Long‐term exercise‐specific neuroprotection in spinal muscular atrophy‐like mice

Key points

• The real impact of physical exercise parameters, i.e. intensity, type of contraction and solicited energetic metabolism, on neuroprotection in the specific context of neurodegeneration remains poorly explored.
• In this study behavioural, biochemical and cellular analyses were conducted to compare the effects of two different long‐term exercise protocols, high intensity swimming and low intensity running, on motor units of a type 3 spinal muscular atrophy (SMA)‐like mouse model.
• Our data revealed a preferential SMA‐induced death of intermediate and fast motor neurons which was limited by the swimming protocol only, suggesting a close relationship between neuron‐specific protection and their activation levels by specific exercise.
• The exercise‐induced neuroprotection was independent of SMN protein expression and associated with specific metabolic and behavioural adaptations with notably a swimming‐induced reduction of muscle fatigability.
• Our results provide new insight into the motor units’ adaptations to different physical exercise parameters and will contribute to the design of new active physiotherapy protocols for patient care.

Abstract

Spinal muscular atrophy (SMA) is a group of autosomal recessive neurodegenerative diseases differing in their clinical outcome, characterized by the specific loss of spinal motor neurons, caused by insufficient level of expression of the protein survival of motor neuron (SMN). No cure is at present available for SMA. While physical exercise might represent a promising approach for alleviating SMA symptoms, the lack of data dealing with the effects of different exercise types on diseased motor units still precludes the use of active physiotherapy in SMA patients. In the present study, we have evaluated the efficiency of two long‐term physical exercise paradigms, based on either high intensity swimming or low intensity running, in alleviating SMA symptoms in a mild type 3 SMA‐like mouse model. We found that 10 months’ physical training induced significant benefits in terms of resistance to muscle damage, energetic metabolism, muscle fatigue and motor behaviour. Both exercise types significantly enhanced motor neuron survival, independently of SMN expression, leading to the maintenance of neuromuscular junctions and skeletal muscle phenotypes, particularly in the soleus, plantaris and tibialis of trained mice. Most importantly, both exercises significantly improved neuromuscular excitability properties. Further, all these training‐induced benefits were quantitatively and qualitatively related to the specific characteristics of each exercise, suggesting that the related neuroprotection is strongly dependent on the specific activation of some motor neuron subpopulations. Taken together, the present data show significant long‐term exercise benefits in type 3 SMA‐like mice providing important clues for designing rehabilitation programmes in patients.

Abbreviations

ChAT

choline acetyltransferase

Chodl

chondrolectin

CK

creatine kinase

CMAP

compound muscle action potential

ERRβ

oestrogen‐related receptor β

MyHC

myosin heavy chain

NMJ

neuromuscular junction

SMA

spinal muscular atrophy

SMN

survival of motor neuron

TBS

Tris‐buffered solution

     

Self‐recognition in everyday life

Introduction: A sample of everyday difficulties was collected, encompassing errors and unusual experiences participants had encountered when recognising their own faces in everyday life, with the aim of characterising similarities and differences between the reported difficulties and the major forms of self‐recognition impairments described in the neuropsychological and neuropsychiatric literatures (prosopagnosia, mirrored‐self misidentification, and Capgras delusion).

Method. A total of 70 participants recalled experiences from memory. Incidents (n = 51) were recorded on questionnaire sheets that were filled out at home. Reports of three categories of incidents were analysed: misidentifications (the participant misidentified her/his own face as being that of another familiar person; n = 5), recognition failures (the participant judged that his/her own face was that of an unfamiliar person; n = 20) and perception of unusual aspects (the participant confidently recognised his/her own face but found that the seen face did not fit well the representation she/he had of his/her own face; n = 26).

Results and discussion. In the reported incidents, experiences showing some similarities to those of patients with prosopagnosia, Capgras delusion or mirrored‐self misidentification were noted. However, across the whole study, no incident involved a failure of reality testing; in contrast to pathological forms of error, in all of the reported incidents from our study the participant realised that a mistake had been made. The importance of decision processes in pathological forms of own‐face misrecognition is discussed.     

