To regenerate muscle, cellular garbage men must become builders
Normally, macrophages – the white blood cells known as wraps and removing bacteria and other infectious agents – are in areas of injury. Once there, they act as scavengers, removing dead cells and release of proinflammatory factors, fending off the infection. After clearing the debris, the macrophages to release pro-inflammatory factors, and start making anti-inflammatory factors that promote repair in the damaged area. This change in cleaning debris from the promotion of construction is known as polarization of macrophages, and Claus Nerlove, Nadia Rosenthal and colleagues showed that it is essential for muscles to regenerate properly.
“There seems to be that point of no return,” says Rosenthal, “If the macrophages do not make this change, the muscle does not repair itself – just ended with the scar, instead of new tissue.
Nerlove and his research group at EMBL were studying a protein called C / EBPb, whose production increases in response to inflammation. They had genetically engineered mice in which they blocked this enhancement of C / EBPb production, to see the effect it had on the development of different cells involved in the immune system. To his dismay, the answer seems to be “almost none.” Transgenic mice developed normally and that normal blood cells – macrophages, but its not polarizing. Although this did not reach the expectations of scientists in understanding how blood cells raises an interesting possibility in the context of the investigation of Rosenthal in muscle regeneration. If these mice can not repair muscle damage properly, it shows that the polarization of macrophages is essential for muscle regeneration.
The two groups came together to investigate how the ability to respond to muscle injury has been affected in mice that C / EBPb boost production had been blocked. Their findings showed that macrophages being migrated to the injured and cleared the rubble, but because he could not do that all important switch, the muscle is not repaired properly, making scars instead.
At a stroke, scientists at the EMBL confirmed the importance of macrophages in the repair of muscle tissue and discovered its genetic basis. Typically, inflammatory factors trigger an increase in C / EBPb production, which in turn activates the genes that cause the macrophage to polarize.
“From a medical standpoint, it seems that the trick to improve muscle repair is to find a way to increase C / EBPb and keep production high,” concludes Nerlove, adding that “if we can now know exactly which key genes C / EBPb controls, giving us even more potential targets.
In addition to investigating other molecular steps in this way, scientists are studying the possible role of polarization of macrophages in the repair of cardiac muscle, with a view to better understanding and treatment of heart disease.
More information: Ruffell, D., Mourkioti, F., Gambardella, A., Kirstetter, P., Lopez, RG, Rosenthal, N. & Nerlove, C. A cascade induces M2 macrophages CREB-C/EBP specific gene expression and promotes the repair of muscle injury, PNAS online Early Edition, 21-25 September 2009