Scientists are now closer to understanding pain mechanisms in endometriosis

Scientists at the University of Warwick and the University of Edinburgh in the UK have shown that immune cells called macrophages could play a key role in the generation of pain in endometriosis.

Macrophages are present in all tissues of the body and play diverse roles in maintaining tissue homeostasis, developmental and repair processes, as well as responding to infection and inflammation.

Green cells are macrophages in endometriosis lesions. Image from: Greaves et al, Am J Pathol 2015

Macrophages are found in high numbers inside endometriosis lesions and in the peritoneal fluid of women with endometriosis. They become modified by disease and, in endometriosis, it is thought that the cells act as though they are repairing a ‘wound’. Instead of trying to clear the ectopic tissue they activate processes that encourage the growth of lesions and infiltration of blood vessels.

In this study the research team used behaviour assessments in a mouse model of induced endometriosis. They found that pain related behaviours were significantly reduced when there were less macrophages in the model, indicating that macrophages are important in generating pain in endometriosis.

Nerves and endometriosis

Nerves grow into the endometriosis lesions and this is thought to be a key contributor to pain in the condition (because the nerves can then be activated by factors inside the lesions which causes a pain response).

Macrophages (red) and nerve fibres (green) in endometriosis lesions.
Image from: Greaves et al, Am J Pathol 2015

To explore the possible factors that macrophages might produce to cause pain, the research team looked at different factors that promote nerve growth in a disease model of endometriosis-like macrophages.

Macrophages change the way they act in response to local signals so the research team exposed healthy human macrophages to peritoneal fluid from women with endometriosis. In response they produced high levels of insulin-like growth factor-1 (IGF-1).

They verified the expression of IGF-1 by macrophages in thin slices of lesions from women with endometriosis and in the lesions recovered from the mouse model. IGF-1 was also decreased in the peritoneal environment when macrophages were depleted.

Relevance to women with endometriosis

Next, the research team investigated how relevant these finding might be in women with endometriosis. They found that IGF-1 was increased in the peritoneal fluid of women with endometriosis and that levels were higher in women that reported higher levels of pain.

The effect that IGF-1 produced by macrophages has on nerve cells was then evaluated. The team found that in rat nerve cells, macrophage-derived IGF-1 increased growth. Furthermore, in a human model of sensory neurons (derived from stem cells) genes important for pain processing were increased by the presence of macrophage-derived IGF-1.

In the final experiment the research group inhibited the receptor for IGF-1 in the mouse model of endometriosis. This approach also caused a reduction in pain-related behaviours.

What does it all mean and how close are we to a treatment?

Macrophages are associated with pain in a mouse model of induced endometriosis. Using different cell models, as well as some samples from women with endometriosis, we can conclude that the increased levels of IGF-1 produced by macrophages in endometriosis can increase the growth of nerves into the lesions as well as increase the expression of genes important for pain processing (which can make nerves more sensitive).

Assistant Professor Erin Greaves, University of Warwick

Research team leader Erin Greaves, from the University of Warwick, said:

We have shown that macrophages are central to pain in endometriosis BUT we have not found the cause of endometriosis and we have certainly not found a cure.

Our work has added to our knowledge regarding the role of macrophages in endometriosis, but we still need to find out more about how macrophages in endometriosis differ from healthy macrophages. Only then can we begin to find ways of targeting ‘disease-promoting’ macrophages in endometriosis.

This research was funded by the Medical Research Council.

Reference

Forster R, et al. Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis. FASEB J 2019 doi: 10.1096/fj.201900797R

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