Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming.

Area of Science:

• Immunology
• Epigenetics
• Metabolic disease

Background:

• Trained immunity involves long-term epigenetic reprogramming of innate immune cells, enhancing responses to secondary infections.
• The role of sterile inflammatory triggers, such as those induced by diet, in initiating trained immunity is not fully understood.

Purpose of the Study:

• To investigate whether sterile triggers of inflammation induce trained immunity.
• To explore the mechanisms underlying diet-induced trained immunity and its impact on myeloid cell function.

Main Methods:

• Utilized Western diet (WD) feeding in Ldlr-/- mice to induce systemic inflammation.
• Analyzed myeloid cell responses, transcriptomic, and epigenomic reprogramming.
• Performed quantitative trait locus (QTL) analysis in human monocytes trained with oxidized low-density lipoprotein (oxLDL) and lipopolysaccharide (LPS).
• Employed Nlrp3-/-/Ldlr-/- mice to assess the role of NLRP3 inflammasome.

Main Results:

• WD feeding induced systemic inflammation and prolonged augmented myeloid cell responses, even after diet reversal.
• WD induced transcriptomic and epigenomic reprogramming in myeloid progenitor cells, increasing proliferation and innate immune responses.
• QTL analysis and Nlrp3-/-/Ldlr-/- mice data implicated NLRP3 inflammasome in mediating WD-induced trained immunity, inflammation, and myeloid progenitor proliferation.

Conclusions:

• Sterile inflammation, induced by a Western diet, triggers trained immunity in myeloid cells.
• NLRP3 inflammasome is a key mediator of diet-induced trained immunity and associated myeloid cell reprogramming.
• This NLRP3-mediated trained immunity may contribute to the detrimental effects of trained immunity in inflammatory diseases.