| First Author | Weber KJ | Year | 2018 |
| Journal | J Immunol | Volume | 201 |
| Issue | 7 | Pages | 2054-2069 |
| PubMed ID | 30143592 | Mgi Jnum | J:265239 |
| Mgi Id | MGI:6199365 | Doi | 10.4049/jimmunol.1800224 |
| Citation | Weber KJ, et al. (2018) PPARgamma Deficiency Suppresses the Release of IL-1beta and IL-1alpha in Macrophages via a Type 1 IFN-Dependent Mechanism. J Immunol 201(7):2054-2069 |
| abstractText | 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. PPARgamma 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 PPARgamma. Contrary to our expectation, PPARgamma knockout (KO) macrophages released significantly less IL-1beta and IL-1alpha 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-beta in activated PPARgammaKO macrophages, and this was confirmed at the protein level. A blocking Ab against the type 1 IFNR restored the release of IL-1beta to wild type levels in PPARgammaKO cells, confirming the mechanistic link between these events. Conversely, PPARgamma activation with rosiglitazone selectively suppressed IFN-beta expression in activated macrophages. Loss of PPARgamma 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. |
