Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming

Abstract

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.

Milk Fat Globule Membrane Inhibits NLRP3 Inflammasome Activation and Enhances Intestinal Barrier Function in a Rat Model of Short Bowel

“…The significantly higher expression of NLRP3, ASC, and caspase‐1 in SBS rats suggests NLRP3 inflammasome activation in SBS. Recent studies indicate that NLRP3 might be regulated by dietary factors, which could be used as potential nutrition interventions in different diseases . Ng et al found that the activation of the NLRP3 inflammasome pathway was inhibited by MUC1, which is a component of MFGM.…”

“…Recent studies indicate that NLRP3 might be regulated by dietary factors, which could be used as potential nutrition interventions in different diseases. 36,37 Ng et al found that the activation of the NLRP3 inflammasome pathway was inhibited by MUC1, 16 which is a component of MFGM. In this study, higher expression of MUC1 with suppression of NLRP3 pathway in ileum was observed in the SBS+MFGM group.…”

Two to Tango: Dialog between Immunity and Stem Cells in Health and Disease

“…Remarkably, mice fed even transiently (4 weeks) with a western diet displayed HSC proliferation, skewing of HSC lineages and exaggerated responses to a variety of inflammatory assaults. HSC chromatin accessibility was altered in a manner that was traced to the inflammasome activator NLRP3 (NLR Family Pyrin Domain Containing 3 NLR Family Pyrin Domain Containing 3), which in response to a “Western” diet metabolite, became activated to process and release the pro-inflammatory cytokine IL-1β (Christ et al, 2018). Exactly how IL1β sets off its downstream effectors to elicit sustained changes in chromatin accessibility remain unclear.…”

Central metabolic interactions of immune cells and microbes: prospects for defeating infections

“…b-glucan and other stimuli including the BCG vaccine and Western diets trigger reprogramming of haematopoietic stem cells within the bone marrow that give rise to circulating trained monocytes, explaining some aspects of the long-lasting effect of trained immunity [70,71]. b-glucan and other stimuli including the BCG vaccine and Western diets trigger reprogramming of haematopoietic stem cells within the bone marrow that give rise to circulating trained monocytes, explaining some aspects of the long-lasting effect of trained immunity [70,71].…”