Heart failure (HF) is a leading cause of mortality. Inflammation is implicated in HF, yet clinical trials targeting pro-inflammatory cytokines in HF were unsuccessful, possibly due to redundant functions of individual cytokines. Searching for better cardiac inflammation targets, here we link T cells with HF development in a mouse model of pathological cardiac hypertrophy and in human HF patients. T cell costimulation blockade, through FDA-approved rheumatoid arthritis drug abatacept, leads to highly significant delay in progression and decreased severity of cardiac dysfunction in the mouse HF model. The therapeutic effect occurs via inhibition of activation and cardiac infiltration of T cells and macrophages, leading to reduced cardiomyocyte death. Abatacept treatment also induces production of anti-inflammatory cytokine interleukin-10 (IL-10). IL-10-deficient mice are refractive to treatment, while protection could be rescued by transfer of IL-10-sufficient B cells. These results suggest that T cell costimulation blockade might be therapeutically exploited to treat HF.

The phosphoinositide 3-kinase γ (PI3Kγ) plays a major role in leukocyte recruitment during acute inflammation and has been proposed to inhibit classical macrophage activation by driving immunosuppressive gene expression. PI3Kγ plays an important role in diet-induced obesity and insulin resistance. In seeking to determine the underlying molecular mechanisms, we showed that PI3Kγ action in high-fat diet-induced inflammation and insulin resistance depended largely on its role in the control of adiposity, which was due to PI3Kγ activity in a nonhematopoietic cell type. However, PI3Kγ activity in leukocytes was required for efficient neutrophil recruitment to adipose tissue. Neutrophil recruitment was correlated with proinflammatory gene expression in macrophages in adipose tissue, which triggered insulin resistance early during the development of obesity. Our data challenge the concept that PI3Kγ is a general suppressor of classical macrophage activation and indicate that PI3Kγ controls macrophage gene expression by non-cell-autonomous mechanisms, the outcome of which is context-dependent.

In this study the effects of administration of cortisone acetate (100 mg kg-1 body weight subcutaneously for 11 days) on distribution and cross-sectional area of different fibre types of rat skeletal muscles were investigated. Diaphragm, parasternal intercostal (PI), extensor digitorum longus (EDL) and soleus muscles were examined in cortisone treated animals (CA) in comparison with ad libitum controls (CTRL) and pair-fed (PF) controls. Four fibre types (I or slow and IIA, IIX, IIB or fast) were identified on the basis of their myosin heavy chain composition using a set of monoclonal antibodies. In CA rats the reduction of cross-sectional area was above 30% in IIX fibres of diaphragm, IIB fibres of PI and in all fast fibres of EDL. In all muscles slow fibres were spared from atrophy. Significant variations in fibre type distribution were found in the muscles of CA rats when compared to CTRL. The percentage of IIB fibres decreased in EDL, PI and diaphragm. This decrease was accompanied by an increase in the percentage of IIA fibres in the same muscles. No changes in the percentage of slow fibres and of fast IIX fibres were observed in EDL, PI and diaphragm of CA rats in comparison with CTRL. In soleus of CA rats the proportion of IIA fibres was lower than in CTRL. In EDL of PF rats atrophy of IIA fibres and changes in fibre type distribution were similar to those observed in CA rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcitonin Gene-Related Peptide (CGRP) inhibits microglia inflammatory activation in vitro. We here analyzed the involvement of CGRP and Receptor Component Protein (RCP) in experimental autoimmune encephalomyelitis (EAE). Alpha-CGRP deficiency increased EAE scores which followed the scale alpha-CGRP null > heterozygote > wild type. In wild type mice, CGRP delivery into the cerebrospinal fluid (CSF) 1) reduced chronic EAE (C-EAE) signs, 2) inhibited microglia activation (revealed by quantitative shape analysis), and 3) did not alter GFAP expression, cell density, lymphocyte infiltration, and peripheral lymphocyte production of IFN-gamma, TNF-alpha, IL-17, IL-2, and IL-4. RCP (probe for receptor involvement) was expressed in white matter microglia, astrocytes, oligodendrocytes, and vascular-endothelial cells: in EAE, also in infiltrating lymphocytes. In relapsing–remitting EAE (R-EAE) RCP increased during relapse, without correlation with lymphocyte density. RCP nuclear localization (stimulated by CGRP in vitro) was I) increased in microglia and decreased in astrocytes (R-EAE), and II) increased in microglia by CGRP CSF delivery (C-EAE). Calcitonin like receptor was rarely localized in nuclei of control and relapse mice. CGRP increased in motoneurons. In conclusion, CGRP can inhibit microglia activation in vivo in EAE. CGRP and its receptor may represent novel protective factors in EAE, apparently acting through the differential cell-specific intracellular translocationof RCP.

