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Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality for which there are no evidence-based therapies. Here we report that concomitant metabolic and hypertensive stress in mice—elicited by a combination of high-fat diet and inhibition of constitutive nitric oxide synthase using N ω -nitro- l -arginine methyl ester ( l -NAME)—recapitulates the numerous systemic and cardiovascular features of HFpEF in humans. Expression of one of the unfolded protein response effectors, the spliced form of X-box-binding protein 1 (XBP1s), was reduced in the myocardium of our rodent model and in humans with HFpEF. Mechanistically, the decrease in XBP1s resulted from increased activity of inducible nitric oxide synthase (iNOS) and S -nitrosylation of the endonuclease inositol-requiring protein 1α (IRE1α), culminating in defective XBP1 splicing. Pharmacological or genetic suppression of iNOS, or cardiomyocyte-restricted overexpression of XBP1s, each ameliorated the HFpEF phenotype. We report that iNOS-driven dysregulation of the IRE1α–XBP1 pathway is a crucial mechanism of cardiomyocyte dysfunction in HFpEF. iNOS-driven dysregulation of the IRE1α–XBP1 pathway leads to cardiomyocyte dysfunction in mice and recapitulates the systemic and cardiovascular features of human heart failure with preserved ejection fraction.

Changes in the microbial community structure are observed in individuals with intestinal inflammatory disorders. These changes are often characterized by a depletion of obligate anaerobic bacteria, whereas the relative abundance of facultative anaerobic Enterobacteriaceae increases. The mechanisms by which the host response shapes the microbial community structure, however, remain unknown. We show that nitrate generated as a by-product of the inflammatory response conferred a growth advantage to the commensal bacterium Escherichia coli in the large intestine of mice. Mice deficient in inducible nitric oxide synthase did not support the growth of E. coli by nitrate respiration, suggesting that the nitrate generated during inflammation was host-derived. Thus, the inflammatory host response selectively enhances the growth of commensal Enterobacteriaceae by generating electron acceptors for anaerobic respiration.

A 51-year-old Iranian man presented with severe CMV infection, which proved to be fatal over the next 29 months. Investigation determined that he had a homozygous frameshift mutation in the gene encoding a nonfunctional NOS2 protein.

As traditional antidepressants act only after weeks/months, the discovery that ketamine, an antagonist of glutamate/ N -methyl- d -aspartate (NMDA) receptors, elicits antidepressant actions in hours has been transformative. Its mechanism of action has been elusive, though enhanced mammalian target of rapamycin (mTOR) signaling is a major feature. We report a novel signaling pathway wherein NMDA receptor activation stimulates generation of nitric oxide (NO), which S-nitrosylates glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Nitrosylated GAPDH complexes with the ubiquitin-E3-ligase Siah1 and Rheb, a small G protein that activates mTOR. Siah1 degrades Rheb leading to reduced mTOR signaling, while ketamine, conversely, stabilizes Rheb that enhances mTOR signaling. Drugs selectively targeting components of this pathway may offer novel approaches to the treatment of depression.

Nitric oxide (NO) production is critical for the host defense against intracellular pathogens; however, it is unclear whether NO-dependent control of intracellular organisms depends on cell-intrinsic or cell-extrinsic activity of NO. For example, NO production by infected phagocytes may enable these cells to individually control their pathogen burden. Alternatively, the ability of NO to diffuse across cell membranes might be critical for infection control. Here, using a murine ear infection model, we found that, during infection with the intracellular parasite Leishmania major, expression of inducible NO synthase does not confer a cell-intrinsic ability to lower parasite content. We demonstrated that the diffusion of NO promotes equally effective parasite killing in NO-producing and bystander cells. Importantly, the collective production of NO by numerous phagocytes was necessary to reach an effective antimicrobial activity. We propose that, in contrast to a cell-autonomous mode of pathogen control, this cooperative mechanism generates an antimicrobial milieu that provides the basis for pathogen containment at the tissue level.

