#apaperaday: Macrophage plasticity in Duchenne muscular dystrophy: a nexus of pathological remodelling with therapeutic implications

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Macrophage plasticity in Duchenne muscular dystrophy: a nexus of pathological remodelling with therapeutic implications.

A review by Petrof et al from the journal of physiology on the involvement of the macrophage in Duchenne pathology. DOI: 10.1113/JP281673. Due to lack of dystrophin Duchenne patients and animal models have chronic damage in the skeletal muscle, resulting in chronic inflammation. The inflammation is a driver of pathology and this was one of the reasons to try corticosteroid treatment (inhibits inflammation).

Indeed corticosteroid treatment slows down disease progression and is now part of the standards of care. Here the focus of the review is on the macrophage involvement in the inflammatory response. In healthy muscle macrophages are crucial for repair of injury.

There are two types of macrophages: M1 and M2. M1 is the pro-inflammatory macrophage that plays a role in clearing the damage, while M2 is anti-inflammatory and plays a role in repair, e.g. by driving the production of connective tissue that surrounds muscle fibers.

Normal tissue repair is a streamlined process where M2 follows M1 activity. However, when damage is chronic, things will go wrong, because there is too much ‘clearing of tissue’ (more damage) and too much making of connective tissue (fibrosis). So too much of both M1 and M2.

The macrophages in the muscle derive from 2 different origins: they can come from the bone marrow, where monocytes are attracted by the damage and migrate into the muscle, and they can come from resident macrophages that were established during embryonic development.

The CCR2 receptor (chemokine receptor 2) plays a role in recognizing injury and without this receptor, monocytes will not migrate into the muscle. How does injury activate the immune system? This occurs via DAMP: damage associated molecular patterns.

When tissue is damaged, ‘stuff’ that normally should not be present is present for immune cells, e.g. DNA. These patterns are recognized by toll-like receptors. For muscle damage TLR2 and TLR4 are involved in recruiting macrophages.

Note that this is the same mechanism through which ASOs and siRNAs can trigger an immune response (TLR9 and TLR7 respectively). The ASOs and siRNA are not the consequence of damage, and also are not part of any bacteria or virus, but the system does not know that.

Finally the author outlines the concept of trained immunity, which was found in mice and may also occur in humans. Due to chronic inflammation the immune cells will have epigenetic changes, through which they are more ‘trigger happy’ to react to even mild stimuli.

Even though I do not like macrophages, I do like the review. It is well written and clearly explains things even for the non initiated. It stresses that the situation is more complex and that a lot of aspects interplay, but it gives enough information to grasp the main mechanisms.