather like a classical signal receptor.
"When I was working in Dallas, we discovered that part of the LRP1, which is located in the cell, can be cleaved when an external signal is given," said May. "This then enables it to detach from the rest of the receptor and enter the cell nucleus where it directly or indirectly influences the activity of certain genes." Following her arrival at the Freiburg Neuroscience Centre, May became head of an Emmy Noether junior researcher group where she began investigating the possible function of LRP1. She was highly successful in this endeavour, and this success led to a publication in the renowned journal Science Signaling. May and her team were able to show what happens when immune cells which are no longer able to produce LRP1, are attacked by bacteria. In order to simulate the bacteria attack in cell cultures, the scientists added lipopolysaccharide (LPS) to the petri dishes. LPS is a constituent of bacterial cell walls and normally triggers signalling cascades that initiate an inflammatory reaction.
“When we switched off the LRP1 gene in the immune cells, this led to an excessive response to LPS,” said May. “This in turn generated large quantities of cytokines, which normally attract immune cells in the body and enhance the inflammatory response.” However, the presence of the LRP1 gene led LPS to trigger the cleavage of the intracellular LRP1 domain, which subsequently migrated into the cell nucleus and attenuated the activity of genes that promote inflammation. It can therefore be assumed that LRP1’s task is to attenuate a reaction of the immune system. This is an important job, as the release of cytokines following attack by bacteria or other intruders potentially drives a positive feedback loop. When the cytokines attract new immune cells, these react again to the bacteria and release further cytokines, and so on. In order to prevent the body from being harmed by the chaos of its own immune response, these feedback loops have to be disrupted or at least their number reduced.
In future, May and her team plan to carry out similar experiments with mammalian animal models. The laboratory in Dallas, with whom the Freiburg researchers still work closely, will provide them with so-called conditional knock-out mice. These rodents are genetically modified in a way that enables the scientists to specifically switch off the LRP1 genes in different tissues with a molecular switch. In future, further experiments will need to show whether the immune-regulatory function of LRP1 also plays a role in vivo. In another project, May and her team are investigating the role of this receptor in the brain. They are also carrying out experiments in mice that are unable to produce LRP1 in the smooth muscle cells of their vascular walls. “These animals are highly susceptible to cholesterol-induced atherosclerosis,” said May who has since been able to show that cholesterol-induced atherosclerosis also has an inflammatory component. Further experiments will show whether there is a decisive link between the lipid metabolism and the immune system.
Further information:Dr. Petra MayCentre for NeuroscienceUniversity of Freiburg Albertstraße 23Room 0.016Tel.: +49 (0)761/203-8421Fax: +49 (0)761/203-8417 E-mail: petra.may(at)zfn.uni-freiburg.de