Carvedilol Modulates In‐Vitro Granulocyte‐Macrophage Colony‐Stimulating Factor‐Induced Interleukin‐10 Production in U937 Cells and Human Monocytes

Both granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and interleukin‐10 (IL‐10) are important mediators regulating inflammatory responses. Inflammatory processes have an important role in atherogenesis. In this paper, the effects of carvedilol on GM‐CSF‐induced IL‐10 production were examined on human monocytic cell line, U937, and purified human monocytes. First, we showed that one‐time carvedilol pretreatment at concentrations 0.3–10 μM dose‐dependently inhibited GM‐CSF‐induced IL‐10 production in U937 cells. In addition, we found carvedilol to be non‐cytotoxic at concentrations equal to or less than 10 μM. However, at concentrations higher than 10 μM, carvedilol induced programmed cell death in U937 cells. The inhibition of GM‐CSF‐induced IL‐10 production by carvedilol was also observed at the expression of mRNA. Furthermore, the inhibition of IL‐10 production was demonstrated in GM‐CSF‐activated purified human peripheral blood monocytes. Finally, long‐term carvedilol pretreatment of U937 cells up to 2 months at concentrations of 1.0 μM mildly enhanced the IL‐10 production. Our observations that carvedilol modulated GM‐CSF‐induced IL‐10 production may have some implication in understanding the broad‐spectrum effects of carvedilol in regulating inflammatory reactions.     

Electrophysiological correlates of word meanings in 14‐month‐old human infants

Two studies were conducted in a preliminary attempt to determine whether electrophysiological procedures could be used to study early word learning in young infants. In Experiment 1, auditory evoked responses (AERs) were recorded from the frontal, temporal, and parietal scalp regions of a group of 14‐month‐old infants while they listened to a series of words. The brain responses reliably discriminated between words the infants were thought (by their parents and two independent raters) to understand versus those that they did not appear to know. A second experiment was conducted with a different group of infants to determine whether familiarity with the sounds alone could produce similar brainwave differences. This study, although showing that the brain‐wave patterns could discriminate familiar from novel speech‐sound sequences, did not demonstrate findings identical to those reported for differences in word understanding. These data are the first indication that AERs can be used to detect differences in word meanings in infants.     

Hyper‐responsive Toll‐like receptor 7 and 9 activation in NADPH oxidase‐deficient B lymphoblasts

Chronic granulomatous disease (CGD) is an inherited immunodeficiency linked with mutations in the multi-subunit leucocyte NADPH oxidase. Myeloid-derived phagocytic cells deficient in NADPH oxidase fail to produce sufficient levels of reactive oxygen species to clear engulfed pathogens. In this study we show that oxidase also influences B-cell functions, including responses to single-stranded RNA or unmethylated DNA by endosomal Toll-like receptors (TLRs) 7 and 9. In response to TLR7/9 ligands, B-cell lines derived from patients with CGD with mutations in either the NADPH oxidase p40^phox or p47^phox subunits produced only low levels of reactive oxygen species. Remarkably, cytokine secretion and p38 mitogen-activated protein kinase activation by these oxidase-deficient B cells was significantly increased upon TLR7/9 activation when compared with oxidase-sufficient B cells. Increased TLR responsiveness was also detected in B cells from oxidase-deficient mice. NADPH oxidase-deficient patient-derived B cells also expressed enhanced levels of TLR7 and TLR9 mRNA and protein compared with the same cells reconstituted to restore oxidase activity. These data demonstrate that the loss of oxidase function associated with CGD can significantly impact B-cell TLR signalling in response to nucleic acids with potential repercussions for auto-reactivity in patients.     

The H‐Y Response in Mid‐Gestation and Long After Delivery in Mice Primed Before Pregnancy

The mechanisms underlying maternal tolerance of the semi‐allogeneic fetus are not completely understood. The maternal immune system's response to the male antigen, H‐Y is an example of the conflicting evidence that both supports and refutes the idea that the immune system in pregnant females is fundamentally different from that in non‐pregnant females. Although multiple pregnancies may inactivate H‐Y specific T cells, the immune system of the pregnant female can also generate a cytotoxic response to this antigen. To help understand this apparent conflict, we immunized female mice against H‐Y with male spleen cells before pregnancy and examined the subsequent anti H‐Y response during mid‐pregnancy. The pregnant mice studied were able to mount cytotoxic immune responses to H‐Y that were equivalent to those generated in their non‐pregnant counterparts. Moreover the experience of pregnancy did not impair the ability to maintain immunologic memory to H‐Y. The data support the idea that pregnancy does not violate general rules of antigen specific immunity, even if the antigen is expressed on the fetus.     

