Heightened NLRP3 inflammasome activation is associated with aging and CMML diseases severity

Aging causes chronic low-grade inflammation known as inflamm-aging. It is a risk factor for chronic myelomonocytic leukemia (CMML), a hematological malignancy that is most prevalent in older people. Recent studies suggest a critical role for the NLRP3 inflammasome in inflamm-aging. However, the mechanisms involved in NLRP3 activation in aging and its involvement in CMML progression are not fully understood. Here, we report that aging increases interleukin-1β production upon NLRP3 activation in human CD14+ monocytes. Interestingly, we found that Toll-like receptor (TLR) 1/2 agonist Pam3Cysk4 directly activates NLRP3 inflammasome without the requirement of second activation signal in monocytes from older but not from younger healthy donors. Further, we observed a dichotomous response to NLRP3 inflammasome activation in monocytes from CMML patients. Intriguingly, CMML patients with heightened NLRP3 activation showed increased treatment dependency and disease severity. Collectively, our results suggest that aging causes increased sensitivity to NLRP3 inflammasome activation at cellular level, which may explain increased inflammation and immune dysregulation in older individuals. Furthermore, NLRP3 inflammasome activation was dysregulated in CMML and positively correlated with disease severity

Nephron-Specific Deletion of Circadian Clock Gene Bmal1 Alters the Plasma and Renal Metabolome and Impairs Drug Disposition.

The circadian clock controls a wide variety of metabolic and homeostatic processes in a number of tissues, including the kidney. However, the role of the renal circadian clocks remains largely unknown. To address this question, we performed a combined functional, transcriptomic, and metabolomic analysis in mice with inducible conditional knockout (cKO) of BMAL1, which is critically involved in the circadian clock system, in renal tubular cells (Bmal1(lox/lox)/Pax8-rtTA/LC1 mice). Induction of cKO in adult mice did not produce obvious abnormalities in renal sodium, potassium, or water handling. Deep sequencing of the renal transcriptome revealed significant changes in the expression of genes related to metabolic pathways and organic anion transport in cKO mice compared with control littermates. Furthermore, kidneys from cKO mice exhibited a significant decrease in the NAD(+)-to-NADH ratio, which reflects the oxidative phosphorylation-to-glycolysis ratio and/or the status of mitochondrial function. Metabolome profiling showed significant changes in plasma levels of amino acids, biogenic amines, acylcarnitines, and lipids. In-depth analysis of two selected pathways revealed a significant increase in plasma urea level correlating with increased renal Arginase II activity, hyperargininemia, and increased kidney arginine content as well as a significant increase in plasma creatinine concentration and a reduced capacity of the kidney to secrete anionic drugs (furosemide) paralleled by an approximate 80% decrease in the expression level of organic anion transporter 3 (SLC22a8). Collectively, these results indicate that the renal circadian clocks control a variety of metabolic/homeostatic processes at the intrarenal and systemic levels and are involved in drug disposition

Investigation of the intrinsic rénal circadian clocks Characterization of the rénal function of XPR1 and ARG2

Investigation of the iritrinsic rénal circadian clocks. Many rénal functions, as glomerular filtration rate, rénal blood flow as well as urine production and electrolytes excretion show circadian oscillations. Physiological circadian rhythms are generated by circadian clocks, feedback loops-interacting molecular networks allowing the organisms to coordinate their physiology and behavior with daily environmental variations. The aims of the projects we conducted are to investigate the rôle of the intrinsic rénal circadian clocks in rénal circadian rhythmicity and in the pathogenesis of diabetic nephropathy. We observed that tubular circadian clocks disruption induces profound altérations in kidney transcriptome and in intrarenal and systemic metabolic processes. Moreover, circadian clock in rénal tubular cells is involved in drug disposition. We also investigated physiological relevance of circadian clocks located in podocytes of the glomerulus and demonstrated that deletion abolishes circadian rhythmicity of glomerular filtration rate and urine production, as well as urinary sodium and potassium excretion. Furthermore, podocyte circadian clock controls expression of various genes having a critical rôle in podocyte function and known to be involved in the pathogenesis of diverse glomerular diseases. Finally, we demonstrated that disruption of tubular, but not podocyte, circadian clocks aggravates général metabolic status and rénal function of type I diabetic mice. Underlying mechanisms remain to be clarified. Characterization of the rénal function of XPR1 and ARG2. Recently published in vitro experiments have demonstrated a rôle for XPR1 in phosphate transport. Initially identified as the receptor used by xenotropic and polytropic murine leukemia retroviruses for cell infection, in vivo physiological rôle of XPR1 remains unknown. Using a mice model carrying an inducible Xpr1 deletion in the entire rénal tubule, we highlighted a relevant function for XPR1 in rénal phosphate homeostasis as demonstrated by the disturbed rénal phosphate handling and the strong bone phenotype exhibited by mice devoid of XPR1. Rénal ARG2 expression is strongly upregulated in many stress-induced kidney injury conditions. Whether this increase is bénéficiai or detrimental is still debated. We studied the rôle of ARG2 in mice carrying kidney-specific Arg2 deletion and subjected to unilatéral rénal ischemia followed either by 24 hours or 2 weeks of reperfusion. Although we have established the protective rôle of ARG2 in short-term ischemia-induced rénal injury, its effect on the long-term recovery is still unclear and remains to be further investigated

Symphonie N °3 en ut mineur / SAINT SAENS ; ANSERMET

Titre uniforme : [Symphonies. No 3. Orgue, orchestre. R 176. Do mineur]BnF-Partenariats, Collection sonore - BelieveContient une table des matière

Renal tubular arginase-2 participates in the formation of the corticomedullary urea gradient and attenuates kidney damage in ischemia-reperfusion injury in mice.

