Benign hepatosteatosis, affected by lipid uptake, de novo lipogenesis and fatty acid (FA) oxidation, progresses to non-alcoholic steatohepatitis (NASH) on stress and inflammation. A key macronutrient proposed to increase hepatosteatosis and NASH risk is fructose, whose excessive intake causes intestinal barrier deterioration and endotoxemia. However, how fructose triggers these alterations and their role in hepatosteatosis and NASH pathogenesis remain unknown. By preventing fructose and endoplasmic reticulum stressdependent barrier deterioration and subsequent endotoxemia using a chemical chaperon, activation of mucosal-regenerative gp130 signaling, administration of the YAP-induced matricellular protein CCN1 or expression of anti-microbial Reg3β peptide, we show that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1 phosphate (F1P) and cytosolic acetyl-CoA. TLR engagement triggers TNF production by liver macrophages to induce lipogenic enzymes that convert F1P and acetyl-CoA to FA in mouse and human hepatocytes.

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• Itpkb produces the soluble messenger IP 4 , which limits cytokine-induced Akt/ mTORC1 activation in HSC.• Itpkb loss in mice activates HSC and impairs their longevity and function, resulting in lethal hematopoietic failure and anemia.

It is well established that sustained increases in cyclic AMP (cAMP) such as those triggered by forskolin inhibit T cell activation. We describe here an unexpected phenomenon: in T cells, a transient cAMP increase triggered by the interaction with a dendritic cell strongly potentiates T cell receptor (TCR) signaling. We discovered this effect by examining the molecular basis of the adhesion-dependent sensitization of T cells. T cell adhesion caused extracellular-signal-regulated kinase (ERK) activation, which was necessary for the sensitization process. T cell sensitization could be mimicked in suspended cells by the uncaging of caged cAMP upon ultraviolet illumination. Calcium responses occurring in T cells upon interaction with dendritic cells were strongly inhibited when protein kinase A activation was blocked. Thus, whereas sustained cAMP increases are well known to inhibit TCR signaling, transient cAMP increases occurring physiologically upon formation of an immunological synapse facilitate antigen detection.

ObjectiveInvestigating the effect of ferroptosis in the tumour microenvironment to identify combinatory therapy for liver cancer treatment.DesignGlutathione peroxidase 4 (GPx4), which is considered the master regulator of ferroptosis, was genetically altered in murine models for hepatocellular carcinoma (HCC) and colorectal cancer (CRC) to analyse the effect of ferroptosis on tumour cells and the immune tumour microenvironment. The findings served as foundation for the identification of additional targets for combine therapy with ferroptotic inducer in the treatment of HCC and liver metastasis.ResultsSurprisingly, hepatocyte-restricted GPx4 loss does not suppress hepatocellular tumourigenesis. Instead, GPx4-associated ferroptotic hepatocyte death causes a tumour suppressive immune response characterised by a CXCL10-dependent infiltration of cytotoxic CD8+T cells that is counterbalanced by PD-L1 upregulation on tumour cells as well as by a marked HMGB1-mediated myeloid derived suppressor cell (MDSC) infiltration. Blocking PD-1 or HMGB1 unleashes T cell activation and prolongs survival of mice withGpx4-deficient liver tumours. A triple combination of the ferroptosis inducing natural compound withaferin A, the CXCR2 inhibitor SB225002 and α-PD-1 greatly improves survival of wild-type mice with liver tumours. In contrast, the same combination does not affect tumour growth of subcutaneously grown CRC organoids, while it decreases their metastatic growth in liver.ConclusionOur data highlight a context-specific ferroptosis-induced immune response that could be therapeutically exploited for the treatment of primary liver tumours and liver metastases.

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β-selection is the most pivotal event determining αβ T cell fate. Here, surface-expression of a pre-T cell receptor (pre-TCR) induces thymocyte metabolic activation, proliferation, survival and differentiation. Besides the pre-TCR, β-selection also requires co-stimulatory signals from Notch receptors - key cell fate determinants in eukaryotes. Here, we show that this Notch-dependence is established through antagonistic signaling by the pre-TCR/Notch effector, phosphoinositide 3-kinase (PI3K), and by inositol-trisphosphate 3-kinase B (Itpkb). Canonically, PI3K is counteracted by the lipid-phosphatases Pten and Inpp5d/SHIP-1. In contrast, Itpkb dampens pre-TCR induced PI3K/Akt signaling by producing IP4, a soluble antagonist of the Akt-activating PI3K-product PIP3. Itpkb-/- thymocytes are pre-TCR hyperresponsive, hyperactivate Akt, downstream mTOR and metabolism, undergo an accelerated β-selection and can develop to CD4+CD8+ cells without Notch. This is reversed by inhibition of Akt, mTOR or glucose metabolism. Thus, non-canonical PI3K-antagonism by Itpkb restricts pre-TCR induced metabolic activation to enforce coincidence-detection of pre-TCR expression and Notch-engagement.DOI: http://dx.doi.org/10.7554/eLife.10786.001

The significant contribution of intestinal bacteria for the pathogenesis of colorectal cancer is widely accepted by now. In this issue of Immunity, two articles by Malik et al. (2018) and Wang et al. (2018) highlight the role of commensal fungi, which so far have been underestimated.