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Immunologic basis of fibrotic reactions in endometriosis: Role of KLF11

Mayo Clinic

Principal Investigator(s):

Khashayarsha Khazaie, PhD DSc / Zaraq Khan, MD

Institution: Mayo Clinic

Abstract:

Endometriosis is a common, systemic disease that is characterized by ectopic implantation of refluxed menstrual endometrium onto intraabdominal structures. The ectopic implants are associated with inflammation and prolific fibrosis that eventually obliterates all recognizable tissue planes between organs to result in a “frozen pelvis”. The immune mechanisms that propagate these inflammatory and fibrotic reactions are poorly understood, hindering effective treatment. TGFß signaling is commonly associated with both inflammation and fibrosis. Our earlier studies indicate that two highly homologous TGFβ regulated transcription factors KLF10 and KLF11 are involved in disease progression and fibrotic scaring.
To better understand the immunologic basis of fibrosis we generated novel mouse models by transplanting pieces of the uterus from KLF10 and KLF11 deficient mice into their peritoneal cavity. The KLF11 implants produced prolific fibrosis. Gene expression analysis of the implants confirmed the importance of the TGFß signaling pathway and provided unexpected insight into the simultaneous upregulation of inflammatory and anti-inflammatory pathways including IL1ß/inflammasome, IL17, and IL10. These findings urge identification of collagen secreting cells and molecular characterization of their responses to the immunologically active analytes. We will, therefore, test the hypothesis that a distinct population of fibroblasts/myofibroblasts unique to the endometrial tissue is responsible for hormone-dependent fibrosis, and that downregulation of KLF11 is a key event in facilitating collagen synthesis and secretion by these cells. We will test this as follows. 1. Determine the cellular sources of collagen using collagen reporter mice and define their role in local and distant fibrotic reactions in the experimental endometriosis lesions. 2. Define how KLF11 deficiency changes the composition and molecular profiles of collagen secreting cells, using single-cell RNA analysis. Validation of our mechanistic studies in human endometriosis will pave the way to targeted intervention.