Cleaning up dead cell corpses: The phosphatidylserine receptor is not needed

An article published today in Journal of Biology shows that the phosphatidylserine receptor, previously thought to be critical for the recognition and engulfment of dying cells, is not in fact necessary for these processes at all. Instead, the researchers found that the receptor is involved in the differentiation of a wide range of tissues during embryogenesis.

When cells undergo programmed cell death, they spill their normally hidden contents and their neighbours can thus recognise them as sick or dead and dispose of them accordingly. A particular recognition signal is provided by the normally internal phospholipid, phosphatidylserine, which dying cells expose on their surface.

Yet, Dr Andreas Lengeling and his colleagues from the German Research Center for Biotechnology found that the same patterns of cell death occurred during development in both wild-type (control) mice and mice lacking the phosphatidylserine receptor (Ptdsr). In addition, macrophages without Ptdsr, when studied in vitro, were just as efficient at ingesting dying cells as wild-type macrophages.

This evidence contradicts previous studies*, which concluded that mice with no Ptdsr are deficient at clearing up apoptosing cells, and consequently that the receptor is essential to this process. It is not yet clear precisely how the earlier studies led to such different conclusions about the role for the receptor, but one factor may be differences in the genetic background of the knockout mice that were studied by the various groups. In addition, Dr. Lengeling and his colleagues made more detailed studies in a wider range of tissue types than other researchers had previously carried out.

Dr Lengeling’s findings open up the possibility that another, as yet unknown, receptor exists that recognises phosphatidylserine on dying cells and promotes their ingestion. Alternatively, the engulfment of apoptosing cells may be mediated via phosphatidylserine-binding proteins and their receptors.

As dead and dying cells spill their otherwise internal contents, their rapid engulfment by neighbouring cells or professional phagocytes is needed to prevent the induction of autoimmune or inflammatory disorders. An accurate understanding of the molecular mechanisms behind the clearance of cell “corpses”, and consequently what might go wrong with this process, could lead to the development of treatments for these disorders – and is important if money and time are not to be wasted creating ineffective remedies.

The experiments performed by Dr Lengeling and his team showed that rather than recognising apoptotic cells, Ptdsr may well be involved in stimulating macrophages to release pro-inflammatory cytokines. Most importantly, however, Ptdsr appears to promote the differentiation of lung, kidney, intestine and other organs. Mice with no Ptdsr died either prior to or shortly after birth, were growth retarded, and experienced delayed organ development. Some knockout mice had severely disturbed eye development.