Peroxisome Proliferator-Activated Receptor δ Regulates Inflammation via NF-κB Signaling in Polymicrobial Sepsis

Abstract

The nuclear peroxisome proliferator-activated receptor δ (PPARδ) is an important regulator of lipid metabolism. In contrast to its known effects on energy homeostasis, its biological role on inflammation is not well understood. We investigated the role of PPARδ in the modulation of the nuclear factor-κB (NF-κB)-driven inflammatory response to polymicrobial sepsis in vivo and in macrophages in vitro. We demonstrated that administration of GW0742, a specific PPARδ ligand, provided beneficial effects to rats subjected to cecal ligation and puncture, as shown by reduced systemic release of pro-inflammatory cytokines and neutrophil infiltration in lung, liver, and cecum, when compared with vehicle treatment. Molecular analysis revealed that treatment with GW0742 reduced NF-κB binding to DNA in lung and liver. In parallel experiments, heterozygous PPARδ-deficient mice suffered exaggerated lethality when subjected to cecal ligation and puncture and exhibited severe lung injury and higher levels of circulating tumor necrosis factor-α (TNFα) and keratinocyte-derived chemokine than wild-type mice. Furthermore, in lipopolysaccharide-stimulated J774.A1 macrophages, GW0742 reduced TNFα production by inhibiting NF-κB activation. RNA silencing of PPARδ abrogated the inhibitory effects of GW0742 on TNFα production. Chromatin immunoprecipitation assays revealed that PPARδ displaced the NF-κB p65 subunit from the κB elements of the TNFα promoter, while recruiting the co-repressor BCL6. These data suggest that PPARδ is a crucial anti-inflammatory regulator, providing a basis for novel sepsis therapies.

Integrative “Omic” Analysis of Experimental Bacteremia Identifies a Metabolic Signature That Distinguishes Human Sepsis from Systemic Inflammatory Response Syndromes

“…We found three PPAR-related transcription factors along with THRA1 and the apoptosis-inducing gene FOXO3 correlated with many of these significantly increased b-oxidation and peroxidation metabolites. Although untested here, we hypothesize PPAR agonists improve survival in septic mice (43)(44)(45)(46) because of mitochondrial biogenesis leading to increased transcription of b-oxidation and BCAAdegradation associated genes. However, it should be noted that PPAR antiinflammatory effects have also been attributed to improved survival, and therefore links to mitochondrial function remains unclear.…”

Peroxisome proliferator-activated receptor delta and cardiovascular disease

“…However, in vivo studies by Lee et al showed that bone marrowed derived macrophages from Ppard deficient mice had reduced expression of pro-inflammatory factors such as Mcp-1 and Il-1β [22]. Conversely, the mouse macrophage cell line (RAW 264.7) stably overexpressing Ppard expressed higher levels of Mcp-1 and Il-1β than control cells suggesting that Ppard has pro-inflammatory effects although treatment with PPARD agonists have anti-inflammatory effects [22,33,34]. The underlying mechanism for these observations is that Ppard forms a complex with the inflammatory suppressor protein B cell lymphoma-6 (Bcl-6).…”

“…In the presence of ligand, Ppard releases Bcl-6, which is then free to exert its anti-inflammatory effects [22]. In addition, activation of Ppard induces the expression of genes that dampen chemokine receptor signaling and inflammatory mediators such as Tnfα [34,35]. Thus, Ppard appears to control the inflammatory status of the macrophage (Table 1) [22].…”

“…The anti-inflammatory effects of PPARD agonists in macrophages have been shown by several groups. In mouse peritoneal or murine J774.A1 macrophages treated with the inflammatory activator lipopolysaccharide, GW0742 reduced the expression of proinflammatory cytokines such as inducible nitric-oxide synthase, cyclooxygenase 2 and Tnfα [33,34]. The reduction of TNFα production was due to a direct inhibition of NF-κB transactivation [34].…”

“…In mouse peritoneal or murine J774.A1 macrophages treated with the inflammatory activator lipopolysaccharide, GW0742 reduced the expression of proinflammatory cytokines such as inducible nitric-oxide synthase, cyclooxygenase 2 and Tnfα [33,34]. The reduction of TNFα production was due to a direct inhibition of NF-κB transactivation [34]. However, in vivo studies by Lee et al showed that bone marrowed derived macrophages from Ppard deficient mice had reduced expression of pro-inflammatory factors such as Mcp-1 and Il-1β [22].…”