SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity.

Cancer cells evade T cell-mediated killing through tumour-immune interactions whose mechanisms are not well understood1,2. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumours3. DC functions are orchestrated by pattern recognition receptors3-5, although other signals involved remain incompletely defined. Nutrients are emerging mediators of adaptive immunity6-8, but whether nutrients affect DC function or communication between innate and adaptive immune cells is largely unresolved. Here we establish glutamine as an intercellular metabolic checkpoint that dictates tumour-cDC1 crosstalk and licenses cDC1 function in activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8+ T cell immunity, and overcomes therapeutic resistance to checkpoint blockade and T cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1s compete for glutamine uptake via the transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid in promoting cDC1 function. Further, glutamine signalling via FLCN impinges on TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner and phenocopies SLC38A2 deficiency by eliminating the anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1s that underpins tumour immune evasion, and reveal glutamine acquisition and signalling in cDC1s as limiting events for DC activation and putative targets for cancer treatment.

Cholesterol Homeostatic Regulator SCAP-SREBP2 Integrates NLRP3 Inflammasome Activation and Cholesterol Biosynthetic Signaling in Macrophages.

Cholesterol metabolism has been linked to immune functions, but the mechanisms by which cholesterol biosynthetic signaling orchestrates inflammasome activation remain unclear. Here, we have shown that NLRP3 inflammasome activation is integrated with the maturation of cholesterol master transcription factor SREBP2. Importantly, SCAP-SREBP2 complex endoplasmic reticulum-to-Golgi translocation was required for optimal activation of the NLRP3 inflammasome both in vitro and in vivo. Enforced cholesterol biosynthetic signaling by sterol depletion or statins promoted NLPR3 inflammasome activation. However, this regulation did not predominantly depend on changes in cholesterol homeostasis controlled by the transcriptional activity of SREBP2, but relied on the escort activity of SCAP. Mechanistically, NLRP3 associated with SCAP-SREBP2 to form a ternary complex which translocated to the Golgi apparatus adjacent to a mitochondrial cluster for optimal inflammasome assembly. Our study reveals that, in addition to controlling cholesterol biosynthesis, SCAP-SREBP2 also serves as a signaling hub integrating cholesterol metabolism with inflammation in macrophages.

Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome.

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.

Immunometabolism of dendritic cells in health and disease.

Dendritic cells (DCs) are crucial mediators that bridge the innate and adaptive immune responses. Cellular rewiring of metabolism is an emerging regulator of the activation, migration, and functional specialization of DC subsets in specific microenvironments and immunological conditions. DCs undergo metabolic adaptation to exert immunogenic or tolerogenic effects in different contexts. Also, beyond their intracellular metabolic and signaling roles, metabolites and nutrients mediate the intercellular crosstalk between DCs and other cell types, and such crosstalk orchestrates DC function and immune responses. Here, we provide a comprehensive review of the metabolic regulation of DC biology in various contexts and summarize the current understanding of such regulation in directing immune homeostasis and inflammation, specifically with respect to infections, autoimmunity, tolerance, cancer, metabolic diseases, and crosstalk with gut microbes. Understanding context-specific metabolic alterations in DCs may identify mechanisms for physiological and pathological functions of DCs and yield potential opportunities for therapeutic targeting of DC metabolism in many diseases.

Type I IFN operates pyroptosis and necroptosis during multidrug-resistant A. baumannii infection.

Multidrug-resistant Acinetobacter baumannii, a common pathogen responsible for nosocomial infections, is the main cause for outbreaks of infectious diseases, such as pneumonia, meningitis, and bacteremia, especially among critically ill patients. Epidemic A. baumannii is a growing public health concern as it is resistant to all existing antimicrobial agents, thereby necessitating the development of new therapeutic approaches to mount an effective immune response against this bacterial pathogen. In this study, we identified a critical role for type I interferon (IFN) in epigenetic regulation during A. baumannii infection and established a central role for it in multiple cell death pathways. A. baumannii infection induced mixed cell death constituted of apoptosis, pyroptosis, and necroptosis. Mechanically, A. baumannii triggered TRIF-dependent type I IFN production, which in turn induced the expression of genes Zbp1, Mlkl, caspase-11, and Gsdmd via KAT2B-mediated and P300-mediated H3K27ac modification, leading to NLRP3 inflammasome activation, and potentially contributed to GSDMD-mediated pyroptosis and MLKL-dependent necroptosis. Our study offers novel insights into the mechanisms of type I IFN and provides potential therapeutic targets for infectious and inflammatory diseases.