In recent years, tumor Adoptive Cell Therapy (ACT), using administration of ex vivo-enhanced T cells from the cancer patient, has become a promising therapeutic strategy. However, efficient homing of the anti-tumoral T cells to the tumor or metastatic site still remains a substantial hurdle. Yet the tumor site itself attracts both tumor-promoting and anti-tumoral immune cell populations through the secretion of chemokines. We attempted to identify these chemokines in a model of spontaneous metastasis, in order to “hijack” their function by expressing matching chemokine receptors on the cytotoxic T cells used in ACT, thus allowing us to enhance the recruitment of these therapeutic cells. Here we show that this enabled the modified T cells to preferentially home into spontaneous lymph node metastases in the TRAMP model, as well as in an inducible tumor model, E.G7-OVA. Due to the improved homing, the modified CD8+ T cells displayed an enhanced in vivo protective effect, as seen by a significant delay in E.G7-OVA tumor growth. These results offer a proof of principle for the tailored application of chemokine receptor modification as a means of improving T cell homing to the target tumor, thus enhancing ACT efficacy. Surprisingly, we also uncover that the formation of the peri-tumoral fibrotic capsule, which has been shown to impede T cell access to tumor, is partially dependent on host T cell presence. This finding, which would be impossible to observe in immunodeficient model studies, highlights possible conflicting roles that T cells may play in a therapeutic context.

PI3Kγ has emerged as a promising target for the treatment of obesity and insulin resistance; however, previous studies have indicated that PI3Kγ activity in pancreatic β cells is required for normal insulin secretion in response to glucose. Hence, a possible deterioration of insulin secretion capacity in patients who are predisposed to the failure of pancreatic β-cell function is a major concern for the pharmacologic inhibition of PI3Kγ. To address this issue, we investigated the effects of PI3Kγ ablation in diabetic mice, a genetic model of obesity-driven β-cell failure and diabetes. Mice that lacked PI3Kγ were backcrossed into mice C57BL/KS (>10 generations) to obtain γ mice. γ mice and control mice were phenotyped for glucose homeostasis, insulin sensitivity, insulin secretion, steatosis, metabolic inflammation, pancreatic islet morphometry, islet cellular composition, and inflammation. Pancreatic β-cell apoptosis and proliferation were also evaluated.γ mice and control mice developed similar body weight, steatosis, glycemia, and insulin levels after a glucose load; however, γ mice displayed improved insulin tolerance, higher levels of fasting serum insulin, and lower pancreatic insulin content. In γ mice, the number of adipose tissue macrophages was similar to control, but displayed reduced adipose tissue neutrophils and M2-polarized adipose tissue gene expression. Finally, γ mice have more pancreatic β cells and larger islets than mice, despite displaying similar islet inflammation. This phenotype could be explained by reduced β-cell apoptosis inγ mice compared with control mice. Our results are consistent with the concept that the beneficial action of PI3Kγ ablation in obesity-driven glucose intolerance is largely a result of its leptin-dependent effects on adiposity and, to a lesser extent, the promotion of adipose tissue neutrophil recruitment and M1 polarization of gene expression. Of importance, our data challenge the concept that PI3Kγ is required for insulin secretion in response to glucose, and indicate that PI3Kγ ablation protects mice from β-cell apoptosis and improves fasting insulin levels. We conclude that PI3Kγ inhibition in obese patients who are predisposed to β-cell failure is not expected to produce adverse effects on insulin secretion.-Breasson, L., Sardi, C., Becattini, B., Zani, F., Solinas, G. PI3Kγ ablation does not promote diabetes in mice, but improves insulin sensitivity and reduces pancreatic β-cell apoptosis.

