Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty ...acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.
•Dietary fatty acids have profound influence on T cell differentiation in the gut•Middle- and long-chain fatty acids (LCFAs) support Th1 and Th17 cell differentiation•Short-chain fatty acids (SCFAs) lead to increased Treg cell differentiation•LCFAs worsen disease in an animal model of MS; SCFAs exert the opposite effect
Haghikia and colleagues show that dietary fatty acids (FAs) influence T cell differentiation in the gut, with short FAs leading to increased Treg cell differentiation and long FAs supporting Th1 and/or Th17 cell differentiation. These FAs differentially affect EAE severity, demonstrating a direct dietary impact on central nervous system autoimmunity.
Microglia are crucial for immune responses in the brain. Although their origin from the yolk sac has been recognized for some time, their precise precursors and the transcription program that is used ...are not known. We found that mouse microglia were derived from primitive c-kit(+) erythromyeloid precursors that were detected in the yolk sac as early as 8 d post conception. These precursors developed into CD45(+) c-kit(lo) CX(3)CR1(-) immature (A1) cells and matured into CD45(+) c-kit(-) CX(3)CR1(+) (A2) cells, as evidenced by the downregulation of CD31 and concomitant upregulation of F4/80 and macrophage colony stimulating factor receptor (MCSF-R). Proliferating A2 cells became microglia and invaded the developing brain using specific matrix metalloproteinases. Notably, microgliogenesis was not only dependent on the transcription factor Pu.1 (also known as Sfpi), but also required Irf8, which was vital for the development of the A2 population, whereas Myb, Id2, Batf3 and Klf4 were not required. Our data provide cellular and molecular insights into the origin and development of microglia.
Summary
A vast number of studies have demonstrated a remarkable role for the gut microbiota and their metabolites in the pathogenesis of inflammatory diseases, including multiple sclerosis (MS). ...Recent studies in experimental autoimmune encephalomyelitis, an animal model of MS, have revealed that modifying certain intestinal bacterial populations may influence immune cell priming in the periphery, resulting in dysregulation of immune responses and neuroinflammatory processes in the central nervous system (CNS). Conversely, some commensal bacteria and their antigenic products can protect against inflammation within the CNS. Specific components of the gut microbiome have been implicated in the production of pro‐inflammatory cytokines and subsequent generation of Th17 cells. Similarly, commensal bacteria and their metabolites can also promote the generation of regulatory T‐cells (Treg), contributing to immune suppression. Short‐chain fatty acids may induce Treg either by G‐protein‐coupled receptors or inhibition of histone deacetylases. Tryptophan metabolites may suppress inflammatory responses by acting on the aryl hydrocarbon receptor in T‐cells or astrocytes. Interestingly, secretion of these metabolites can be impaired by excess consumption of dietary components, such as long‐chain fatty acids or salt, indicating that the diet represents an environmental factor affecting the complex crosstalk between the gut microbiota and the immune system. This review discusses new aspects of host–microbiota interaction and the immune system with a special focus on MS as a prototype T‐cell‐mediated autoimmune disease of the CNS.
Recent studies revealed that modifying distinct intestinal bacterial populations may influence immune cell activation in the periphery, thus resulting in dysregulation of immune responses and neuroinflammatory processes in the central nervous system (CNS). While some bacteria and their antigenic products may protect against inflammation, others have been implicated in the production of pro‐inflammatory cytokines and subsequent generation of Th17 cells. This review discusses new aspects of host–microbiota interaction and the immune system with a special focus on multiple sclerosis as a prototype T‐cell‐mediated autoimmune disease of the CNS.
Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor ...activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-gamma, or tumor necrosis factor-alpha activate the tryptophan- and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes - counteracting this metabolism due to the lack of an enzyme of this metabolism - have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid.
Neutrophil gelatinase‐associated lipocalin (NGAL), a 25 kDa protein produced by injured nephron epithelia, is one of the most promising new markers of renal epithelial injury. In contrast to serum ...creatinine and urinary output, which are the measures of kidney function, NGAL is specifically induced in the damaged nephron and then released into blood and urine, where it can be readily measured. Careful proof‐of‐concept studies using defined animal models have uncovered the sources and trafficking of NGAL in acute kidney injury (AKI) and have addressed the contributions of renal and non‐renal sources. Clinical studies indicate that NGAL, unlike creatinine, is a marker responsive to tissue stress and nephron injury, but less so to adaptive hemodynamic responses. In certain clinical settings, NGAL is an earlier marker compared with serum creatinine. In addition, clinical studies have shown that NGAL is a powerful predictor of poor clinical outcomes, which can be used to risk stratify patients when combined with serum creatinine. NGAL has important limitations, including its responsiveness in systemic inflammation, which is partially uncoupled from its response to kidney injury and which needs to be considered when interpreting NGAL results clinically. This review covers the biology and pathophysiology of NGAL and summarizes the results of the growing body of clinical studies that have addressed the utility of NGAL in the early diagnosis of AKI, in the distinction of intrinsic AKI and in the prognostic assessment of broad patient populations.
