Regulation of Lymphocyte Function by PPARgamma: Relevance to Thyroid Eye Disease-Related Inflammation

Abstract

Thyroid eye disease (TED) is an autoimmune condition in which intense inflammation leads to orbital tissue remodeling, including the accumulation of extracellular macromolecules and fat. Disease progression depends upon interactions between lymphocytes and orbital fibroblasts. These cells engage in a cycle of reciprocal activation which produces the tissue characteristics of TED. Peroxisome proliferator-activated receptor-gamma (PPARgamma) may play divergent roles in this process, both attenuating and promoting disease progression. PPARgamma has anti-inflammatory activity, suggesting that it could interrupt intercellular communication. However, PPARgamma activation is also critical to adipogenesis, making it a potential culprit in the pathological fat accumulation associated with TED. This review explores the role of PPARgamma in TED, as it pertains to crosstalk between lymphocytes and fibroblasts and the development of therapeutics targeting cell-cell interactions mediated through this signaling pathway.

Figure 1

According to one current model, TED is triggered by binding and activation of orbital fibroblasts by autoantibodies. These autoantibodies could be specific for antigens such as TSH-R and/or IGF-1R. Activated orbital fibroblasts release chemokines, including IL-16, RANTES, and CXCL10, which recruit T lymphocytes into the orbit. These lymphocytes then interact with fibroblasts, potentially activating each other, further promoting cytokine production (IFNγ, TNFα, PGD₂, and 15d-PGJ₂) and secretion of T cell-activating factors by the fibroblasts (IL-8 and CXCL10). Fibroblasts are also stimulated to secrete IL-6 (promoting B cell differentiation) and to increase autoantigen presentation, both of which amplify the overall response. The interactions of fibroblasts with T cells result in the deposition of extracellular matrix molecules, fibroblast proliferation, and fat accumulation.

Figure 2

T lymphocytes in TED patients express constitutively elevated levels of Cox-2, one enzyme critical to the production of the naturally-occurring PPARγ ligand 15d-PGJ₂. When these lymphocytes infiltrate the orbit, 15d-PGJ₂ is secreted in resident fibroblasts result in their differentiation into adipocytes.