Identifying disease promoting macrophages and tissue-identity in endometriosis

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Endometriosis affects 176 million women worldwide and is associated with debilitating pelvic pain and/or infertility. Endometriosis is defined by the presence of tissue similar to womb lining (endometrium) outside the womb (lesions), most commonly on the wall of the pelvic cavity. Endometriosis is currently treated by invasive surgery or with drugs that suppress sex hormones. Sadly, in many women symptoms recur after surgery and available medical treatments have undesirable side-effects and are contraceptive. New treatments for endometriosis are desperately needed. Why some, but not all, women with endometriosis develop debilitating symptoms is unknown. What we do know is that endometriosis lesions contain nerves and have high numbers of immune cells called 'macrophages' within them. Macrophages are known to adapt their function depending upon the tissues in which they exist and several types have been identified. Long-lived 'tissue-resident' macrophages maintain normal tissue function. In contrast, during inflammation or following injury immature 'macrophages' called monocytes infiltrate tissues where they mature into macrophages (monocyte-derived macrophages) and play roles vital in clearing cell debris and microbes as well as stimulating the immune system.In endometriosis, macrophages play an essential role in controlling the growth of lesions and regulating the infiltration of blood vessels. Using an experimental mouse model of endometriosis, we have shown that macrophages can regulate the infiltration of nerves into lesions and play an important role in generating a pain response. Currently, we do not know if different 'types' of macrophages exist in endometriosis lesions or if a specific type promotes disease. If we can identify the 'type' of macrophage that drives the disease we could target it without affecting 'good' macrophages elsewhere in the body and develop new treatments for endometriosis that do not involve surgery or hormonal manipulation and associated side-effects. Our preliminary data shows that macrophages in lesions have different origins: the endometrium shed from the uterus, the fluid lubricating the pelvic cavity, and others are monocyte-derived (from blood). Our latest findings suggest that amongst these there are multiple different 'types' of macrophages and we believe these different macrophages play distinct roles in endometriosis. In this project, we will identify which macrophages drive the disease. We also aim to define what it is about the lesion that can cause macrophages to change into a type of macrophage that supports and increases the severity of the disease.We will initially use our laboratory mouse model of endometriosis and extend our findings using biopsies from women with endometriosis. Our objectives are:1. To determine how many different 'types' of endometriosis macrophages exist and determine the genetic 'signature' of each population 2. To identify where macrophages in endometriosis lesions come from and what happens to them (do they multiply, die or change 'type')3. To determine which 'type' of macrophage promotes endometriosis4. Identify what it is about endometriosis lesions that create a pro-disease 'type' of macrophage. Our world-class research environment, clinical resources and experienced team of investigators means we are uniquely placed to exploit new methods that will allow us to identify the disease causing 'type' of macrophages in this debilitating disorder and develop new therpeutic interventions.