Cell
Volume 172, Issues 1–2, 11 January 2018, Pages 162-175.e14
Journal home page for Cell

Article
Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming

https://doi.org/10.1016/j.cell.2017.12.013Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Western diet triggers innate immunity, NOD-like, and IFN signaling pathways

  • Western diet alters in vivo LPS responses of GMPs

  • Western diet induces long-lasting trained immunity in myeloid cells

  • NLRP3 recognizes Western diet and mediates trained immunity

Summary

Long-term epigenetic reprogramming of innate immune cells in response to microbes, also termed “trained immunity,” causes prolonged altered cellular functionality to protect from secondary infections. Here, we investigated whether sterile triggers of inflammation induce trained immunity and thereby influence innate immune responses. Western diet (WD) feeding of Ldlr−/− mice induced systemic inflammation, which was undetectable in serum soon after mice were shifted back to a chow diet (CD). In contrast, myeloid cell responses toward innate stimuli remained broadly augmented. WD-induced transcriptomic and epigenomic reprogramming of myeloid progenitor cells led to increased proliferation and enhanced innate immune responses. Quantitative trait locus (QTL) analysis in human monocytes trained with oxidized low-density lipoprotein (oxLDL) and stimulated with lipopolysaccharide (LPS) suggested inflammasome-mediated trained immunity. Consistently, Nlrp3−/−/Ldlr−/− mice lacked WD-induced systemic inflammation, myeloid progenitor proliferation, and reprogramming. Hence, NLRP3 mediates trained immunity following WD and could thereby mediate the potentially deleterious effects of trained immunity in inflammatory diseases.

Keywords

trained immunity
innate immune memory
sterile inflammation
granulocyte macrophage progenitors
Western diet feeding
epigenetic reprogramming
NLRP3 inflammasome
atherosclerosis
non-communicable diseases
ASC

Cited by (0)

12

These authors contributed equally

13

Lead Contact