What Does Galectin-3 Do?
Galectin-3 is secreted by macrophages. Macrophages are versatile cells that play many roles in defending our body in response to injury or infection. Macrophages are found in tissues and in blood. They migrate to areas in the body where they are needed. Macrophages need to be activated by injury or infection to secrete galectin-3.
When macrophages are activated and secrete galectin-3 in the space around cells they activate fibroblasts and start the formation of fibrosis. Galectin-3 stimulates and regulates the fibrosis forming in a number of ways. Although galectin-3 was found to be associated with other effects, the fibrosis forming is believed the be the most important effect of galectin-3. Fibrosis is thickening and scarring of tissue, often replacing or impairing the function of the tissue where this occurs. With the fibrosis also comes a stiffening and hardening of the organ.
The fibrous changes in organs following injury should not be confused with connective tissue. Connective tissue is made of the same or similar fibrous material, but is formed as part of normal development or functioning. This normal connective tissue is not galectin-3 dependent as illustrated by animal experiments with animals that do not have the galectin-3 gene and hence cannot produce galectin-3. These animals have a normal appearance and function normally. They can successfully reproduce and have normal organ weights. In summary, galectin-3 is not involved with development of fibrous connective tissue, but regulates and promotes the formation of organ fibrosis in places where it is produced in response to injury or inflammation.
Macrophages are migratory cells that can reach any organ and it is probably safe to say that galectin-3 mediated effects have been found in every organ where it was investigated. Macrophage activation that stimulate galectin-3 dependent fibrosis may occur as a result of injury, inflammation or hormones, such as aldosterone. There is a complex interplay between the factors that stimulate it, but ultimately galectin-3 secretion is required for the diffuse organ fibrosis to occur.
The Galectin-3 Paradox Explained
Galectin-3 appears to be a critical regulator of tissue fibrosis in response to injury while at the same time absence of galectin-3 or suppression by therapy seems to be without adverse effects. How can galectin-3 be critical for an important process while there appear to be no consequences of its absence? The explanation is that the process has largely lost its relevance.
Galectin-3 is well preserved throughout evolution. The simple roundworm (C. elegans) relies on galectin-3 to create and maintain its fibrous outer layer. Animals (including humans) require galectin-3 to seal off areas that sustained massive injury. For example, a limb could be ripped off and an animal could be saved with the help of galectin-3-mediated rapid formation of a massive fibrotic sheet to seal of the injured area.
Humans have reached a stage in evolution where this biological process has now turned mostly harmful. Massive injury is no longer left to natural healing but treated surgically. However galectin-3-mediated organ fibrosis can be triggered by smaller injuries, such as heart attack, hypertension, or chronic infection. The heart attacks offers a clear example – the heart attack injures the heart muscle, a local repair mechanism heals the damaged area but in some individuals a delayed more diffuse galectin-3 mediated fibrotic reaction may occur that limits the function of the heart and in doing so causes heart failure to occur. Secondarily galectin-3 levels in the blood may rise and secondarily involving other organs, such the kidney and the lung.
Although every analogy has its shortcoming, there is an analogy to how in ancient times storages of excess consumed energy in body fat was very valuable when individuals needed to survive harsh winters or nurse infants in periods when food was scarce, while the same energy-storage function in the body has now turned harmful. For most individuals around the world it would be better if excess calorie intake would be excreted in the urine – not stored in fat tissues. Hence a biological function that was extremely valuable throughout evolution has lost its benefits in modern times and is now a major cause of morbidity and mortality. The same can be said for the galectin-3 mediated response to injury.