Sex‐related differences in premature cardiovascular disease in familial hypercholesterolemia

BackgroundFamilial hypercholesterolemia (FH) is associated with an increased prevalence of premature atherosclerotic cardiovascular disease (ASCVD), however, little is known about sex-specific differences in premature ASCVD and its risk factors.ObjectiveThe present study seeks to assess the burden and risk factors for premature ASCVD among men and women with FH.MethodsIn this study we retrospectively examined sex-specific differences in ASCVD prevalence, risk factor burdens, and lipid treatment outcomes in 782 individuals with clinically or genetically confirmed FH treated in 5 U.S. lipid and genetics clinics. A generalized linear model using Binomial distribution with random study site effect and sex-stratified analysis was used to determine the strongest predictors of premature ASCVD, and lipid treatment outcomes. Covariates included age, sex, diabetes mellitus (DM), hypertension, and current smoking.ResultsAmong the cohort, 98/280 men (35%) and 89/502 women (18%) had premature ASCVD (defined as <55 years in men and <65 years in women). Women with premature ASCVD had higher mean treated total cholesterol (216 vs. 179 mg/dl, p=<0.001) and LDL-C (135 vs. 109 mg/dl, p= 0.005).ConclusionThese data confirm that high percentages of women and men with FH develop premature ASCVD, and suggest that FH may narrow the observed sex difference in premature ASCVD onset. These data support more aggressive prevention and treatment strategies in FH, including in women, to reduce non-lipid risk factors and residual hypercholesterolemia.     

Effect of L‐Arginine on Age‐Related Changes in Macrophage Phagocytic Activity

Aging is associated with decline in the functioning of immune cells and reductions in serum L‐arginine and excretion of nitric oxide metabolites. Studies have shown that L‐arginine plays an important role in many physiological, biological and immunological processes. The present study was performed to determine if treatment with L‐arginine could prevent age‐related changes in phagocytic function of peritoneal macrophages. The effects of L‐arginine on phagocytic activity of peritoneal macrophages were compared between young and middle‐aged rats. Studies were performed in four groups of rats for 8 weeks: group 1 (3 month‐old) received physiological saline; group 2 (3 month‐old) received L‐arginine (160 mg/kg/day); group 3 (12 month‐old) received physiological saline; group 4 (12 month‐old) received L‐arginine (160 mg/kg/day). There were no significant differences in percentage of cells which were phagocytized. However, the phagocytosis of activated charcoal by peritoneal macrophages reduced with age. Thus, the phagocytic index was lower in macrophages of middle‐aged rats. L‐arginine treatment increased phagocytosis by peritoneal macrophages of both young and middle‐aged rats. L‐arginine‐induced augmentation in phagocytosis by macrophages were much higher in the middle‐aged rats compared with young rats. In summary, we found that L‐arginine prevented the age‐related reduction in phagocytic capability of peritoneal macrophages.     

A shift in paradigm towards human biology‐based systems for cholestatic‐liver diseases

