Defining the role of monocytes and monocyte-derived macrophages in the pathophysiology of endometriosis to accelerate clinical translation
Lead Research Organisation:
University of Warwick
Department Name: Warwick Medical School
Abstract
Endometriosis affects approx. 190 million women worldwide and is associated with chronic debilitating pelvic pain and infertility. It is a common incurable disorder characterized by the growth of tissue like the lining of the womb (endometrium), outside the womb (as 'lesions'), most commonly on the lining of the abdominal wall. Currently, endometriosis is diagnosed by invasive surgery and is treated by surgical removal of lesions 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 non-invasive diagnostic approaches and treatments for endometriosis are desperately needed.
Why some women develop endometriosis is not well understood. However, immune cells called macrophages and their precursors (monocytes) are evidently linked with the disorder. For example, women with endometriosis develop low-grade systemic inflammation characterized by increased numbers of monocytes in circulating blood. The abdominal cavity and endometriosis lesions also contain increased numbers of monocytes and macrophages that promote the growth of lesions and contribute to generating pain by stimulating nerve growth and activation. 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 monocytes infiltrate tissues where they mature into macrophages and play roles vital in clearing cell debris and microbes as well as stimulating the immune system. Our work leading up to this proposal has identified that different 'types' of macrophages are present in the abdominal cavity and in lesions. Some promote lesion growth, whilst others protect the abdominal cavity from establishment of lesions. We propose that in women with endometriosis a defect must exist in the protective macrophages (monocyte-derived macrophages).
Our previous funding focused on using the mouse as a model. Now, we plan to use samples from women with endometriosis to validate our recent findings. We predict that monocytes and monocyte-derived macrophages are different in women with endometriosis and that we can exploit these differences to develop new, much needed diagnostic and therapeutic approaches.
Specifically, our objectives are:
1. To determine the gene expression profile and altered function of monocytes and monocyte-derived macrophages in the abdominal cavity of women with endometriosis compared to women without.
2. To identify unique genes on circulating blood monocytes that can be used as a new non-invasive diagnostic test for endometriosis.
We have assimilated an ideal team with the required expertise, methodology and equipment required to deliver this ambitious project that will significantly advance the field of endometriosis and bring us closer to development of a new non-invasive, non-hormonal medical 'immunotherapy' and a non-invasive diagnosis that could improve the lives of millions of women.
Why some women develop endometriosis is not well understood. However, immune cells called macrophages and their precursors (monocytes) are evidently linked with the disorder. For example, women with endometriosis develop low-grade systemic inflammation characterized by increased numbers of monocytes in circulating blood. The abdominal cavity and endometriosis lesions also contain increased numbers of monocytes and macrophages that promote the growth of lesions and contribute to generating pain by stimulating nerve growth and activation. 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 monocytes infiltrate tissues where they mature into macrophages and play roles vital in clearing cell debris and microbes as well as stimulating the immune system. Our work leading up to this proposal has identified that different 'types' of macrophages are present in the abdominal cavity and in lesions. Some promote lesion growth, whilst others protect the abdominal cavity from establishment of lesions. We propose that in women with endometriosis a defect must exist in the protective macrophages (monocyte-derived macrophages).
Our previous funding focused on using the mouse as a model. Now, we plan to use samples from women with endometriosis to validate our recent findings. We predict that monocytes and monocyte-derived macrophages are different in women with endometriosis and that we can exploit these differences to develop new, much needed diagnostic and therapeutic approaches.
Specifically, our objectives are:
1. To determine the gene expression profile and altered function of monocytes and monocyte-derived macrophages in the abdominal cavity of women with endometriosis compared to women without.
2. To identify unique genes on circulating blood monocytes that can be used as a new non-invasive diagnostic test for endometriosis.
We have assimilated an ideal team with the required expertise, methodology and equipment required to deliver this ambitious project that will significantly advance the field of endometriosis and bring us closer to development of a new non-invasive, non-hormonal medical 'immunotherapy' and a non-invasive diagnosis that could improve the lives of millions of women.
Technical Summary
Endometriosis is an enigmatic, incurable condition with insufficient therapeutic options. There is also no non-invasive diagnostic option for peritoneal endometriosis (most common form) and visualization of lesions at laparoscopy remains the gold-standard.
Monocytes and macrophages are intimately linked with the pathophysiology of endometriosis. In a mouse model of induced endometriosis, we have demonstrated diverse populations of macrophages that differentially impact lesion development, with a protective role for monocyte-derived large peritoneal macrophages (LpM). Thus, if monocyte-derived LpM are protective against the development of endometriosis, we postulate that a defect in monocytes / monocyte-derived macrophage function will be evident in women with endometriosis.
We will use single cell discovery and in vitro functional assays to phenotype and characterize peritoneal monocytes and macrophages and peripheral blood monocytes in women with endometriosis.
Our objectives are:
1. To use single cell (sc)RNA-seq and in vitro functional assays to define the phenotypic and functional adaptations of monocytes and monocyte-derived macrophages isolated from the peritoneal cavity of women with endometriosis.
2. To identify a unique expression signature on peripheral blood monocytes from women with endometriosis using scRNA-seq and evaluation for diagnostic potential in independent cohorts.
Monocytes and macrophages are intimately linked with the pathophysiology of endometriosis. In a mouse model of induced endometriosis, we have demonstrated diverse populations of macrophages that differentially impact lesion development, with a protective role for monocyte-derived large peritoneal macrophages (LpM). Thus, if monocyte-derived LpM are protective against the development of endometriosis, we postulate that a defect in monocytes / monocyte-derived macrophage function will be evident in women with endometriosis.
We will use single cell discovery and in vitro functional assays to phenotype and characterize peritoneal monocytes and macrophages and peripheral blood monocytes in women with endometriosis.
Our objectives are:
1. To use single cell (sc)RNA-seq and in vitro functional assays to define the phenotypic and functional adaptations of monocytes and monocyte-derived macrophages isolated from the peritoneal cavity of women with endometriosis.
2. To identify a unique expression signature on peripheral blood monocytes from women with endometriosis using scRNA-seq and evaluation for diagnostic potential in independent cohorts.