Obesity and insulin resistance are associated with oxidative stress, which may be implicated in the progression of obesity-related diseases. The kinase JNK1 has emerged as a promising drug target for the treatment of obesity and type 2 diabetes. JNK1 is also a key mediator of the oxidative stress response, which can promote cell death or survival, depending on the magnitude and context of its activation. In this article, we describe a study in which the long-term effects of JNK1 inactivation on glucose homeostasis and oxidative stress in obese mice were investigated for the first time. Mice lacking JNK1 (JNK1(-/-)) were fed an obesogenic high-fat diet (HFD) for a long period. JNK1(-/-) mice fed an HFD for the long term had reduced expression of antioxidant genes in their skin, more skin oxidative damage, and increased epidermal thickness and inflammation compared with the effects in control wild-type mice. However, we also observed that the protection from obesity, adipose tissue inflammation, steatosis, and insulin resistance, conferred by JNK1 ablation, was sustained over a long period and was paralleled by decreased oxidative damage in fat and liver. We conclude that compounds targeting JNK1 activity in brain and adipose tissue, which do not accumulate in the skin, may be safer and most effective.-Becattini, B., Zani, F., Breasson, L., Sardi, C., D'Agostino, V. G., Choo, M.-K., Provenzani, A., Park, J. M., Solinas, G. JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage.

SUMMARY A 5 year old child, previously diagnosed as having tetralogy of Fallot, was admitted to hospital in severe congestive heart failure. The electrocardiogram showed left anterior hemiblock and incomplete right bundle-branch block, neither of which was previously present. The child died in intractable congestive heart failure and the necropsy showed a double outlet right ventricle with complete spontaneous closure of the subaortic ventricular septal defect by fibrous tissue. The possible mechanism involved in the production of this unusual complication of double outlet right ventricle is discussed, together with an explanation for the electrocardiographic changes.It is well known that an isolated ventricular septal defect can reduce in size spontaneously, and even close completely.'"3 Occasionally, this development has been described in patients with complex congenital heart disease, in whom the ventricular septal defect was physiologically advantageous such as the "classic" double outlet right ventricle, that is with bilateral conus,46 or tricuspid atresia.7 8 Conversely, complete spontaneous closure of a ventricular septal defect has never been described, to our knowledge, in patients with tetralogy of Fallot or with double outlet right ventricle and infundibular features of Fallot's tetralogy.We report the clinical and anatomical findings of a case of double outlet right ventricle with some infundibular features of Fallot's tetralogy, in which there was spontaneous closure of the ventricular septal defect.Case report A 5 year old girl was born with a cyanotic cardiac defect. She was admitted to our hospital in congestive heart failure.A heart murmur had been heard since birth.Cyanosis appeared when she was 5 months old. At 3 years of age she underwent a right heart catheterisation in another institution which disclosed tetralogy of Fallot. The electrocardiogram showed right ventricular hypertrophy including QRS right axis deviation (Fig. IA) There was oedema at the ankles, hepatomegaly, ascites, and bilateral pleural effusions. The precordium was hyperactive. The first heart sound was normal and the second sound was single. A 3/6 ejection systolic murmur and a third heart sound were heard in the third left intercostal space on the sternal border.The chest x-ray film showed cardiac enlargement, pulmonary venous congestion, bilateral pleural effusions, and a left aortic arch.The electrocardiogram recorded on admission (Fig. IB) showed normal sinus rhythm, PR interval 0-18 s, left atrial enlargement, QRS width 0-08 s, and QRS mean frontal axis -60°. The QRS pattern indicated left anterior hemiblock; QRS morphology was Qrs, QS, and rS in VI, V2, and V6, respectively, indicating a posterior, rightward, and counterclockwise inscription of the QRS forces in the transverse plane.Another electrocardiogram was recorded four days later (Fig. IC) and disclosed an incomplete right ventricular conduction defect (qR morphology in VI, with tall R wave and mild increase in QRS width). A more pronounced superior deviation...