IntroductionLiver and gall bladder diseases are very common all over the world, posing a significant health burden worldwide (Shaheen et al. 2006; Williams, 2006). It is now known that diseases related to modern lifestyle such as obesity, diabetes, non‐alcoholic fatty liver disease and other nutritional/metabolic disorders are either the cause or the consequences of liver and gall bladder diseases (Fig. 1). Liver is a very complex vital organ performing a diverse range of metabolic functions including the regulation of carbohydrate metabolism; lipid synthesis and secretion of plasma lipoproteins; cholesterol metabolism; synthesis and secretion of bile salts; digestion; storage of nutrients, vitamins and minerals; synthesis and secretion of serum albumin, clotting factors, enzymes and other proteins; ammonia detoxification through urea and glutamine formation; and biotransformation/detoxification of drugs and other xenobiotics. Liver disorders can result from various insults such as infections, drugs, toxins, ischaemia and autoimmune disorders. Persisting disturbances in liver functions due to resulting hepatocellular injury lead to chronic liver disease(s). The diverse functions of liver are performed by parenchymal (hepatocytes) and non‐parenchymal cells (mainly Kupffer cells, stellate cells, sinusoidal endothelial cells and biliary epithelial cells) communicating and working together. The liver parenchyma accounts for approximately 60% of total liver mass with non‐parenchymal cells making up the rest.Open in a separate windowFigure 1 Diseases of civilization are usually a cause or consequence of liver and gall bladder diseases Biliary epithelial cells or cholangiocytes constitute around 5% of liver cells (Sirica et al. 2008). These form an intricate network of tiny channels (bile canaliculi) that merge to form the bile ducts channeling and collecting bile from liver lobules for storage in the gall bladder and subsequent intestinal secretion. Cholangiocytes that line the bile ducts have secretory functions and those that line the smaller bile ducts and canaliculi play roles in inflammatory and proliferative responses.Bile mainly comprises the bile acids (BAs), which are the end products of cholesterol metabolism. From cholesterol to BAs, there are 17 energy consuming enzymatic reactions (Russell, 2009); and hence a very efficient and controlled recycling system for BAs exists in humans. About 95% of BAs are reabsorbed through the enterohepatic circulation. The functional BA pool is maintained by an extended system of transporters (Thomas et al. 2008) as shown in Fig. 2. As hepatocytes in the liver are organized over the sinusoids, specific hepatic transporters are expressed at the polarized membranes (Table 1). These transporters are involved in adaptive response to BAs overload and accumulation e.g. in disease conditions such as cholestasis. BAs, having hormonal functions; exert effects via the nuclear receptors (Fig. 3) in the regulation of a variety of metabolic effects – including glucose, lipid and energy metabolism (Watanabe et al. 2006; Lefebvre et al. 2009; Wei et al. 2009; Torres et al. 2012; Li & Chiang, 2015); cholesterol uptake, metabolism and secretion (De Fabiani et al. 2003); xenobiotic metabolism (Hofmann & Hagey, 2008; Zollner & Trauner, 2009); endocrine (Houten et al. 2006; Keitel et al. 2008) and immunological signalling (Ishizawa et al. 2008; Makishima et al. 2002) – and have antimicrobial effects in the digestive tract (Begley et al. 2005; Kurdi et al. 2006).ConclusionCLDs are complex and although manifest as cholestasis resulting from perturbed bile acid homeostasis, they are intertwined with glucose, lipid and energy metabolism as well as the immune response of the patient. Such complex pathogenesis requires a systems understanding leaning on new technologies. Although animal studies have advanced our knowledge of CLDs, there has not been significant clinical translation of that knowledge in the treatment or prevention of these diseases. There is a huge amount of clinical and animal data available on cholestasis. Modern in vitro methods based on human cells (and co‐cultures) maintained in in vivo‐like conditions provide an invaluable tool for the investigation and validation of human‐relevant mechanisms involved in the development of cholestasis and its progression. Omics technologies and computational modelling will enhance the knowledge and allow prediction. The shift in paradigm towards a human‐relevant systems approach to the understanding of cholestasis seems essential to bring a breakthrough that will pave the way for new therapeutic options for CLDs and eventually personalized therapy.     