Signs of an inflammatory process, in particular increased pro-inflammatory cytokines and increased levels of prostaglandine E(2) (PGE(2)), have repeatedly been described in major depression (MD). As ...cyclooxygenase-2 (COX-2) inhibitors inhibit the PGE(2) production and the production of pro-inflammatory cytokines, we performed a therapeutic trial with the COX-2 inhibitor celecoxib. In a prospective, double-blind, add-on study, 40 patients suffering from an acute depressive episode were randomly assigned to either reboxetine and celecoxib or to reboxetine plus placebo. After a wash-out period, 20 patients received 4-10 mg reboxetine plus placebo and 20 received reboxetine plus 400 mg celecoxib for 6 weeks. The treatment effect was calculated by analysis of variance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or reboxetine dose or plasma levels. Over 6 weeks, both groups of patients showed significant improvement in scores of the Hamilton Depression Scale. However, the celecoxib group showed significantly greater improvement compared to the reboxetine-alone group. Additional treatment with celecoxib has significant positive effects on the therapeutic action of reboxetine with regard to depressive symptomatology. Moreover, the fact that treatment with an anti-inflammatory drug showed beneficial effects on MD indicates that inflammation is related to the pathomechanism of the disorder, although the exact mechanisms remain to become elucidated.
A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory ...effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt-induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis.
In joint action literature it is often assumed that acting together is driven by pervasive and automatic process of co-representation, that is, representing the co-actor's part of the task in ...addition to one's own. Much of this research employs joint stimulus-response compatibility tasks varying the stimuli employed or the physical and social relations between participants. In this study we test the robustness of co-representation effects by focusing instead on variation in response modality. Specifically, we implement a mouse-tracking version of a Joint Simon Task in which participants respond by producing continuous movements with a computer mouse rather than pushing discrete buttons. We have three key findings. First, in a replication of an earlier study we show that in a classical individual Simon Task movement trajectories show greater curvature on incongruent trials, paralleling longer response times. Second, this effect largely disappears in a Go-NoGo Simon Task, in which participants respond to only one of the cues and refrain from responding to the other. Third, contrary to previous studies that use button pressing responses, we observe no overall effect in the joint variants of the task. However, we also detect a notable diversity in movement strategies adopted by the participants, with some participants showing the effect on the individual level. Our study casts doubt on the pervasiveness of co-representation, highlights the usefulness of mouse-tracking methodology and emphasizes the need for looking at individual variation in task performance.
Little is known about the effects of reduced sensory input and motor output in the human brain. Therefore, we conducted a longitudinal study to investigate whether limb immobilization after ...unilateral arm injury is reflected in structural plastic changes in gray matter (cortical thickness) and white matter (fractional anisotropy FA).
We examined 10 right-handed subjects with injury of the right upper extremity that required at least 14 days of limb immobilization. Subjects underwent 2 MRI examinations, the first within 48 hours postinjury and the second after an average time interval of 16 days of immobilization. Based on the MRI scans, we measured cortical thickness of sensorimotor regions and FA of the corticospinal tracts.
After immobilization, we revealed a decrease in cortical thickness in the left primary motor and somatosensory area as well as a decrease in FA in the left corticospinal tract. In addition, the motor skill of the left (noninjured) hand improved and is related to increased cortical thickness and FA in the right motor cortex.
The present study illustrates that cortical thickness of the sensorimotor cortex and FA of the corticospinal tract changed during right arm immobilization and that these changes are associated with skill transfer from the right to the left hand. Thus, immobilization induces rapid reorganization of the sensorimotor system. Given that limb immobilization is a standard intervention technique in constraint-induced therapy, therapists should be aware of both the positive and negative effects of this intervention.
The idea that increasing salt intake increases drinking and urine volume is widely accepted. We tested the hypothesis that an increase in salt intake of 6 g/d would change fluid balance in men living ...under ultra-long-term controlled conditions.
Over the course of 2 separate space flight simulation studies of 105 and 205 days' duration, we exposed 10 healthy men to 3 salt intake levels (12, 9, or 6 g/d). All other nutrients were maintained constant. We studied the effect of salt-driven changes in mineralocorticoid and glucocorticoid urinary excretion on day-to-day osmolyte and water balance.
A 6-g/d increase in salt intake increased urine osmolyte excretion, but reduced free-water clearance, indicating endogenous free water accrual by urine concentration. The resulting endogenous water surplus reduced fluid intake at the 12-g/d salt intake level. Across all 3 levels of salt intake, half-weekly and weekly rhythmical mineralocorticoid release promoted free water reabsorption via the renal concentration mechanism. Mineralocorticoid-coupled increases in free water reabsorption were counterbalanced by rhythmical glucocorticoid release, with excretion of endogenous osmolyte and water surplus by relative urine dilution. A 6-g/d increase in salt intake decreased the level of rhythmical mineralocorticoid release and elevated rhythmical glucocorticoid release. The projected effect of salt-driven hormone rhythm modulation corresponded well with the measured decrease in water intake and an increase in urine volume with surplus osmolyte excretion.
Humans regulate osmolyte and water balance by rhythmical mineralocorticoid and glucocorticoid release, endogenous accrual of surplus body water, and precise surplus excretion.
Federal Ministry for Economics and Technology/DLR; the Interdisciplinary Centre for Clinical Research; the NIH; the American Heart Association (AHA); the Renal Research Institute; and the TOYOBO Biotechnology Foundation. Food products were donated by APETITO, Coppenrath und Wiese, ENERVIT, HIPP, Katadyn, Kellogg, Molda, and Unilever.
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