Background:The ability of glucocorticoids to regulate the expression and function of the NOD-like receptors is unknown. Results: Glucocorticoids enhance the expression and function of NLRP3, promoting the secretion of IL-1␤ in response to ATP. Conclusion: Glucocorticoids sensitize the innate immune system to specific stimuli. Significance: This work demonstrates a novel, proinflammatory role for glucocorticoids, enhancing the activation of the innate immune system in response to danger signals.

Background The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (apo)E, a lipid-trafficking protein that impacts inflammation, has well-described ‘wild type’ (ε3) and disease-associated (ε2, ε4) alleles, but its connection to human innate immunity is undefined. Objective To define the relationship of APOε4 to the human innate immune response. Methods We evaluated APOε4 in several functional models of the human innate immune response including intravenous lipopolysaccharide challenge in human subjects, and assessed APOε4 association to organ injury in human severe sepsis, a disease driven by dysregulated innate immunity. Results Whole blood from healthy APOε3/APOε4 volunteers induced higher cytokines upon ex vivo stimulation with Toll like Receptor (TLR)2, TLR4, or TLR5 ligands than blood from APOε3/APOε3 subjects, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APOε3/APOε4 monocytes. By contrast, APOε3/APOε3 and APOε3/APOε4 serum neutralized lipopolysaccharide equivalently and supported similar lipopolysaccharide responses in Apoe-deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous lipopolysaccharide, APOε3/APOε4 human subjects had higher hyperthermia and plasma TNFα and earlier plasma IL-6 than APOε3/APOε3 subjects. APOE4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury, and altered splenic lymphocyte apoptosis after systemic lipopolysaccharide compared with APOE3 counterparts. In a cohort of 828 severe sepsis patients, APOε4 was associated with increased coagulation system failure among European American subjects. Conclusions APOε4 is a determinant of the human innate immune response to multiple TLR ligands, and associates with altered patterns of organ injury in human sepsis.

In recent years the functions that the p53 tumor suppressor plays in human biology have been greatly extended beyond “guardian of the genome.” Our studies of promoter response element sequences targeted by the p53 master regulatory transcription factor suggest a general role for this DNA damage and stress-responsive regulator in the control of human Toll-like receptor (TLR) gene expression. The TLR gene family mediates innate immunity to a wide variety of pathogenic threats through recognition of conserved pathogen-associated molecular motifs. Using primary human immune cells, we have examined expression of the entire TLR gene family following exposure to anti-cancer agents that induce the p53 network. Expression of all TLR genes, TLR1 to TLR10, in blood lymphocytes and alveolar macrophages from healthy volunteers can be induced by DNA metabolic stressors. However, there is considerable inter-individual variability. Most of the TLR genes respond to p53 via canonical as well as noncanonical promoter binding sites. Importantly, the integration of the TLR gene family into the p53 network is unique to primates, a recurrent theme raised for other gene families in our previous studies. Furthermore, a polymorphism in a TLR8 response element provides the first human example of a p53 target sequence specifically responsible for endogenous gene induction. These findings—demonstrating that the human innate immune system, including downstream induction of cytokines, can be modulated by DNA metabolic stress—have many implications for health and disease, as well as for understanding the evolution of damage and p53 responsive networks.