How the body senses emergency

A receptor on macrophages can detect excessive cell death and recruit help

A receptor, induced on the surface of macrophages under stressful conditions, can detect tissue injury, stimulating inflammation and possibly repair, a RIKEN-led team of molecular biologists has discovered. Their work could provide new leads for anti-inflammatory drugs and healing.

Stress, age and body maintenance generate a continuous supply of dead cells, which normally are cleaned up by the macrophages that engulf pathogens and cellular debris. This mechanism, however, becomes overwhelmed at times of large-scale tissue damage, such as that caused by radiation or injury. To deal with such emergencies, the body needs a sensor which not only can detect the scale of the problem, but also that the dead tissue is not foreign.

Earlier research by another group had suggested that cellular stress leads to an upsurge in the activity of a gene, Mincle, which codes for a surface receptor in macrophages. So the RIKEN-led research team investigated the function of this receptor further. Their findings were published recently in Nature Immunology (1).

Initially, the researchers found that the Mincle receptor is associated with another signaling receptor chain, FcRã and triggers macrophage activation through a specific sequence known as the immunoreceptor tyrosine-based activation motif (ITAM). This stimulates the release of cellular hormones—cytokines and chemokines—that summon neutrophils to take part in inflammation and possibly tissue repair. Using a system involving green fluorescent protein to detect ITAM-mediated cell activation, the researchers found that Mincle responds to the presence of dead cells.

They then purified protein material from dead cells bound to the Mincle receptor, and discovered it was SAP130, a protein found in cell nuclei. SAP130 is released from cells where it can come into contact with the Mincle receptor only after they die and break down. In further experiments, the researchers determined the Mincle alert system works in mammals by showing that in living mice in which thymus cells had been killed by irradiation, the recruitment of neutrophils to the site of the damage was prevented by Mincle-specific antibody.

According to the team leader, Takashi Saito of the RIKEN Center for Allergy and Immunology in Yokohama, the research group now wants to determine the role of the alert system in diseases involving tissue damage; how activation of Mincle is related to the induction of autoimmune diseases such as rheumatoid arthritis; and whether it is possible to inhibit or cure inflammation and/or autoimmune diseases by blocking Mincle.

Reference

1. Yamasaki, S., Ishikawa, E., Sakuma, M., Hara, H., Ogata, K. & Saito, T. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nature Immunology 9, 1179–1188 (2008).

The corresponding author for this highlight is based at the RIKEN Laboratory for Cell Signaling