Arginase 2 (ARG2) is a mitochondrial enzyme that catalyses hydrolysis of l-arginine into urea and l-ornithine. In the kidney, ARG2 is localized to the S3 segment of the proximal tubule. It has been shown that expression and activity of this enzyme are upregulated in a variety of renal pathologies, including ischemia-reperfusion (IR) injury. However, the (patho)physiological role of ARG2 in the renal tubule remains largely unknown. We addressed this question in mice with conditional knockout of Arg2 in renal tubular cells (Arg2 <sup>lox/lox</sup> /Pax8-rtTA/LC1 or, cKO mice). We demonstrate that cKO mice exhibit impaired urea concentration and osmolality gradients along the corticomedullary axis. In a model of unilateral ischemia-reperfusion injury (UIRI) with an intact contralateral kidney, ischemia followed by 24 hours of reperfusion resulted in significantly more pronounced histological damage in ischemic kidneys from cKO mice compared to control and sham-operated mice. In parallel, UIRI-subjected cKO mice exhibited a broad range of renal functional abnormalities, including albuminuria and aminoaciduria. Fourteen days after UIRI, the cKO mice exhibited complex phenotype characterized by significantly lower body weight, increased plasma levels of early predictive markers of kidney disease progression (asymmetric dimethylarginine and symmetric dimethylarginine), impaired mitochondrial function in the ischemic kidney but no difference in kidney fibrosis as compared to control mice. Collectively, these results establish the role of ARG2 in the formation of corticomedullary urea and osmolality gradients and suggest that this enzyme attenuates kidney damage in ischemia-reperfusion injury

Increased Inflammasome Activation Is Associated with Aging and Chronic Myelomonocytic Leukemia Disease Severity.

Aging causes chronic low-grade inflammation known as inflamm-aging. It is a risk factor for several chronic disorders, including chronic myelomonocytic leukemia (CMML), a hematological malignancy that is most prevalent in older people. Recent studies suggest a critical role for the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome in inflamm-aging. However, the mechanisms involved in NLRP3 activation in aging and its involvement in CMML progression are not fully understood. In this study, we report that aging increases IL-1β production upon NLRP3 activation in human CD14+ monocytes. Interestingly, we found that the TLR1/2 agonist Pam3CSK4 directly activates the NLRP3 inflammasome in monocytes from older but not from younger healthy donors. Furthermore, we observed a dichotomous response to NLRP3 inflammasome activation in monocytes from a small cohort of CMML patients, and some patients produced high levels of IL-1β and some patients produced low levels of IL-1β compared with older healthy donors. Intriguingly, CMML patients with heightened NLRP3 activation showed increased treatment dependency and disease severity. Collectively, our results suggest that aging causes increased sensitivity to NLRP3 inflammasome activation at a cellular level, which may explain increased inflammation and immune dysregulation in older individuals. Furthermore, NLRP3 inflammasome activation was dysregulated in a small cohort of CMML patients and was positively correlated with disease severity

Mutual recognition of parental and F1 lymphocytes. Selective abrogation of eytotoxic potential of FI lymphoeytes by parental lymphocytes.J. Exp. Med

The injection of F1 hybrid animals with parental spleen or lymph node cells leads to the activation of specific parental lymphocytes which recognize major histocompatibility complex (MHC) 1-coded antigens of the other parental haplotype expressed by the F1 host (1). Such recognition can result in graft-vs.-host (GVH) reactions which are frequently associated with depressed in vivo cell-mediated immune functions, such as resistance to bacterial infection (2), skin graft rejection (2, 3), T-helper cell dysfunction (4), as well as antibody responses to thymic-dependent and-independent antigens (5-8). The depression of T-cell-mediated lympholysis (CML) responses by cells from F1 hybrid mice injected with parental lymphocytes has not been reported but could provide a useful approach for investigating T-cell receptors because self MHC-restricted as well as allogeneic CML responses can be analyzed. This report describes an experimental system in which intravenous injection of F1 hybrid mice with parental T-splenic lymphocytes can result in the abrogation or severe depression of CML potential. This loss of CML activity did not appear to be specific for self determinants because responses to alloantigens, trinitrophenyl (TNP)modified F1 cells (TNP-self), and TNP-modified parental cells were all affected. However, an unexpected finding was the observation that the parental-induced CML depression was dependent upon the H-2 type of the injected parental lymphocytes. Thus, the injection of H-2 a, H-2 k, or H-2 a, but not H-2 6, parental lymphocytes resulted in depressed CML potential. These findings are discussed with respect to (a) the selective resistance of F1 mice to H-2 b parental lymphocytes, and (b) the possibility that Fa lymphocytes recognize idiotypic determinants specific for non-H-2 b antigens on H-2 b lymphocytes, but not those for H-2 b antigens on non-H-2 b lymphocytes

Deletion of the serine protease CAP2/Tmprss4 leads to dysregulated renal water handling upon dietary potassium depletion

International audienc

Musique d'orchestre / Saint-Saëns, Chabrier, Ravel, comp. ; orchestre de la Suisse Romande ; Ernest Ansermet, dir.

Titre uniforme : [España. D 44]Titre uniforme : [Joyeuse marche. Orchestre. D 62]Titre uniforme : [Pavane pour une infante défunte. Orchestre. O 19]Titre uniforme : [Danse macabre. R 171 (Poème symphonique)]Titre uniforme : [Le rouet d'Omphale. R 169]Comprend : Danse macabre, op. 40 / Saint-Saëns, comp. - Le rouet d'Omphale, op. 31 / Saint-Saëns, comp. - Marche joyeuse / Chabrier, comp. - España / Chabrier, comp. - Pavane pour une infante défunte / Ravel, comp.BnF-Partenariats, Collection sonore - BelieveContient une table des matière