MPTP-mouse model constitutes a well-known model of neuroinflammation and mitochondrial failure occurring in Parkinson's disease (PD). Although it has been extensively reported that nitric oxide (NO●) plays a key role in the pathogenesis of PD, the relative roles of nitric oxide synthase isoforms iNOS and nNOS in the nigrostriatal pathway remains, however, unclear. Here, the participation of iNOS/nNOS isoforms in the mitochondrial dysfunction was analyzed in iNOS and nNOS deficient mice. Our results showed that MPTP increased iNOS activity in substantia nigra and striatum, whereas it sharply reduced complex I activity and mitochondrial bioenergetics in all strains. In the presence of MPTP, mice lacking iNOS showed similar restricted mitochondrial function than wild type or mice lacking nNOS. These results suggest that iNOS-dependent elevated nitric oxide, a major pathological hallmark of neuroinflammation in PD, does not contribute to mitochondrial impairment. Therefore, neuroinflammation and mitochondrial dysregulation seem to act in parallel in the MPTP model of PD. Melatonin administration, with well-reported neuroprotective properties, counteracted these effects, preventing from the drastic changes in mitochondrial oxygen consumption, increased NOS activity and prevented reduced locomotor activity induced by MPTP. The protective effects of melatonin on mitochondria are also independent of its anti-inflammatory properties, but both effects are required for an effective anti-parkinsonian activity of the indoleamine as reported in this study.

Aims/hypothesis Diabetes results in the upregulation of the production of several components of the inflammatory response in the retina, including inducible nitric oxide synthase (iNOS). The aim of this study was to investigate the role of iNOS in the pathogenesis of the early stages of diabetic retinopathy using iNOS-deficient mice (iNos -/-). Materials and methods iNos -/- mice and wild-type (WT; C57BL/6J) mice were made diabetic with streptozotocin or kept as non-diabetic controls. Mice were killed at different time points after the induction of diabetes for assessment of vascular histopathology, cell loss in the ganglion cell layer (GCL), retinal thickness, and biochemical and physiological abnormalities. Results The concentrations of nitric oxide, nitration of proteins, poly(ADP-ribose) (PAR)-modified proteins, endothelial nitric oxide synthase, prostaglandin E₂, superoxide and leucostasis were significantly (p < 0.05) increased in retinas of WT mice diabetic for 2 months compared with non-diabetic WT mice. All of these abnormalities except PAR-modified proteins in retinas were inhibited (p < 0.05) in diabetic iNos -/- mice. The number of acellular capillaries and pericyte ghosts was significantly increased in retinas from WT mice diabetic for 9 months compared with non-diabetic WT controls, these increases being significantly inhibited in diabetic iNos -/- mice (p < 0.05 for all). Retinas from WT diabetic mice were significantly thinner than those from their non-diabetic controls, whereas diabetic iNos -/- mice were protected from this abnormality. We found no evidence of cell loss in the GCL of diabetic WT or iNos -/- mice. Deletion of iNos had no beneficial effect on diabetes-induced abnormalities on the electroretinogram. Conclusions/interpretation We demonstrate that the inflammatory enzyme iNOS plays an important role in the pathogenesis of vascular lesions characteristic of the early stages of diabetic retinopathy in mice.

