Recent data indicate that PPARγ and PPARδ are critical transcriptional ‘gatekeepers’, i.e. they control transcriptional modules that influence macrophage phenotype. PPAR activation inhibits the expression of M1 genes in cells exposed to M1-type stimuli and enhances the expression of M2 markers in the presence of M2 stimuli. In particular, activation of these PPARs in macrophages induces the M2 markers Arg1, CD206, YM1 and FIZZ1; these effects are lost in mice deficient for either receptor (Bouhlel et al., 2007; Odegaard et al., 2007, 2008; Gallardo-Soler et al., 2008; Kang et al., 2008). PPAR activation produces similar effects in microglia (Storer et al., 2005a; Xu et al., 2005b; Ramanan et al., 2009; Antonietta Ajmone-Cat et al., 2012). For instance, PPAR activation of microglia promotes phagocytosis of pathological protein aggregates and is neuroprotective in models of MS and Alzheimer's disease (Mandrekar-Colucci et al., 2012; Yamanaka et al., 2012). Activation of all three PPAR isoforms inhibits NF-κB (nuclear factor κB)-mediated induction of inflammatory cytokine genes (Chawla, 2010). PPARγ achieves this through ligand-activated sumolyation of the receptor, which then binds to and stabilizes the interaction between NF-κB and its co-repressor complex, thereby preventing the transcription of inflammatory cytokines (Pascual et al., 2005).
