PPAR-𝛾: Therapeutic Potential for Multiple Sclerosis

Figure 1

Effects of PPAR-γ on immune cell function. Glial cells including microglia and astrocytes may become activated in response to inflammatory stimuli including stress, trauma, and pathogens. Upon activation, microglia, and astrocytes produce a wide range of cytokines as well as NO. These molecules may be toxic to CNS cells, including myelin-producing oligodendrocytes and neurons, which are compromised in the course of MS. PPAR-γ agonists block the activation of glial cells resulting in repression of production of cytokines and NO, and protect oligodendrocytes and neurons from the toxic effects of these molecules. PPAR-γ agonists can also directly protect neurons from a variety of neurotoxic agents including NMDA and apolipoprotein E4. Chemokines secreted by activated glia cells establish a concentration gradient to which target cell populations migrate, and play important roles in recruiting cells into inflammatory sites in the CNS. PPAR-γ agonists may regulate the extravasation of peripheral immune cells into the CNS by suppressing chemokine expression. In addition, activated microglia serve as the major antigen-presenting cells (APCs) in the CNS, and dendritic cells and macrophages serve as APCs in the periphery. These APCs are capable of secreting IL-12 family cytokines upon activation. IL-12 and IL-23 play a critical role in the development of Th₁ and TJ₂ cells. PPAR-γ agonists may inhibit Th₁ and Th₁₇ cell production by repressing IL-12 family cytokine secretion by these APCs, which is believed to protect against EAE/MS.