PPARγ Deficiency Suppresses the Release of IL-1β and IL-1α in Macrophages via a Type 1 IFN–Dependent Mechanism

Abstract

Obesity and diabetes modulate macrophage activation, often leading to prolonged inflammation and dysfunctional tissue repair. Increasing evidence suggests that the NLRP3 inflammasome plays an important role in obesity-associated inflammation. We have previously shown that activation of the lipotoxic inflammasome by excess fatty acids in macrophages occurs via a lysosome-dependent pathway. However, the mechanisms that link cellular lipid metabolism to altered inflammation remain poorly understood. PPARγ is a nuclear receptor transcription factor expressed by macrophages that is known to alter lipid handling, mitochondrial function, and inflammatory cytokine expression. To undercover novel links between metabolic signaling and lipotoxic inflammasome activation, we investigated mouse primary macrophages deficient in PPARγ. Contrary to our expectation, PPARγ knockout (KO) macrophages released significantly less IL-1β and IL-1α in response to lipotoxic stimulation. The suppression occurred at the transcriptional level and was apparent for multiple activators of the NLRP3 inflammasome. RNA sequencing revealed upregulation of IFN-β in activated PPARγKO macrophages, and this was confirmed at the protein level. A blocking Ab against the type 1 IFNR restored the release of IL-1β to wild type levels in PPARγKO cells, confirming the mechanistic link between these events. Conversely, PPARγ activation with rosiglitazone selectively suppressed IFN-β expression in activated macrophages. Loss of PPARγ also resulted in diminished expression of genes involved in sterol biosynthesis, a pathway known to influence IFN production. Together, these findings demonstrate a cross-talk pathway that influences the interplay between metabolism and inflammation in macrophages.

The Interplay Between Tissue Niche and Macrophage Cellular Metabolism in Obesity

“…This can be stimulated by fatty acids as palmitate and may require mitochondrial ROS production (141,142). In line with this data, deletion of PPARγ in macrophages leads to a reduction IL-1β production and release in response to NLRP3 activators, an effect mediated by IFN-β (143). Thus, FAO and resultant metabolic byproducts play a complex role in the regulation of macrophage reparative and inflammatory functions.…”

Viral Infections and Interferons in the Development of Obesity

“…It is likely that the dysbiotic microbiome in the obesity and NAFLD patients may harbor persistent infections. In turn, through over-production of long-chain fatty acid (LFA) and leptin by expanding adipocytes, obesity is accompanied with general immune suppression including aberration of antiviral IFN signaling, which leads to high susceptibility to viral infections (Figure 3) [4,11,48,107,109]. Therefore, in most cases of infectobesity, obesity and viral infections may interact dynamically as a reciprocal causality rather than a simple sequential relationship of “chicken or the egg” [14].…”

Frontline Science: Acyl-CoA synthetase 1 exacerbates lipotoxic inflammasome activation in primary macrophages

“…In both preclinical and clinical studies, therapeutics that target the NLRP3 inflammasome and/or neutralize its primary product, IL‐1β, have been associated with improved wound healing, reduced atherosclerosis, and decreased severity of heart failure . We, and others, have demonstrated that excess fatty acids (FAs) can trigger inflammasome activation in macrophages in the setting of obesity and diabetes, the so‐called lipotoxic inflammasome . However, the molecular pathways that influence how FAs produce toxicity in macrophages and lead to this inflammatory response are not well understood.…”