Author Correction: Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors.

This corrects the article DOI: 10.1038/ncomms15732.

A rapid administration of GW4064 inhibits the NLRP3 inflammasome activation independent of farnesoid X receptor agonism.

GW4064 is a small molecule known to be an agonist of the nuclear farnesoid X receptor (FXR). We found that GW4064 inhibits the NLR family CARD domain containing 3 (NLRP3) inflammasome activation in an FXR-independent manner as evidenced by its similar inhibitory effect on NLRP3 inflammasome activation in FXR-deficient macrophages. Interestingly, GW4064 decreases the nigericin-induced oligomerization and ubiquitination of ASC which is critical for the NLRP3 inflammasome activation. In vivo results indicate that GW4064 could partially rescue the symptoms of NLRP3-dependent inflammatory disease models. These results not only necessitate cautious interpretation of the biological function of GW4064 as an FXR agonist, but also provide a potential therapeutic approach using GW4064 in the treatment of NLRP3-related diseases.

Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors.

Thymocyte-expressed, positive selection-associated 1 (Tespa1) is important in T cell receptor (TCR)-driven thymocyte development. Downstream of the TCR, Tespa1 is a crucial component of the linker for activation of T cells (LAT) signalosome, facilitating calcium signalling and subsequent MAPK activation. However, it is unknown how Tespa1 elicits calcium signalling. Here, we show that inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) is crucial for Tespa1-optimized, TCR-induced Ca2+ flux and thymocyte development. Upon TCR stimulation, Tespa1 directly interacts with IP3R1 and recruits it to the TCR complex, where IP3R1 is phosphorylated at Y353 by Fyn. This Tespa1-IP3R1 interaction is mediated by the F187 and F188 residues of Tespa1 and the amino-terminus of IP3R1. Tespa1-F187A/F188A mutant mice phenocopy Tespa1-deficient mice with impaired late thymocyte development due to reduced IP3R1 translocation to the TCR-proximal region. Our work elucidates the function of Tespa1 in T cell development and the regulation of TCR-induced Ca2+ signalling through IP3R1.

Tespa1 negatively regulates FcεRI-mediated signaling and the mast cell-mediated allergic response.

Antigen-mediated cross-linking of IgE on mast cells triggers a signaling cascade that results in their degranulation and proinflammatory cytokine production, which are key effectors in allergic reactions. We show that the activation of mast cells is negatively regulated by the newly identified adaptor protein Tespa1. Loss of Tespa1 in mouse mast cells led to hyper-responsiveness to stimulation via FcεRI. Mice lacking Tespa1 also displayed increased sensitivity to IgE-mediated allergic responses. The dysregulated signaling in KO mast cells was associated with increased activation of Grb2-PLC-γ1-SLP-76 signaling within the LAT1 (linker for activation of T cells family, member 1) signalosome versus the LAT2 signalosome. Collectively, these findings show that Tespa1 orchestrates mast cell activation by tuning the balance of LAT1 and LAT2 signalosome assembly.

Highly enantioselective direct aldol reaction catalyzed by cinchona derived primary amines.

Highly enantioselective aldol reactions of aldehydes with cyclic ketones catalyzed by a primary amine derived from cinchonine are reported. Aromatic aldehydes reacted with various cyclic ketones cleanly to afford the anti-aldol adducts in up to 99% yield, with good diastereoselectivities (up to 9 : 1) and excellent enantioselectivities (up to 99% ee).