Immune disturbance caused by PPARγ deficiency

Abstract

Metabolism and autoimmune disease have experienced a dramatic increase in industrialized countries. A common factor regulating both metabolic and autoimmune balance is suggested. PPARγ is a nuclear transcription factor that modulates diverse functions, including lipid biosynthesis, glucose metabolism and inflammation. However, its specific role in the balance of immunity in vivo has not been fully explored. PpargC/- mice expressing PPARγ at 25% normal level exhibited higher levels of autoantibodies and developed lupus nephritis, resembling the development of a lupus-like autoimmune syndrome by 14 months of age. These symptoms are preceded by splenomegaly in the early age, which is associated with increases of splenocyte accumulation and B-cell activation, but not relocation of hematopoiesis to the spleen. Reduced expression of sphingosine-1-phosphate receptor 1 (S1P1) and diminished migration toward S1P in the PpargC/- splenocytes supports the hindrance of lymphocyte egression as a mechanism for their accumulation. Mechanistically, increased Th17 polarization and IL-17 signaling in the PpargC/- CD4+ T-cells contributed to the B-cell hyper-activation in the spleen. Finally, activation of the remaining PPARγ in PpargC/- mice by pioglitazone increased S1P1 level, decreased Th17 population in the spleen, and ameliorated splenomegaly. Together, our data demonstrate that reduction of Pparg expression in T-helper cells is a critical factor for spontaneous lupus-like autoimmune diseases and define a novel role of PPARγ in lymphocyte trafficking and crosstalk between Th17 and B-cells.

Date of Award	2015
Original language	English
Supervisor	Pei-Jane Tsai (Supervisor)