In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors.

T helper (Th)17 cells producing interleukin (IL)-17 play a role in autoimmune and allergic inflammation. Here, we show that IL-23 induces IL-17 in the lung and IL-17 is required during antigen sensitization to develop allergic asthma, as shown in IL-17R-deficient mice. Since IL-17 expression increased further upon antigen challenge, we addressed its function in the effector phase. Most strikingly, neutralization of IL-17 augmented the allergic response in sensitized mice. Conversely, exogenous IL-17 reduced pulmonary eosinophil recruitment and bronchial hyperreactivity, demonstrating a novel regulatory role of IL-17. Mechanistically, IL-17 down modulated eosinophil-chemokine eotaxin (CCL11) and thymus- and activation-regulated chemokine/CCL17 (TARC) in lungs in vivo and ex vivo upon antigen restimulation. In vitro, IL-17 reduced TARC production in dendritic cells (DCs)-the major source of TARC-and antigen uptake by DCs and IL-5 and IL-13 production in regional lymph nodes. Furthermore, IL-17 is regulated in an IL-4-dependent manner since mice deficient for IL-4Ralpha signaling showed a marked increase in IL-17 concentration with inhibited eosinophil recruitment. Therefore, endogenous IL-17 is controlled by IL-4 and has a dual role. Although it is essential during antigen sensitization to establish allergic asthma, in sensitized mice IL-17 attenuates the allergic response by inhibiting DCs and chemokine synthesis.

OBJECTIVE

Obesity is associated with a low-grade inflammation, insulin resistance, and macrophage infiltration of adipose tissue. The role of CC chemokines and their respective receptors in human adipose tissue inflammation remains to be determined.

METHODS

sc and visceral adipose tissue of obese patients (body mass index 53.1 +/- 11.3 kg/m(2)) compared with lean controls (body mass index 25.9 +/- 3.8 kg/m(2)) was analyzed for alterations in inflammatory gene expression.

RESULTS

Macrophage infiltration was increased in sc and visceral adipose tissue of obese patients as determined by increased mRNA expression of a macrophage-specific marker (CD68) and by elevated macrophage infiltration. Gene expression of CC chemokines involved in monocyte chemotaxis (CCL2, CCL3, CCL5, CCL7, CCL8, and CCL11) and their receptors (CCR1, CCR2, CCR3, and CCR5) was higher in sc and visceral adipose tissue of obese patients. Serum concentrations of the inflammatory marker IL-6 and C-reactive protein were elevated in obese patients compared with lean controls. Obese patients revealed increased insulin resistance as assessed by the homeostasis model assessment of insulin resistance index and reduced plasma adiponectin concentrations. Adipose tissue expression of many CC chemokines and their receptors in the obese group positively correlated with CD68 expression.

CONCLUSIONS

Up-regulation of the CC chemokines and their respective receptors in adipose tissue occurs in human obesity and is associated with increased systemic inflammation.

Transgenic mice expressing the mouse interleukin 33 (IL-33) gene driven by a keratin 14 promoter were generated. The skin-selective expression of the IL-33 gene was enhanced, and intense immunofluorescence for IL-33 was evident in the nuclei of the epidermis. Spontaneous itchy dermatitis developed in those mice at 6-8 wk of age in specific pathogen-free conditions. In the lesional skin, the epidermis was thickened and the eosinophils were infiltrated with increased expression of the eosinophil peroxidase and major basic protein genes. Mast cells were also abundant there, and blood histamine and total IgE levels were high. Those phenotypes closely resemble the features of atopic dermatitis. In peripheral blood and lesional skin, IL-5, IL-13, regulated upon activation, normally T-expressed, and presumably secreted (RANTES)/CCL5, and Eotaxin 1/CCL11 were increased, whereas TNF-α, IFN-γ, and thymic stromal lymphopoietin (TSLP) were unaltered. Furthermore, the proportion of group 2 innate lymphoid cells (ILC2s), which produce IL-5, were significantly increased in the lesional skin, peripheral blood, and regional lymph nodes. The dermatitis with eosinophil infiltration was improved by the administration of an anti-IL-5 antibody. These results suggest that the expression of IL-33 in the skin activates an immune response involving ILC2 and that this process might play a crucial role in the pathogenesis of allergic inflammation that is characteristic of atopic dermatitis.

