Inflammation – sometimes a good thing

(When it produces insulin-like growth factor-1)
by Guest Writer, Michael Todd Sapko, MD, PhD

Researchers from the Cleveland Clinic and University of California, San Francisco have demonstrated something that may sound counterintuitive: sometimes, inflammation is a good thing. In fact, in the case of damaged muscle, this study shows that inflammation is a critical part of the healing process. Without inflammation, damaged muscle does not regenerate nearly as well. Moreover, these researchers showed that a substance called insulin-like growth factor-1 is critical to muscle regeneration.

How does one stop inflammation?

Experimentally demonstrating the critical importance of inflammation in muscle regeneration is no small feat. For example, how do you block inflammation? One could use anti-inflammatory drugs, but even then the inflammatory process is inhibited, rather than stopped. Dr. Lu and colleagues used a very special mouse, called a knockout mouse, to turn off inflammation. Knockout mice are genetically engineered to lack a specific gene. In this case, mice were engineered to lack the gene that codes for a protein called CC Chemokine receptor 2 or CCR2. That means these mice grow up without making the protein CCR2.

Before you think to yourself “so what?” you should know that CCR2 is a pretty important protein. While it might not sound very impressive, not having CCR2 is a bad situation for these special mice. If you damage their muscles experimentally, say by depriving the muscles of oxygen or injecting them with a toxin that kills muscle cells, they cannot mount an inflammatory response like normal mice would. Because they do not have CCR2, injured muscle is unable to recruit immune system cells called macrophages. Macrophages are the cleanup crew of the body. They “eat” dead cells and dying tissue (like dead muscle cells). It has been speculated that macrophages also release other factors that promote muscle regeneration.

A mouse without an inflammatory response

In the experiment, scientists injured muscles in normal (wild type) mice and CCR2 knockout mice with barium salt solution. They allowed the mice time to heal, including time for the inflammatory process and muscle regeneration to take place. As expected, knockout mice had essentially no inflammation present. This is mainly because the cleanup crew (a legion of macrophages) was never called to the scene. Likewise, knockout mouse muscle did not regain its pre-injury size and remained smaller than normal mouse muscle.

Three days after the injury, the researchers noticed that macrophages called to the scene in normal mice excreted large amounts of a substance called insulin-like growth factor-1 or IGF-1. Since there were no macrophages recruited in knockout mouse muscle (How could they? They do not have CCR2 receptors), IGF-1 levels in those mice stayed low. Could IGF-1 be playing a role in muscle regeneration after injury?

The most extraordinary finding of the paper was that when IGF-1was injected into the injured muscle of knockout mice, even though they still had no macrophages present, muscle regeneration was nearly completely restored.In other words, IGF-1-treated CCR2 knockout mice were able to regenerate their muscles even though inflammation did not recruit macrophages to the injured muscle.

Macrophages are recruited during inflammation and release a key healing substance: IGF-1

Taken together, this is extremely strong evidence that macrophages must respond to the site of muscle injury for normal muscle healing and regeneration. In addition, the key substance released by these responding macrophages is IGF-1. Therefore, IGF-1 plays an integral role in muscle healing and regeneration.As the authors conclude in their paper, IGF-1 may represent a clinically useful tool to promote acute skeletal muscle injury repair.

How can we apply the results of this research right now?

For years we have been told that first aid for a muscle injury is RICE: Rest, Ice, Compression, Elevation. However this research suggests that applying ice and other anti-inflammatory interventions may be the exactly wrong thing to do after an acute injury. Swelling and pain can be very disconcerting for patients and using RICE can shorten both the duration of swelling and pain, which is probably why it has been traditionally used.However ice and anti-inflammatory drugs like NSAIDs block the inflammatory response. They slow the recruitment of macrophages to the site of injury and, as such, those macrophages cannot release IGF-1 into the affected tissues.

While ice and NSAIDs may make you feel better after an injury, by using those agents, you are preventing the body from repairing itself. At best, this greatly prolongs healing. At worst, you may not regain the full potential of that injured muscle. Resting an injured muscle (temporarily) is still sound advice, but now we know that it is best to skip the ice.

1.    Lu H, Huang D, Saederup N, Charo IF, Ransohoff RM, Zhou L. Macrophages recruited via CCR2 produce insulin-like growth factor-1 to repair acute skeletal muscle injury. FASEB J. Jan 2011;25(1):358-369.