Loss of Cxcr4 in Endometriosis Reduces Proliferation and Lesion Number while Increasing Intraepithelial Lymphocyte Infiltration.

Hyperactivation of the CXCL12-CXCR4 axis occurs in endometriosis; the therapeutic potential of treatments aimed at global inhibition of the axis was recently demonstrated. As CXCR4 is predominantly expressed on epithelial cells in the uterus, our aim was to explore the effects of targeted disruption of CXCR4 in endometriosis lesions. Uteri derived from adult female mice homozygous for a floxed allele of CXCR4 and co-expressing Cre recombinase under control of progesterone receptor were sutured onto the peritoneum of cycling GFP+ host mice. Four weeks post endometriosis induction the number of lesions that developed was found to be significantly lower in Cxcr4-conditional knockout lesions relative to that of controls (37.5% vs. 68.8% vs. respectively). In Cxcr4-knockout lesions that developed, reduced epithelial proliferation was associated with a lower ratio of epithelial to total lesion area compared to controls. Moreover, while in control lesions CD3+ lymphocytes were largely excluded from the epithelial compartment, in Cxcr4-knockout lesions CD3+ lymphocytes infiltrated the Cxcr4-deficient epithelium in the diestrus and proestrus stages. Our data demonstrate that local CXCR4 expression is necessary for proliferation of the epithelial compartment of endometriosis lesions, its absence compromising lesion numbers, and suggests a role for epithelial CXCR4 in lesion immune evasion.