BACKGROUND

Juvenile idiopathic arthritis (JIA) consists of a heterogeneous group of disorders with, for the most part, an unknown immunopathogenesis. Although onset and disease course differ, the subtypes of JIA share the occurrence of chronic inflammation of the joints, with infiltrations of immunocompetent cells that secrete inflammatory mediators.

OBJECTIVE

To identify a panel of cytokines specifically related to the inflammatory process in JIA.

METHODS

Using a new technology, the multiplex immunoassay, 30 cytokines were measured in plasma of 65 patients with JIA, of which 34 were paired with synovial fluid. These data were compared with plasma of 20 healthy controls and 9 patients with type I diabetes, a chronic inflammatory disease.

RESULTS

Patients with JIA had, irrespective of their subclassification, significantly higher levels of tumour necrosis factor alpha, macrophage inhibitory factor (MIF), CCL2, CCL3, CCL11, CCL22 and CXCL9 in plasma than controls. In paired plasma and synovial fluid samples of patients with JIA, significantly higher levels of interleukin (IL)6, IL15, CCL2, CCL3, CXCL8, CXCL9 and CXCL10 were present in synovial fluid. Cluster analysis in all patients with JIA revealed a predominant pro-inflammatory cytokine cluster during active disease and a regulatory/anti-inflammatory-related cytokine cluster during remission. Whether a discrimination profile of various cytokines could help in the determination of disease classification was tested.

CONCLUSIONS

It is suggested that several cytokines (IL18, MIF, CCL2, CCL3, CCL11, CXCL9 and CXCL10) may correspond to the activation status during inflammation in JIA and could be instrumental in monitoring disease activity and outcomes of (new) immunotherapies.

BACKGROUND

Cryptococcal meningitis (CM)-related immune reconstitution inflammatory syndrome (IRIS) complicates antiretroviral therapy (ART) in 20%-40% of ART-naive persons with AIDS and prior CM. Pathogenesis is unknown.

METHODS

We compared initial cerebrospinal fluid (CSF) cultures, inflammatory markers, and cytokine profiles in ART-naive patients with AIDS who did or did not subsequently develop IRIS after starting ART. We also compared results obtained at IRIS events or CM relapse.

RESULTS

Of 85 subjects with CM, 33 (39%) developed CM-related IRIS and 5 (6%) developed culture-positive CM relapse. At CM diagnosis, subjects subsequently developing IRIS had less inflammation, with decreased CSF leukocytes, protein, interferon-gamma, interleukin-6, interleukin-8, and tumor necrosis factor-alpha, compared with subjects not developing IRIS (P<.05, for each). Initial CSF white blood cell counts < or =25 cells/microL and protein levels < or =50 mg/dL were associated with development of IRIS (odds ratio, 7.2 [95% confidence interval, 2.7-18.7]; P<.001). Compared with baseline levels, we identified CSF elevations of interferon-gamma, tumor necrosis factor-alpha, granulocyte colony-stimulating factor, vascular-endothelial growth factor, and eotaxin (CCL11) (P<.05, for each) at the time of IRIS but minimal inflammatory changes in those with CM relapse.

CONCLUSIONS

Patients who subsequently develop CM-related IRIS exhibit less initial CSF inflammation at the time of CM diagnosis, compared with those who do not develop IRIS. The inflammatory CSF cytokine profiles observed at time of IRIS can distinguish IRIS from CM relapse.

Allergic asthma is an inflammatory disease characterized by lung eosinophilia controlled by type 2 cytokines. Cysteine proteases are potent triggers of allergic inflammation by causing barrier disruption in lung epithelial cells inducing the elevation of interleukin-5 (IL-5) and IL-13 from natural helper (NH) cells, a member of ILC2s, which leads to lung eosinophilia. In this study, we found that basophils play a crucial role in NH cell-mediated eosinophilic inflammation induced by protease allergens. Conditional deletion of basophils caused a resolution of the papain-induced eosinophilia and mucus production. Resolution of eosinophilia was also observed in mice lacking IL-4 specifically in basophils, indicating that basophil-derived IL-4 enhanced expression of the chemokine CCL11, as well as IL-5, IL-9, and IL-13 in NH cells, thus attracting eosinophils. These results demonstrate that IL-4 from basophils has an important role in the NH-derived cytokine and chemokine expression, subsequently leading to protease allergen-induced airway inflammation.