Impact of sympathetic nervous system activity on post‐exercise flow‐mediated dilatation in humans

AbstractTransient reduction in vascular function following systemic large muscle group exercise has previously been reported in humans. The mechanisms responsible are currently unknown. We hypothesised that sympathetic nervous system activation, induced by cycle ergometer exercise, would contribute to post‐exercise reductions in flow‐mediated dilatation (FMD). Ten healthy male subjects (28 ± 5 years) undertook two 30 min sessions of cycle exercise at 75% HR_max. Prior to exercise, individuals ingested either a placebo or an α₁‐adrenoreceptor blocker (prazosin; 0.05 mg kg⁻¹). Central haemodynamics, brachial artery shear rate (SR) and blood flow profiles were assessed throughout each exercise bout and in response to brachial artery FMD, measured prior to, immediately after and 60 min after exercise. Cycle exercise increased both mean and antegrade SR (P < 0.001) with retrograde SR also elevated under both conditions (P < 0.001). Pre‐exercise FMD was similar on both occasions, and was significantly reduced (27%) immediately following exercise in the placebo condition (t‐test, P = 0.03). In contrast, FMD increased (37%) immediately following exercise in the prazosin condition (t‐test, P = 0.004, interaction effect P = 0.01). Post‐exercise FMD remained different between conditions after correction for baseline diameters preceding cuff deflation and also post‐deflation SR. No differences in FMD or other variables were evident 60 min following recovery. Our results indicate that sympathetic vasoconstriction competes with endothelium‐dependent dilator activity to determine post‐exercise arterial function. These findings have implications for understanding the chronic impacts of interventions, such as exercise training, which affect both sympathetic activity and arterial shear stress.

Abbreviations

BF

blood flow

CO

cardiac output

FMD

flow‐mediated dilatation

HR

heart rate

LBNP

lower body negative pressure

MAP

mean arterial pressure

MSNA

muscle sympathetic nerve activity

SNS

sympathetic nervous system

SR

shear rate

SR_AUC

shear rate area under curve

SV

stroke volume

TPRi

total peripheral resistance index

     

Open‐ and closed‐loop smooth‐pursuit eye movements in normal children: An analysis of a step‐ramp task

We previously reported that the visual ability to track a moving target (smooth‐pursuit tracking) improves as children age from 8 to 15 years old. This study used infrared oculography during step‐ramp tasks to determine whether the age‐related improvement in smooth‐pursuit tracking is due to developmental changes in the ability to perceive and match eye velocity to target velocity (open‐loop tracking). Infrared oculography was used to assess the ability to track a moving stimulus (smooth‐pursuit tracking) during step‐ramp tasks in 51 normal children between 8 and 15 years old. The first 100 msec of tracking (initial pursuit) occurs before any visual feedback (open‐loop tracking) and represents sensorimotor transformation. Ongoing pursuit (measured by smooth‐pursuit gain) includes feedback information as to the success of pursuit (closed‐loop pursuit) and depends on sensorimotor transformation as well as higher order abilities, including the ability to sustain focused attention. Open‐loop pursuit is not affected by age of the subject. In contrast, during closed‐loop pursuit, when target step and target motion are in opposite directions, age is significantly correlated with closed‐loop pursuit gain, Spearman's R = 0.40, p < .003. The ability to perceive and match eye velocity to target velocity is fully developed by 8 years of age.     

Theory of mind and perceptual context‐processing in schizophrenia

Introduction. A series of studies have suggested that schizophrenia patients are deficient in theory of mind (ToM). However, the cognitive mechanisms underlying ToM deficits in schizophrenia are largely unknown. The present study examined the hypothesis that impaired ToM in schizophrenia can be understood as a deficit in context processing.

Methods. Disorganised schizophrenia patients (N = 12), nondisorganised schizophrenia patients (N = 36), and nonpsychotic psychiatric patients (N = 26) were tested on three ToM tasks and a visual size perception task, a measure of perceptual context processing. In addition, statistical analyses were carried out which compared chronic, treatment‐refractory schizophrenia patients (N = 28) to those with an episodic course of illness (N = 20).

Results. Overall, ToM performance was linked to deficits in context processing in schizophrenia patients. Statistical comparisons showed that disorganised as well as chronic schizophrenia patients were more impaired in ToM but more accurate in a visual size perception task where perceptual context is misleading.

Conclusions. This pattern of results is interpreted as indicating a possible link between deficits in ToM and perceptual context processing, which together with deficits in perceptual grouping, are part of a broader dysfunction in cognitive coordination in schizophrenia.     

