Impact of metabolism on immune responses

Producción CientíficaMetabolic processes have been long seen as means to generate energy in a live organism. However, recent discoveries on the field of immunology and metabolism have shown an increasing interrelation between these processes. The field of immunometabolism is gaining momentum and presents a huge impact for the clinical practice. Of particular attention is the chronic inflammation state in obesity, as well as asthma to mention a few. This special issue offers a selected and articulated overview of the examined topic. For this issue, we have included an interesting mix of reviews and original research articles, which underscore the relevance of metabolism in immune responses

Autonomous Vascular Networks Synchronize GABA Neuron Migration in the Embryonic Forebrain

GABA neurons, born in remote germinative zones in the ventral forebrain (telencephalon), migrate tangentially in two spatially distinct streams to adopt their specific positions in the developing cortex. The cell types and molecular cues that regulate this divided migratory route remains to be elucidated. Here we show that embryonic vascular networks are strategically positioned to fulfill the task of providing support as well as critical guidance cues that regulate the divided migratory routes of GABA neurons in the telencephalon. Interestingly, endothelial cells of the telencephalon are not homogeneous in their gene expression profiles. Endothelial cells of the periventricular vascular network have molecular identities distinct from those of the pial network. Our data suggest that periventricular endothelial cells have intrinsic programs that can significantly mold neuronal development and uncovers new insights into concepts and mechanisms of CNS angiogenesis from both developmental and disease perspectives

NAD+ protects against EAE by regulating CD4+ T-cell differentiation

CD4+ T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD+) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4+IFNγ+IL-10+ T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD+ regulates CD4+ T-cell differentiation through tryptophan hydroxylase-1 (Tph1), independently of well-established transcription factors. In the presence of NAD+, the frequency of T-bet−/− CD4+IFNγ+ T cells was twofold higher than wild-type CD4+ T cells cultured in conventional T helper 1 polarizing conditions. Our findings unravel a new pathway orchestrating CD4+ T-cell differentiation and demonstrate that NAD+ may serve as a powerful therapeutic agent for the treatment of autoimmune and other diseases

Mast cells regulate CD4+ T-cell differentiation in the absence of antigen presentation

Producción CientíficaBackground: Given their unique capacity for antigen uptake, processing, and presentation, antigen-presenting cells (APCs) are critical for initiating and regulating innate and adaptive immune responses. We have previously shown the role of nicotinamide adenine dinucleotide (NAD+) in T-cell differentiation independently of the cytokine milieu, whereas the precise mechanisms remained unknown. Objective: The objective of this study is to further dissect the mechanism of actions of NAD+ and determine the effect of APCs on NAD+-mediated T-cell activation. Methods: Isolated dendritic cells and bone marrow–derived mast cells (MCs) were used to characterize the mechanisms of action of NAD+ on CD4+ T-cell fate in vitro. Furthermore, NAD+-mediated CD4+ T-cell differentiation was investigated in vivo by using wild-type C57BL/6, MC−/−, MHC class II−/−, Wiskott-Aldrich syndrome protein (WASP)−/−, 5C.C7 recombination-activating gene 2 (Rag2)−/−, and CD11b-DTR transgenic mice. Finally, we tested the physiologic effect of NAD+ on the systemic immune response in the context of Listeria monocytogenes infection. Results: Our in vivo and in vitro findings indicate that after NAD+ administration, MCs exclusively promote CD4+ T-cell differentiation, both in the absence of antigen and independently of major APCs. Moreover, we found that MCs mediated CD4+ T-cell differentiation independently of MHC II and T-cell receptor signaling machinery. More importantly, although treatment with NAD+ resulted in decreased MHC II expression on CD11c+ cells, MC-mediated CD4+ T-cell differentiation rendered mice resistant to administration of lethal doses of L monocytogenes. Conclusions: Collectively, our study unravels a novel cellular and molecular pathway that regulates innate and adaptive immunity through MCs exclusively and underscores the therapeutic potential of NAD+ in the context of primary immunodeficiencies and antimicrobial resistance.National Institutes of Health (grants R01NS073635 , R01MH110438 , R01HL096795 , U01HL126497 and R01AG039449)Instituto de Salud Carlos III (grant PI10/02 511)Fundación Ramón Areces (grant CIVP16A1843

Rôle de l'interaction mésenchyme-épithélium dans l'expression, la maturation protéolytique et la déposition de la laminine 5

La lamine 5 (a3b3g2) est une glycoprotéine composant la lame basale de la peau et elle est importante pour la cohésion de la jonction dermo-épidermique. Cette protéine est synthétisée et sécrétée par les cellules épithéliales sous forme d'un précurseur de 490 kDa qui est converti en formes matures de 440 et 440 kDa, par clivage des domaines N-terminaux des chaînes a3 et g2. Ce clivage est important pour la maturation de la lamine 5 et l'objectif de ce travail a été de mettre en évidence le rôle des interactions épithélio-mésenchymateuses physiologiques et pathologiques sur le clivage et la déposition de la laminine 5. Les effets de l'interaction épithélio-mésenchymateuse sur la laminine 5 ont été reproduits en co-cultivant ou pas des cellules éphitéliales normales ou tumorales avec des fibroblastes...Laminin 5 (a3b3g2), a glycoprotein, is a component of basement membranes and is important for the dermal-epidermal stability. This protein is synthesised and secreted by epithelial cells under a precursor from of 490 kDa which is converted into a mature from of 440 kDa and 400 kDa, after cleavage of the a3 and g2 N-terminal domains. Cleavage is important for the maturation of laminin 5. The aim of this study was to find out the phyiological and pathological role of the epithelial-mesenchymal interaction as a result of the cleavage and deposition of laminin 5....PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF

NAD(+) regulates Treg cell fate and promotes allograft survival via a systemic IL-10 production that is CD4(+) CD25(+) Foxp3(+) T cells independent

This work is licensed under a Creative Commons Attribution 4.0 International License.-- et al.CD4+ CD25+ Foxp3+ Tregs have been shown to play a central role in immune homeostasis while preventing from fatal inflammatory responses, while Th17 cells have traditionally been recognized as pro-inflammatory mediators implicated in a myriad of diseases. Studies have shown the potential of Tregs to convert into Th17 cells, and Th17 cells into Tregs. Increasing evidence have pointed out CD25 as a key molecule during this transdifferentiation process, however molecules that allow such development remain unknown. Here, we investigated the impact of NAD+ on the fate of CD4+ CD25+ Foxp3+ Tregs in-depth, dissected their transcriptional signature profile and explored mechanisms underlying their conversion into IL-17A producing cells. Our results demonstrate that NAD+ promotes Treg conversion into Th17 cells in vitro and in vivo via CD25 cell surface marker. Despite the reduced number of Tregs, known to promote homeostasis, and an increased number of pro-inflammatory Th17 cells, NAD+ was able to promote an impressive allograft survival through a robust systemic IL-10 production that was CD4+ CD25+ Foxp3+ independent. Collectively, our study unravels a novel immunoregulatory mechanism of NAD+ that regulates Tregs fate while promoting allograft survival that may have clinical applications in alloimmunity and in a wide spectrum of inflammatory conditions.This work was supported by a grant of the Instituto de la Salud Carlos Slim, National Institutes of Health (R01AG039449) (S.G.T.), R01 HL096795 (I.G.). K.E. was supported by DFG project KFO243/1 and M.A.d.l.F was supported by FIS-ISCIII (grant PI10/02 511) and Fundación Ramón Areces (CIVP16A1843).Peer Reviewe

Aspects of Tryptophan and Nicotinamide Adenine Dinucleotide in Immunity: A New Twist in an Old Tale

Increasing evidence underscores the interesting ability of tryptophan to regulate immune responses. However, the exact mechanisms of tryptophan’s immune regulation remain to be determined. Tryptophan catabolism via the kynurenine pathway is known to play an important role in tryptophan’s involvement in immune responses. Interestingly, quinolinic acid, which is a neurotoxic catabolite of the kynurenine pathway, is the major pathway for the de novo synthesis of nicotinamide adenine dinucleotide (NAD+). Recent studies have shown that NAD+, a natural coenzyme found in all living cells, regulates immune responses and creates homeostasis via a novel signaling pathway. More importantly, the immunoregulatory properties of NAD+ are strongly related to the overexpression of tryptophan hydroxylase 1 (Tph1). This review provides recent knowledge of tryptophan and NAD+ and their specific and intriguing roles in the immune system. Furthermore, it focuses on the mechanisms by which tryptophan regulates NAD+ synthesis as well as innate and adaptive immune responses

NAD⁺ prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages

Septic shock is characterized by an excessive inflammatory response depicted in a cyto-kine storm that results from invasive bacterial, fungi, protozoa, and viral infections. Non-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and proinflammatory cytokine production via caspase-11 and gasdermin D (GSDMD). Here, we show that NAD+ treatment protected mice toward bacterial and lipopolysaccharide (LPS)-induced endotoxic shock by blocking the non-canonical inflammasome specifically. NAD+ administration impeded systemic IL-1β and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-β/STAT-1 signaling machinery. More importantly, NAD+ administration not only improved casp-11 KO (knockout) survival but rendered wild type (WT) mice completely resistant to septic shock via the IL-10 signaling pathway that was independent from the non-canonical inflammasome. Here, we delineated a two-sided effect of NAD+ blocking septic shock through a specific inhibition of the non-canonical inflammasome and promoting immune homeostasis via IL-10, underscoring its unique therapeutic potential.</p

NAD+ prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages

Septic shock is characterized by an excessive inflammatory response depicted in a cytokine storm that results from invasive bacterial, fungi, protozoa, and viral infections. Non-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and proinflammatory cytokine production via caspase-11 and gasdermin D (GSDMD). Here, we show that NAD+ treatment protected mice toward bacterial and lipopolysaccharide (LPS)-induced endotoxic shock by blocking the non-canonical inflammasome specifically. NAD+ administration impeded systemic IL-1β and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-β/STAT-1 signaling machinery. More importantly, NAD+ administration not only improved casp-11 KO (knockout) survival but rendered wild type (WT) mice completely resistant to septic shock via the IL-10 signaling pathway that was independent from the non-canonical inflammasome. Here, we delineated a two-sided effect of NAD+ blocking septic shock through a specific inhibition of the non-canonical inflammasome and promoting immune homeostasis via IL-10, underscoring its unique therapeutic potential