Abstract
Inflammation and remodelling of orbital tissue associated with enhanced adipogenesis commonly occur in Graves’ ophthalmopathy (GO), however, the underlying mechanisms that link immune cells and adipocytes in orbital inflammation are not well-known. The primary aim of this study was to elucidate how a genetically determined shift in the T-cell repertoire toward self-reactive T-cells could drive orbital adipogenesis. To induce the T-cell-mediated autoimmune response, SKG mice were intraperitoneally injected with zymosan A once at 8 weeks of age. After three months, orbital magnetic resonance imaging (MRI), histopathologic studies, and in vitro analyses were performed to evaluate inflammation and adipogenesis. The eyes of the zymosan A-treated SKG mice displayed proptosis and blepharitis. A detailed analysis of orbital adipose tissue showed enhanced orbital adipogenesis and cellular infiltration compared to controls. In addition, increased secretion of adipokines and other cytokines in the periorbital tissue was observed, together with elevated serum concentration of inflammatory cytokines. Orbital adipogenesis was enhanced in zymosan A-treated SKG mice, a novel mouse model for GO-like inflammatory adipose phenotypes most likely induced by T-cell mediated autoimmune responses. This mouse model gives us the opportunity to examine the underlying molecular mechanisms of enhanced adipogenesis in GO, ultimately providing a potential therapeutic target alternative to conventional GO treatment.
Highlights
Graves’ ophthalmopathy (GO) is defined as autoimmune inflammatory disorder involving the orbit and periorbital tissues, related to the systemic autoimmune process underlying Graves’ disease[1]
These findings indicate that zymosan A treatment in SKG mice induces blepharitis and proptosis, which are similar to GO phenotypes
We demonstrate that induction of T-cell-mediated autoimmune response in zymosan A-treated SKG mice results in enhanced orbital adipogenesis
Summary
Graves’ ophthalmopathy (GO) is defined as autoimmune inflammatory disorder involving the orbit and periorbital tissues, related to the systemic autoimmune process underlying Graves’ disease[1]. Glucocorticoids and orbital radiotherapy only reduce inflammatory signs and symptoms in patients in active phase of GO, minimally affecting proptosis and occasionally causing dose-limiting www.nature.com/scientificreports side effects[6] This unfulfilled medical need is resulting from the poorly understood underlying mechanisms of the disease; periorbital tissues in GO patients can be obtained only during the chronic phase of the disease because surgical decompression of the orbit is usually performed at that phase. A previous study using blood samples of patients with Graves’ disease reported that a single nucleotide polymorphism within the lymphoid tyrosine phosphatase (LYP), a potent inhibitor of signal transduction and activation of T-cells, had a highly significant association with Graves’ disease compared to healthy controls[10] Considering these interesting reports, we decided to evaluate whether zymosan A-treated SKG mice exhibited GO phenotypes, and if so, the precise molecular mechanism underlying the enlargement of orbital fat
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