Selective attention to threatening faces in delusion‐prone individuals

Introduction. Selective attention to threat‐related information has been associated with clinical delusions in schizophrenia and nonclinical delusional ideation in healthy individuals. However, it is unclear whether biased attention for threat reflects early engagement effects on selective attention, or later difficulties in disengaging attention from perceived threat. The present study examined which of these processes operate in nonclinical delusion‐prone individuals.

Methods. A total of 100 psychologically healthy participants completed the Peters et al. () Delusions Inventory (PDI). Twenty‐two scoring in the upper quartile (high‐PDI group) and 22 scoring in the lower quartile (low‐PDI group) completed a modified dot‐probe task. Participants detected dot‐probes appearing 200, 500, or 1250 ms after an angry‐neutral face pair or a happy‐neutral face pair.

Results. High‐PDI individuals responded faster to dot‐probes presented in the same location as angry compared to happy faces at the short 200 ms stimulus onset asynchrony (SOA), but only when the emotional faces were presented to the left visual field. At the two longer SOAs (500 ms, 1250 ms), the high‐PDI group were also faster to respond to dot‐probes presented in the same location as angry compared to happy faces and slower to respond to dot‐probes presented in different spatial locations to angry (vs. happy) faces. The latter effects were seen whether emotional faces were presented to the left or the right visual field.

Conclusions. Results support the operation of emotion‐selective engagement and defective disengagement for threat‐related facial expressions (i.e., anger) in delusion‐prone individuals.     

GABAB receptor‐mediated feed‐forward circuit dysfunction in the mouse model of fragile X syndrome

Key points

• Cortico‐hippocampal feed‐forward circuits formed by the temporoammonic (TA) pathway exhibit a marked increase in excitation/inhibition ratio and abnormal spike modulation functions in Fmr1 knock‐out (KO) mice.
• Inhibitory, but not excitatory, synapse dysfunction underlies cortico‐hippocampal feed‐forward circuit abnormalities in Fmr1 KO mice.
• GABA release is reduced in TA‐associated inhibitory synapses of Fmr1 KO mice in a GABA_B receptor‐dependent manner.
• Inhibitory synapse and feed‐forward circuit defects are mediated predominately by presynaptic GABA_B receptor signalling in the TA pathway of Fmr1 KO mice.
• GABA_B receptor‐mediated inhibitory synapse defects are circuit‐specific and are not observed in the Schaffer collateral pathway‐associated inhibitory synapses in stratum radiatum.

Abstract

Circuit hyperexcitability has been implicated in neuropathology of fragile X syndrome, the most common inheritable cause of intellectual disability. Yet, how canonical unitary circuits are affected in this disorder remains poorly understood. Here, we examined this question in the context of the canonical feed‐forward inhibitory circuit formed by the temporoammonic (TA) branch of the perforant path, the major cortical input to the hippocampus. TA feed‐forward circuits exhibited a marked increase in excitation/inhibition ratio and major functional defects in spike modulation tasks in Fmr1 knock‐out (KO) mice, a fragile X mouse model. Changes in feed‐forward circuits were caused specifically by inhibitory, but not excitatory, synapse defects. TA‐associated inhibitory synapses exhibited increase in paired‐pulse ratio and in the coefficient of variation of IPSPs, consistent with decreased GABA release probability. TA‐associated inhibitory synaptic transmission in Fmr1 KO mice was also more sensitive to inhibition of GABA_B receptors, suggesting an increase in presynaptic GABA_B receptor (GABA_BR) signalling. Indeed, the differences in inhibitory synaptic transmission between Fmr1 KO and wild‐type (WT) mice were eliminated by a GABA_BR antagonist. Inhibition of GABA_BRs or selective activation of presynaptic GABA_BRs also abolished the differences in the TA feed‐forward circuit properties between Fmr1 KO and WT mice. These GABA_BR‐mediated defects were circuit‐specific and were not observed in the Schaffer collateral pathway‐associated inhibitory synapses. Our results suggest that the inhibitory synapse dysfunction in the cortico‐hippocampal pathway of Fmr1 KO mice causes hyperexcitability and feed‐forward circuit defects, which are mediated in part by a presynaptic GABA_BR‐dependent reduction in GABA release.

