Balance of proliferation and cell death between thyrocytes and myofibroblasts regulates thyroid fibrosis in granulomatous experimental autoimmune thyroiditis (G-EAT)

Abstract

Severe granulomatous experimental autoimmune thyroiditis (G-EAT), which progresses to fibrosis, is induced in DBA/1 mice by adoptive transfer of mouse thyroglobulin-primed and -activated spleen cells. There is extensive destruction of thyrocytes and inflammatory cell infiltration including T cells, macrophages, neutrophils, and myofibroblasts (myofbs). Suppression of transforming growth factor-beta (TGF-beta) and deficiency of interferon-gamma (IFN-gamma) inhibit fibrosis, and inflammation eventually resolves. Thyrocyte destruction in wild-type (WT) mice was a result of apoptosis, as many deoxynucleotide triphosphate nick-end labeling + apoptotic thyrocytes were present in these thyroids. The balance of apoptosis and proliferation between thyrocytes and myofbs may be important factors determining the outcome of inflammation to fibrosis versus resolution. Apoptosis and proliferation in thyrocytes versus myofbs were evaluated by dual-staining of cell-proliferating marker (Ki-67) or in situ cell death and cytokeratin or alpha-smooth muscle actin and were analyzed by confocal microscopy. Apoptotic and antiapoptotic molecules in G-EAT thyroids were detected by immunostaining. In WT thyroids, which develop fibrosis, only a few myofbs were apoptotic, and many myofbs were Ki-67+, Fas-associated death domain protein-like interleukin-1beta-converting enzyme-like inhibitory protein (FLIP)+, and Bcl-XL+. In contrast, proliferation was predominant on thyrocytes of IFN-gamma-/- mice or anti-TGF-beta-treated WT mice. These results indicate that apoptosis of inflammatory cells and regeneration of thyrocytes in IFN-gamma-/- mice and anti-TGF-beta-treated WT mice may limit development of fibrosis, whereas excessive proliferation of myofbs and loss of thyrocytes in WT mice may contribute to fibrosis.