Immunoglobulin-A (IgA) is the main immunoglobulin found in mucous sectretions. B cell class-switch recombination to IgA in mucosa-associated tissues is regulated by a subset of dendritic cells which produce TNF-α and inducible nitric oxide in response to the recognition of commensal bacteria by toll-like receptors Immunoglobulin-A has an irreplaceable role in the mucosal defence against infectious microbes 1 , 2 , 3 , 4 , 5 , 6 . In human and mouse, IgA-producing plasma cells comprise ∼20% of total plasma cells of peripheral lymphoid tissues, whereas more than 80% of plasma cells produce IgA in mucosa-associated lymphoid tissues (MALT) 1 , 2 , 3 , 4 , 5 , 6 . One of the most biologically important and long-standing questions in immunology is why this ‘biased’ IgA synthesis takes place in the MALT but not other lymphoid organs. Here we show that IgA class-switch recombination (CSR) is impaired in inducible-nitric-oxide-synthase-deficient ( iNOS -/- ; gene also called Nos2 ) mice. iNOS regulates the T-cell-dependent IgA CSR through expression of transforming growth factor-β receptor, and the T-cell-independent IgA CSR through production of a proliferation-inducing ligand (APRIL, also called Tnfsf13) and a B-cell-activating factor of the tumour necrosis factor (TNF) family (BAFF, also called Tnfsf13b). Notably, iNOS is preferentially expressed in MALT dendritic cells in response to the recognition of commensal bacteria by toll-like receptor. Furthermore, adoptive transfer of iNOS + dendritic cells rescues IgA production in iNOS -/- mice. Further analysis revealed that the MALT dendritic cells are a TNF-α/iNOS-producing dendritic-cell subset, originally identified in mice infected with Listeria monocytogenes 7 , 8 . The presence of a naturally occurring TNF-α/iNOS-producing dendritic-cell subset may explain the predominance of IgA production in the MALT, critical for gut homeostasis.

IgA secreting plasma cells in the lamina propria are shown to be an important source of iNOS and TNF required to maintain the homeostatic balance between intestinal microbes and the immune system. Gut lymphocytes strike a balance The gut contains a vast number of bacteria that are essential for the health of the organism, but it is also a rich source of lymphocytes that exist to eliminate infections. How do lymphocytes restrain themselves from attacking beneficial bacteria, yet maintain their ability to respond to true pathogens? Fritz et al . show that as B cells differentiate into plasma cells in the gut, they adopt a phenotype reminiscent of innate immune cells — inflammatory monocytes — while maintaining their ability to produce immunoglobulin. The resulting immunoglobulin-A-secreting plasma cells in the lamina propria are shown to be the main source of the antimicrobial mediators tumour necrosis factor-α and inducible nitric oxide synthase, which are required to maintain the homeostatic balance between intestinal microbes and the immune system. The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1 ). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells 2 . However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA + plasma cells also produce the antimicrobial mediators tumour-necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA + plasma cells can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multifunctional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNF-α and iNOS in B-lineage cells resulted in a reduction in IgA production, altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B-lineage cells.

Converging evidence supports the involvement of pro-inflammatory pathways and the gut microbiome in major depressive disorder (MDD). Pre-clinical and clinical studies suggest that decreasing pro-inflammatory signaling may provide clinical benefit in MDD. In this study, we used the chronic unpredictable stress (CUS) paradigm to assess whether mice lacking the pro-inflammatory caspase 1, interferon gamma-receptor, and nitric oxide synthase ( Casp1, Ifngr, Nos2 ) −/− present altered depressive- and anxiety-like behaviour at baseline and in response to CUS. In comparison to wild-type (wt) mice, ( Casp1, Ifngr, Nos2 ) −/− mice displayed decreased depressive- and anxiety-like behaviour, and increased hedonic-like behaviour and locomotor activity at baseline, and resistance to developing anhedonic-like behaviour and a heightened emotional state following stress. Plasma levels of ACTH and CORT did not differ between the triple knockout and wt mice following stress. The faecal microbiome of ( Casp1, Ifngr, Nos2 ) −/− mice differed from that of wt mice at baseline and displayed reduced changes in response to chronic stress. Our results demonstrate that simultaneous deficit in multiple pro-inflammatory pathways has antidepressant-like effects at baseline, and confers resilience to stress-induced anhedonic-like behaviour. Moreover, accompanying changes in the gut microbiome composition suggest that CASP1, IFNGR and NOS2 play a role in maintaining microbiome homeostasis.