Abbreviations

AP

action potential

APV

2‐amino‐5‐phosphonopentanoic acid

CV

coefficient of variation

DNQX

6,7‐dinitroquinoxaline‐2,3‐dione

E/I

excitatory/inhibitory

EPSP

excitatory postsynaptic potential

FFI

feed‐forward inhibitory

FMRP

fragile X mental retardation protein

Fmr1

fragile X mental retardation 1

FWHM

full‐width half‐maximum

FXS

fragile X syndrome

GABA_AR

γ‐aminobutyric acid type A receptor

GABA_BR

γ‐aminobutyric acid type B receptor

IPSP

inhibitory postsynaptic potential

KO

knock‐out

PPR

paired‐pulse ratio

RMS

root mean square

SC

Schaffer collateral

SLM

stratum lacunosum moleculare

SR

stratum radiatum

TA

temporoammonic

WT

wild‐type

     

Interleukin‐23 (IL‐23), independent of IL‐17 and IL‐22, drives neutrophil recruitment and innate inflammation during Clostridium difficile colitis in mice

Our objective was to determine the role of the inflammatory cytokine interleukin‐23 (IL‐23) in promoting neutrophil recruitment, inflammatory cytokine expression and intestinal histopathology in response to Clostridium difficile infection. Wild‐type (WT) and p19^−/− (IL‐23KO) mice were pre‐treated with cefoperazone in their drinking water for 5 days, and after a 2‐day recovery period were challenged with spores from C. difficile strain VPI 10463. Interleukin‐23 deficiency was associated with significant defects in both the recruitment of CD11b^High Ly6G^High neutrophils to the colon and the expression of neutrophil chemoattractants and stabilization factors including Cxcl1, Cxcl2, Ccl3 and Csf3 within the colonic mucosa as compared with WT animals. Furthermore, the expression of inflammatory cytokines including Il33, Tnf and Il6 was significantly reduced in IL‐23‐deficient animals. There was also a trend towards less severe colonic histopathology in the absence of IL‐23. The induction of Il17a and Il22 was also significantly abrogated in IL‐23KO mice. Inflammatory cytokine expression and neutrophilic inflammation were not reduced in IL‐17a‐deficient mice or in mice treated with anti‐IL‐22 depleting monoclonal antibody. However, induction of RegIIIg was significantly reduced in animals treated with anti‐IL‐22 antibody. Taken together, these data indicate that IL‐23, but not IL‐17a or IL‐22, promotes neutrophil recruitment and inflammatory cytokine and chemokine expression in the colon in response to C. difficile infection.     

A Toxicokinetic Study of Nickel‐Induced Immunosuppression in Rats

Abstract

The aim of the present study was to investigate dose‐ and time‐dependent effects of NiCl₂ on T‐lymphocyte and macrophage‐derived cytokine production in rats. Moreover we have determined the concentrations of nickel in the plasma that are required to elicit alterations in T‐lymphocyte and macrophage function. NiCl₂ suppressed T‐lymphocyte proliferation and Th1 (IFN‐γ) and Th2 (IL‐10) cytokine production in a dose‐ and time‐dependent fashion. In addition, NiCl₂ inhibited production of the pro‐inflammatory cytokine TNF‐α and increased production of the anti‐inflammatory cytokine IL‐10 from lipopolysaccharide (LPS) stimulated cultures. We have determined that the minimal plasma concentrations of nickel required to provoke immunosuppression are in the range 209–585 ng/mL. In the time‐course study NiCl₂ (3.3 mg/kg) provoked immunological changes that were maximal 1 h following administration, and some of these changes persisted for up to 24 h post administration. Overall these data clearly demonstrate that NiCl₂ suppresses T‐cell function and promotes an immunosuppressive macrophage phenotype in rats. This study also indicates that measuring T‐cell proliferation is as sensitive a marker of NiCl₂‐induced immunotoxicity as measuring T‐cell or macrophage cytokine production. Co‐measurement of circulating nickel concentrations and immune parameters yields valuable information with regard to the potency of nickel to alter immune function in vivo. These data also suggest that quite a large quantity of nickel needs to reach the systemic circulation before any adverse effects on immune function are observed.