Host immunity and KLF 11 deficiency together promote fibrosis in a mouse model of endometriosis.

Abstract

BackgroundEndometriosis is a debilitating disease typically characterized by prolific fibrotic scarring. Earlier we reported downregulation of two transcription factors belonging TGF-βR signaling pathway Sp/Krüppel-like factor 11 (KLF11) and 10 (KLF10) in human endometriosis lesions. Here we investigated the role of these nuclear factors and immunity in the scaring fibrosis associated with endometriosis. MethodsWe used a well characterized experimental mouse model of endometriosis. WT, KLF10 or KLF11 deficient mice were compared. The lesions were evaluated histologically, fibrosis was quantified with Masons' Trichome staining, immune-infiltrates were quantified by immunohistochemistry, peritoneal adhesions were score, gene expression was evaluated by bulk RNA sequencing. ResultsIntense fibrotic reactions and large changes in gene expression were detected in KLF11 deficient implants associated with squamous metaplasia of the ectopic endometrium, as compared to KLF10 deficient or WT implants. Fibrosis was mitigated with pharmacologic agents that blocked histone acetylation or TGF-βR signaling or with genetic deficiency for SMAD3. The lesions were richly infiltrated with T-cells, regulatory T-cells, and innate immune cells. Fibrosis was exacerbated when implants expressed ectopic genes implicating autoimmunity as a major factor contributing to the scaring fibrosis. ConclusionsOur findings identify KLF11 and TGF-βR signaling as cell intrinsic mechanisms and autoimmune responses as cell extrinsic mechanisms of scaring fibrosis in ectopic endometrium lesions. General significanceImmunological factors associated with inflammation and tissue repair drive scaring fibrosis in experimental endometriosis, providing the rationale for immune therapy of endometriosis.