Lysine deacetylation by the NAD(+)-dependent family of sirtuins has been recognized as an important post-translational modification regulating a wide range of cellular processes. These lysine deacetylases have attracted much interest based on their ability to promote survival in response to stress. Sirtuins require NAD(+) for their enzymatic activity, suggesting that these enzymes may represent molecular links between cell metabolism and several human disorders, including diabetes and cancer. Inflammation represents a pathological situation with clear connections to metabolism and aging in humans, raising the possibility that sirtuins may also play an important role during a normal and/or a pathological immune response. A growing body of data has confirmed the immunomodulatory properties of sirtuins, although often with contrasting and opposing conclusions. These observations will be summarized herein and the possible strategies that may lead to the development of novel therapeutic approaches to treat inflammation briefly discussed.

Renal ischemia-reperfusion injury (IRI) is a major risk factor for delayed graft function in renal transplantation. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against IRI. However, the role of myeloid HO-1 during IRI remains poorly characterized. Mice with myeloid-restricted deletion of HO-1 (HO-1M-KO), littermate (LT), and wild-type (WT) mice were subjected to renal IRI or sham procedures and sacrificed after 24 hours or 7 days. In comparison to LT, HO-1M-KO exhibited significant renal histological damage, pro-inflammatory responses and oxidative stress 24 hours after reperfusion. HO-1M-KO mice also displayed impaired tubular repair and increased renal fibrosis 7 days after IRI. In WT mice, HO-1 induction with hemin specifically upregulated HO-1 within the CD11b+ F4/80lo subset of the renal myeloid cells. Prior administration of hemin to renal IRI was associated with significant increase of the renal HO-1+ CD11b+ F4/80lo myeloid cells in comparison to control mice. In contrast, this hemin-mediated protection was abolished in HO-1M-KO mice. In conclusion, myeloid HO-1 appears as a critical protective pathway against renal IRI and could be an interesting therapeutic target in renal transplantation.

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Cellular necrosis has long been regarded as an incidental and uncontrolled form of cell death. However, a regulated form of cell death termed necroptosis has been identified recently. Necroptosis can be induced by extracellular cytokines, pathogens and several pharmacological compounds, which share the property of triggering the formation of a RIPK3-containing molecular complex supporting cell death. Of interest, most ligands known to induce necroptosis (including notably TNF and FASL) can also promote apoptosis, and the mechanisms regulating the decision of cells to commit to one form of cell death or the other are still poorly defined. We demonstrate herein that intracellular nicotinamide adenine dinucleotide (NAD + ) has an important role in supporting cell progression to necroptosis. Using a panel of pharmacological and genetic approaches, we show that intracellular NAD + promotes necroptosis of the L929 cell line in response to TNF. Use of a pan-sirtuin inhibitor and shRNA-mediated protein knockdown led us to uncover a role for the NAD + -dependent family of sirtuins, and in particular for SIRT2 and SIRT5, in the regulation of the necroptotic cell death program. Thus, and in contrast to a generally held view, intracellular NAD + does not represent a universal pro-survival factor, but rather acts as a key metabolite regulating the choice of cell demise in response to both intrinsic and extrinsic factors. + as a substrate in a number of regulatory processes has shed a new light on its role in cell physiology. Indeed, NAD + represents a substrate for a wide range of enzymes including cADP-ribose synthases, poly (ADP-ribose) polymerases (PARPs) and the sirtuin family of NAD + -dependent deacylases (SIRTs). In marked contrast to its role in energy metabolism, the involvement of NAD + in these enzymatic reactions is based on its ability to function as a donor of ADP-ribose, a reaction that, if sustained, can lead to the depletion of the intracellular NAD + pool. 1-5The pro-survival role of NAD + has been particularly well described in cells exposed to genotoxic/oxidative stress. In response to DNA damage, PARP1, the founding and most abundant member of the PARP family, binds to DNA strand breaks and initiates a repair response by catalyzing the posttranslational modification of several nuclear proteins, including itself. This protective response is characterized by the transfer of successive units of the ADP-ribose moiety (up to 200 units) from NAD + to other proteins, compromising therefore both energy production (slowing the rate of glycolysis, electron transport and ATP formation) and activity of other NAD + -dependent enzymes through NAD + depletion. 6,7 Moreover, PARP1-synthesized PAR polymers can be degraded into free oligomers, known to translocate to the mitochondria where they can trigger the release of AIF from mitochondria to the nucleus. [8][9][10][11] The precise molecular steps linking PARP1 activation to this form of stress-induced cell death, termed parthanatos, have not been fully elucidated, and...

The ectonucleotidases CD39 and CD73 sequentially degrade the extracellular ATP pool and release immunosuppressive adenosine, thereby regulating inflammatory responses. This control is likely to be critical in the gastrointestinal tract where high levels of ATP are released in particular by commensal bacteria. The aim of this study was therefore to evaluate the involvement of the adenosinergic regulation in the intestine of mice in steady-state conditions and on acute infection with Toxoplasma gondii. We show that both conventional (Tconv) and regulatory (Treg) CD4(+) T lymphocytes express CD39 and CD73 in the intestine of naive mice. CD73 expression was downregulated during acute infection with T. gondii, leading to impaired capacity to produce adenosine. Interestingly, the expression of adenosine receptors was maintained and treatment with receptor agonists limited immunopathology and dysbiosis, suggesting that the activation of adenosine receptors may constitute an efficient approach to control intestinal inflammation associated with decreased ectonucleotidase expression.

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The liver ischemia‐reperfusion (IR) injury that occurs consequently to hepatic resection performed in patients with metastases can lead to tumor relapse for not fully understood reasons. We assessed the effects of liver IR on tumor growth and the innate immune response in a mouse model of colorectal (CR) liver metastasis. Mice subjected to liver ischemia 2 days after intrasplenic injection of CR carcinoma cells displayed a higher metastatic load in the liver, correlating with Kupffer cells (KC) death through the activation of receptor‐interating protein 3 kinase (RIPK3) and caspase‐1 and a recruitment of monocytes. Interestingly, the immunoregulatory mediators, tumor necrosis factor‐α (TNF‐α) and heme oxygenase‐1 (HO‐1) were strongly upregulated in recruited monocytes and were also expressed in the surviving KC following IR. Using TNFflox/flox LysMcre/wt mice, we showed that TNF deficiency in macrophages and monocytes favors tumor progression after IR. The antitumor effect of myeloid cell‐derived TNF involved direct tumor cell apoptosis and a reduced expression of immunosuppressive molecules such as transforming growth factor‐β, interleukin (IL)‐10, inducible nitric oxyde synthase (iNOS), IL‐33 and HO‐1. Conversely, a monocyte/macrophage‐specific deficiency in HO‐1 (HO‐1flox/flox LysMcre/wt) or the blockade of HO‐1 function led to the control of tumor progression post‐liver IR. Importantly, host cell RIPK3 deficiency maintains the KC number upon IR, inhibits the IR‐induced innate cell recruitment, increases the TNF level, decreases the HO‐1 level and suppresses the tumor outgrowth. In conclusion, tumor recurrence in host undergoing liver IR is associated with the death of antitumoral KC and the recruitment of monocytes endowed with immunosuppressive properties. In both of which HO‐1 inhibition would reinforce their antitumoral activity.

The mechanisms regulating the choice of cell demise remain largely unknown. NAD+, a key metabolite with well-known roles in cell metabolism, has been shown to counteract apoptosis while promoting necroptosis, a form of proinflammatory cell death. This observation identifies NAD+ availability as an important parameter with contrasting roles in the regulation of distinct regulated cell death programs.