RI-MUHC team uncovers new mechanism of inflammation in muscular dystrophy
A new study reveals how signals sent from damaged muscles to the bone marrow can induce long-lasting changes in immune cells that exacerbate harmful inflammation
Published today in Nature Communications, work by researchers from the Research Institute of the McGill University Health Centre (RI-MUHC) may lead to new approaches in the treatment of Duchenne muscular dystrophy, a devastating and fatal genetic disorder that affects the breathing muscles of children and young adults. Their new study reveals how signals sent from damaged muscles to the bone marrow can induce long-lasting changes in immune cells that exacerbate harmful inflammation.
Basil Petrof, MD, senior scientist at the Meakins-Christie Laboratories and in the Translational Research in Respiratory Diseases Program at the RI-MUHC, led the study. His team aimed to determine whether macrophages, the dominant immune cell type found in the diseased muscles, undergo a form of cellular reprogramming known as trained immunity. “Trained immunity allows the innate immune system, which is the first line of defense against infections, to acquire a type of ‘memory’ of prior infections and trigger a more vigorous inflammatory response when another infection occurs,” says Dr. Petrof. “This is generally very useful, as it buys time for the adaptive immune system to kick in.”
This inflammatory response could be counterproductive, he cautions, in non-infectious inflammatory conditions. For example, exaggerated inflammation plays a major role in worsening muscular dystrophy, but its current therapy has very limited benefits and induces significant side effects. The study asked whether molecules released from chronically damaged muscles in muscular dystrophy could also induce trained immunity and thereby promote pathological inflammation.
“We found that in muscular dystrophy, macrophages show the classical elements of trained immunity, including epigenetic changes that can cause long-term maintenance of the abnormal inflammatory behaviour of these cells,” explains first author Salyan Bhattarai, PhD, a postdoctoral fellow supervised by Dr. Petrof.
“The features of trained immunity occur even before the cells invade the diseased muscles,” adds Salyan Bhattarai. “It appears that the chronic release of muscle damage molecules into the bloodstream is able to reprogram macrophage precursors in the bone marrow at a distance.”
“These findings could open the door to new therapies based on targeting of the epigenetic and metabolic mechanisms known to promote trained immunity, or by manipulation of innate immune system receptors,” says Dr. Petrof. “It will also be important to determine if trained immunity affects the efficacy of various gene therapy strategies currently under evaluation.”
About the study:
The study “TLR4 is a regulator of trained immunity in a murine model of Duchenne muscular dystrophy” was conducted by Salyan Bhattarai, Qian Li, Jun Ding, Feng Liang, Ekaterina Gusev, Orsolya Lapohos, Gregory J. Fonseca, Eva Kaufmann, Maziar Divangahi and Basil J. Petrof.
Read the publication in Nature Communications
The authors gratefully acknowledge support from the Canadian Institutes of Health Research.
February 15, 2022