Reciprocal interactions between the metabolic system and immune cells play pivotal roles in diverse inflammatory diseases, but the underlying mechanisms remain elusive. The activation of bile acid-mediated signaling has been linked to improvement in metabolic syndromes and enhanced control of inflammation. Here, we demonstrated that bile acids inhibited NLRP3 inflammasome activation via the TGR5-cAMP-PKA axis. TGR5 bile acid receptor-induced PKA kinase activation led to the ubiquitination of NLRP3, which was associated with the PKA-induced phosphorylation of NLRP3 on a single residue, Ser 291. Furthermore, this PKA-induced phosphorylation of NLRP3 served as a critical brake on NLRP3 inflammasome activation. In addition, in vivo results indicated that bile acids and TGR5 activation blocked NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation, alum-induced peritoneal inflammation, and type-2 diabetes-related inflammation. Altogether, our study unveils the PKA-induced phosphorylation and ubiquitination of NLRP3 and suggests TGR5 as a potential target for the treatment of NLRP3 inflammasome-related diseases.

Although the physiological role of tissue‐specific translational control of gene expression in mammals has long been suspected on the basis of biochemical studies, direct evidence has been lacking. Here, we report on the targeted disruption of the gene encoding the heme‐regulated eIF2α kinase (HRI) in mice. We establish that HRI, which is expressed predominantly in erythroid cells, regulates the synthesis of both α‐ and β‐globins in red blood cell (RBC) precursors by inhibiting the general translation initiation factor eIF2. This inhibition occurs when the intracellular concentration of heme declines, thereby preventing the synthesis of globin peptides in excess of heme. In iron‐deficient HRI−/− mice, globins devoid of heme aggregated within the RBC and its precursors, resulting in a hyperchromic, normocytic anemia with decreased RBC counts, compensatory erythroid hyperplasia and accelerated apoptosis in bone marrow and spleen. Thus, HRI is a physiological regulator of gene expression and cell survival in the erythroid lineage.

The ability to produce vigorous immune responses that spare self tissues and organs depends on elimination of autoreactive T and B cells. However, purging of immature and mature self-reactive T and B cells is incomplete and may require additional censorship by cells programmed to suppress immune responses 1. Regulatory T cells belonging to the CD4+ T cell subset may play a role in preventing untoward inflammatory responses, but T cell subsets programmed to inhibit the development of autoantibody formation and SLE-like disease have not been defined 2. Here we delineate a CD8+ regulatory T cell lineage that is essential for maintenance of self tolerance and prevention of autoimmune disease. Genetic disruption of the inhibitory interaction between these CD44+ ICOSL+ CD8+ T cells and their target Qa-1+ follicular T helper cells results in the development of a lethal SLE-like autoimmune disease. These findings define a sublineage of CD8 T cells programmed to suppress rather than activate immunity that represents an essential regulatory element of the immune response and a guarantor of self tolerance.

The observation that the T-bet transcription factor allows tissue-specific upregulation of intracellular osteopontin (Opn-i) in plasmacytoid dendritic cells (pDCs) suggests that Opn might contribute to the expression of interferon-α (IFN-α) in those cells. Here we show that Opn deficiency substantially reduced Toll-like receptor 9 (TLR9)-dependent IFN-α responses but spared expression of transcription factor NF-κB-dependent proinflammatory cytokines. Shortly after TLR9 engagement, colocalization of Opn-i and the adaptor molecule MyD88 was associated with induction of transcription factor IRF7-dependent IFN-α gene expression, whereas deficient expression of Opn-i was associated with defective nuclear translocation of IRF7 in pDCs. The importance of the Opn-IFN-α pathway was emphasized by its essential involvement in crosspresentation in vitro and in anti-herpes simplex virus 1 IFN-α response in vivo. The finding that Opn-i selectively coupled TLR9 signaling to expression of IFN-α but not to that of other proinflammatory cytokines provides new molecular insight into the biology of pDCs.Increasing evidence that innate immune responses can determine both the type and intensity of adaptive immune responses has stimulated great interest in the underlying regulatory mechanisms. The recognition phase of innate responses depends on a series of patternrecognition receptors, including Toll-like receptors (TLRs) expressed by dendritic cells (DCs), which detect a wide range of pathogen-associated molecules carried by bacteria and viruses 1 . Engagement of the TLR9 family of endosomal receptors by microbe-derived DNA triggers the production of large amounts of interferons α and β (IFN-αβ) 2 , key mediators that regulate the development of both innate and adaptive immunity [3][4][5][6] . However, the pathway initiated by TLR9 engagement that culminates in IFN-αβ production is not fully understood.