It is now generally accepted type 2 T helper (Th2) cytokines and some chemoattractants play an essential role in the pathogenesis of the allergic inflammation. The effects of Th2 cytokines, such as interleukin (IL)-4, IL-5, IL-9, and IL-13, account for virtually all the pathophysiological manifestations of allergy and asthma. Moreover, both Th2 cells and the effector cells usually present in the areas of allergic inflammation (basophils, mast cells, and eosinophils) express chemoattractant receptors, such as CCR3, CCR4, CCR8 and CRTH2. Therefore, interactions of eotaxin(s), eotaxin/CCL11, RANTES/CCL5, and MCP-1/CCL2, MCP-2/CCL8, MCP-3/CCL7, MCP-4/CCL13 with CCR3 are responsible for the recruitment of basophils, eosinophils and mast cells, whereas interactions of CCR4 with MDC/CCL22 or TARC/CCL17, CCR8 with I-309/CCL1, and CRTH2 with prostaglandin D(2) play a critical role in the allergen-induced recruitment of Th2 cells in the target tissues of allergic inflammation. The demonstration that Th2-polarized responses against allergens represent the triggering event for the development of allergic diseases, together with the recognition that some chemoattractants are responsible for the recruitment of both Th2 cells and other effector cells of allergic inflammation, can provide the conceptual basis for the development of new therapeutic strategies in allergic conditions.

BACKGROUND

The diabetes mellitus drug metformin is under investigation in cardiovascular disease, but the molecular mechanisms underlying possible benefits are poorly understood.

OBJECTIVE

Here, we have studied anti-inflammatory effects of the drug and their relationship to antihyperglycemic properties.

RESULTS

In primary hepatocytes from healthy animals, metformin and the IKKβ (inhibitor of kappa B kinase) inhibitor BI605906 both inhibited tumor necrosis factor-α-dependent IκB degradation and expression of proinflammatory mediators interleukin-6, interleukin-1β, and CXCL1/2 (C-X-C motif ligand 1/2). Metformin suppressed IKKα/β activation, an effect that could be separated from some metabolic actions, in that BI605906 did not mimic effects of metformin on lipogenic gene expression, glucose production, and AMP-activated protein kinase activation. Equally AMP-activated protein kinase was not required either for mitochondrial suppression of IκB degradation. Consistent with discrete anti-inflammatory actions, in macrophages, metformin specifically blunted secretion of proinflammatory cytokines, without inhibiting M1/M2 differentiation or activation. In a large treatment naive diabetes mellitus population cohort, we observed differences in the systemic inflammation marker, neutrophil to lymphocyte ratio, after incident treatment with either metformin or sulfonylurea monotherapy. Compared with sulfonylurea exposure, metformin reduced the mean log-transformed neutrophil to lymphocyte ratio after 8 to 16 months by 0.09 U (95% confidence interval, 0.02-0.17; P=0.013) and increased the likelihood that neutrophil to lymphocyte ratio would be lower than baseline after 8 to 16 months (odds ratio, 1.83; 95% confidence interval, 1.22-2.75; P=0.00364). Following up these findings in a double-blind placebo controlled trial in nondiabetic heart failure (trial registration: NCT00473876), metformin suppressed plasma cytokines including the aging-associated cytokine CCL11 (C-C motif chemokine ligand 11).

CONCLUSIONS

We conclude that anti-inflammatory properties of metformin are exerted irrespective of diabetes mellitus status. This may accelerate investigation of drug utility in nondiabetic cardiovascular disease groups.

BACKGROUND

Name of the trial registry: TAYSIDE trial (Metformin in Insulin Resistant Left Ventricular [LV] Dysfunction). URL: https://www.clinicaltrials.gov. Unique identifier: NCT00473876.