Low-Dose Endotoxin Induces Inflammation by Selectively Removing Nuclear Receptors and Activating CCAAT/Enhancer-Binding Protein δ

Abstract

Subclinical levels of circulating endotoxin are associated with the pathogenesis of diverse human inflammatory diseases, by mildly inducing the expression of proinflammatory mediators. In this study, we examined the molecular mechanism responsible for the effect of low-dose LPS in macrophages. In contrast to high-dose LPS, which activates NF-κB and induces the robust expression of proinflammatory mediators, we observed that low-dose LPS failed to activate NF-κB. Instead, it selectively activated C/EBPδ and removed nuclear repressors, including peroxisome proliferator-activated receptor α and retinoic acid receptor α, enabling a mild and leaky expression of proinflammatory mediators. The effect of low-dose LPS required IRAK-1, which interacts with and acts upstream of IκB kinase ε to contribute to LPS-mediated induction of C/EBPδ and proinflammatory mediators. Additionally, mice fed a high-fat diet acquired elevated levels of endotoxin and proinflammatory mediators in an IRAK-1–dependent fashion. Taken together, these data reveal a distinct pathway preferentially used by low-dose endotoxin in initiating low-grade inflammation.

Monocyte and Macrophage Plasticity in Tissue Repair and Regeneration

“…95 The let-7c down-regulates C/EBP-d, an important transcriptional factor that is required for a sustained Toll-like receptor 4einduced inflammatory response, which promotes the M1 phenotype. 95,96 Similar to the role of let-7c, miR-124 diminishes M1 polarization and enhances M2 polarization in bone marrowederived macrophages from mice. Overexpression of miR-124 reduces expression of the surface markers CD45, CD11b, F4/80, major histocompatibility complex class II, and CD86, but increases the expression of the M2 phenotypic markers found in inflammatory zone 1 (FIZZ1) and arginine-1.…”

Dynamic modulation of innate immunity programming and memory

“…Recent studies from our group and other suggest another intriguing aspect of innate immunity programming and memory, in that innate leukocytes may not only be able to recognize different combinations of extra-cellular stimulants, but also discern their relative signal strength (Baker et al, 2014;Deng et al, 2013;Lu et al, 2015;Maitra et al, 2012;Maitra et al, 2011;Morris et al, 2014). This is reflected in the cardinal example of endotoxin priming and tolerance.…”

“…For example, we and others demonstrated that nuclear receptors (e.g. RAR, ROR) activated by retinoic acid can not only synergize with signal transducer and activator of transcription 4 (STAT4) activated by IL-4, but also can potently suppress the inflammatory NFB pathway activated by LPS Maitra et al, 2011).…”

Dose Effects of LAB on Modulation of Rotavirus Vaccine Induced Immune Responses

“…From these data, it is clear that the same probiotic strain at different doses can exert qualitatively different modulating effects on DCs and consequently on adaptive immune responses induced by rotavirus vaccines. It has been reported that the effect of low dose microbe-associated pattern molecular (MAPM), such as lipopolysaccharide, was strikingly different as compared to that of high dose on macrophage cell functions: low dose lipopolysaccharide induced a strong inflammatory response in macrophages (Maitra et al, 2011). It is plausible that a similar interaction occurs between the MAPM from LA and DCs in the gut.…”