Investigating the Role of Neutrophils in Endometriosis Pathophysiology
Endometriosis is a debilitating gynecological disease characterized by the presence of endometrial-like tissue lesions outside of the uterus. Chronic inflammation is a hallmark feature of endometriosis, which has been observed in the form of elevated cytokines, chemokines, and immune cell populations such as neutrophils within the systemic circulation and peritoneal fluid of endometriosis patients. However, whether and how neutrophils actively contribute to endometriosis pathophysiology have remained poorly understood. With emerging roles for neutrophils in chronic and sterile inflammatory processes, we sought to provide in-depth characterization of neutrophil involvement in endometriosis using patient specimens and an established mouse model. We demonstrated that neutrophils reside within patient ovarian endometriotic lesions and that patient lesions possess elevated expression of various factors known to influence neutrophil recruitment and function. We also provided first evidence that systemic circulating neutrophils from endometriosis patients display unique transcriptomic differences compared to healthy control neutrophils. Through extensive time-course characterization of our syngeneic, immunocompetent mouse model of endometriosis, we revealed that neutrophils are rapidly recruited to the peritoneal environment early after surgical endometriotic lesion establishment and remain present in murine lesions long term. Furthermore, neutrophil recruitment was associated with elevated peritoneal fluid and systemic chemokines, inflammatory cytokines, and pro-angiogenic mediators. In vivo neutrophil depletion altered the peritoneal and systemic immune microenvironment of endometriosis mice as demonstrated by alterations in inflammatory cytokines and a reduction in the pro-angiogenic vascular endothelial growth factor. Taken together, these findings highlight a novel dimension for neutrophils in early events such as modulation of the local inflammatory environment and angiogenesis associated with development of endometriotic lesions.