The effect of macrophages on fibroblast activity and lesion development in mouse models of endometriosis.

M. Zahied Johan
2014 · W2586909760
dissertation OA: green CC0
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Endometriosis-like lesion development in mice was suppressed by host TGFB1 deficiency, reducing macrophages, myofibroblasts, and collagen, while macrophages shifted from inflammatory to tissue-repair phenotypes during lesion progression.

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Abstract

Endometriosis is a gynaecological disease characterised by the growth of endometrial tissues at ectopic sites. Although this disease affects 10-15% of women worldwide, its pathogenesis is still poorly understood. Human eutopic endometrial tissues were xenografted into two strains of immunodeficient (SCID) mice with 1) a null mutation for Tgfb1 gene (Tgfb1-/-) and 2) macrophage-restricted expression of GFP (CSF-1R-eGFP/MacGreen). The resulting xenografts were collected at day 10 post-implantation for Tgfb1-/- mice and at days 4, 7, 10 and 14 in a time course study using MacGreen mice. Five xenografts collected from Tgfb1-/- mice were embedded in paraffin and were compared to Tgfb1+/+ tissues for macrophage number, myofibroblast staining (αSMA), proliferating cell number and blood vessel density. Another five xenografts from Tgfb1-/- mice and all xenografts from MacGreen mice were frozen in OCT to assess macrophage markers, MHC class II, iNOS, arginase 1 and scavenger receptor A, and collagen type 1. Using Tgfb1-/-/SCID mice, we demonstrated that in the absence of host TGFB1, development of endometriosis-like lesions was suppressed and their glandular area was reduced. We also observed lower numbers of macrophages and a reduced density of myofibroblasts in the lesions from Tgfb1-/- mice. Using MacGreen/SCID mice, we followed the changes in macrophage phenotypes during endometrial xenograft development. Macrophages were phenotypically diverse and pre-dominantly expressed the inflammatory markers MHC class II and iNOS at the early stage of disease development (days 4 and 7). The tissue repair marker, arginase 1, appeared later in lesion development at day 7. Meanwhile, another macrophage marker for tissue healing, scavenger receptor A was higher at day 14 than at the earlier time point. In addition, collagen type 1 staining increased throughout lesion development with its highest intensity evident at day 14. In the absence of host TGFB1, the number of cells expressing MHC class II was significantly reduced at day 10 compared to the lesions from the wildtype controls. Similarly, iNOS-positive cells were decreased in lesions from Tgfb1-/- mice. The number of arginase 1-positive cells was not altered in the lesions from Tgfb1-/- mice, suggesting TGFB1 was not critical for arginase 1 expression in these tissues. The abundance of cells expressing scavenger receptor A was significantly reduced in lesions from Tgfb1-/- mice. A reduction in the collagen type 1 density was detected in the lesions which developed in a TGFB1-deficient environment. These studies show that host-derived TGFB1 is critical during endometriosis-like lesion development. The presence of this cytokine altered the abundance of infiltrating macrophages and myofibroblasts. In a time course study, macrophages shifted from inflammatory phenotypes at the early stage to an alternatively activated phenotype associated with tissue healing at later stages. The secretion of collagen type 1 fibres was increased and this was associated with the transition to a remodelling macrophage population. Lesion development appeared to be interrupted when lesions were grown in a TGB1-deficient environment resulting in diminished lesion weight. The understanding behind macrophage activation in endometriotic lesions may provide new information on how endometriosis may be interrupted by moderating macrophage behaviours.

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endometriosis

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