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temic expansion of ST2 + Tregs (29,30). IL-33 expressed by fibrogenic/adipogenic progenitors in skeletal muscle has also been shown to regulate skeletal muscle Treg homeostasis and support muscle regeneration (31). Related studies have suggested a direct, cardioprotective role for rIL-33 against hypertrophy resulting from cardiac overload (32) and fibrosis after myocardial infarction (33). However, delivery of rIL-33 also aggravates autoimmune eosinophilic pericarditis during coxsackievirus B3 infection (34), suggesting that IL-33 can contribute to cardiac inflammation. IL-33 expression has been reported in cardiac fibroblasts (32) and the vasculature ( 35), yet how the expression of this alarmin is modulated in cardiac allografts or impacts outcomes was unknown.Using IL-33-deficient heart grafts in a mouse chronic rejection model we have established that IL-33 stands out among identified alarmins and limits differentiation of proinflammatory macrophages to prevent chronic rejection. Specifically, transplants lacking IL-33 displayed dramatically accelerated chronic rejectionassociated vasculopathy and subsequent fibrosis orchestrated by graft-infiltrating recipient proinflammatory macrophages. IL-33expressing heart grafts in recipients with ST2-deficient macrophages also displayed increased graft infiltration by proinflammatory macrophages and accelerated graft loss. Mechanistic studies demonstrated that IL-33 promoted a reparative macrophage phenotype through a metabolic reprograming involving augmented oxidative phosphorylation (OXPHOS) and fatty acid (FA) uptake. We also revealed that IL-33 prevents proinflammatory stimuli-induced disruption of the tricarboxylic acid (TCA) cycle that shifts macrophage metabolism to anaerobic glycolysis and generates proinflammatory metabolites (36,37). Restoration of IL-33 to IL-33-deficient heart transplants using vesicles in ECM-derived hydrogel immediately after transplantation profoundly reduced the frequency of proinflammatory myeloid cells in the graft and prevented graft loss to chronic rejection. Thus, the local delivery of IL-33 in ECM-based materials after transplantation may be a practical and promising biologic for chronic rejection prophylaxis.

Obesity often leads to obesity‐related cardiac hypertrophy (ORCH), which is suppressed by zinc‐induced inactivation of p38 mitogen‐activated protein kinase (p38 MAPK). In this study, we investigated the mechanisms by which zinc inactivates p38 MAPK to prevent ORCH.Mice (4‐week old) were fed either high fat diet (HFD, 60% kcal fat) or normal diet (ND, 10% kcal fat) containing variable amounts of zinc (deficiency, normal and supplement) for 3 and 6 months. P38 MAPK siRNA and the p38 MAPK inhibitor SB203580 were used to suppress p38 MAPK activity in vitro and in vivo, respectively. HFD activated p38 MAPK and increased expression of B‐cell lymphoma/CLL 10 (BCL10) and caspase recruitment domain family member 9 (CARD9). These responses were enhanced by zinc deficiency and attenuated by zinc supplement. Administration of SB203580 to HFD mice or specific siRNA in palmitate‐treated cardiomyocytes eliminated the HFD and zinc deficiency activation of p38 MAPK, but did not significantly impact the expression of BCL10 and CARD9. In cultured cardiomyocytes, inhibition of BCL10 expression by siRNA prevented palmitate‐induced increased p38 MAPK activation and atrial natriuretic peptide (ANP) expression. In contrast, inhibition of p38 MAPK prevented ANP expression, but did not affect BCL10 expression. Deletion of metallothionein abolished the protective effect of zinc on palmitate‐induced up‐regulation of BCL10 and phospho‐p38 MAPK. HFD and zinc deficiency synergistically induce ORCH by increasing oxidative stress‐mediated activation of BCL10/CARD9/p38 MAPK signalling. Zinc supplement ameliorates ORCH through activation of metallothionein to repress oxidative stress‐activated BCL10 expression and p38 MAPK activation.

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AMP-activated protein kinase (AMPK) signaling pathway plays a pivotal role in intracellular adaptation to energy stress during myocardial ischemia. Notch1 signaling in the adult myocardium is also activated in response to ischemic stress. However, the relationship between Notch1 and AMPK signaling pathways during ischemia remains unclear. We hypothesize that Notch1 as an adaptive signaling pathway protects the heart from ischemic injury via modulating the cardioprotective AMPK signaling pathway. C57BL/6J mice were subjected to an in vivo ligation of left anterior descending coronary artery and the hearts from C57BL/6J mice were subjected to an ex vivo globe ischemia and reperfusion in the Langendorff perfusion system. The Notch1 signaling was activated during myocardial ischemia. A Notch1 γ-secretase inhibitor, dibenzazepine (DBZ), was intraperitoneal injected to mice to inhibit Notch1 signaling pathway by ischemia. The inhibition of Notch1 signaling by DBZ significantly augmented cardiac dysfunctions caused by myocardial infarction. Intriguingly, DBZ treatment also significantly blunted the activation of AMPK signaling pathway. The immunoprecipitation experiments demonstrated that an interaction between Notch1 and liver kinase beta1 (LKB1) modulated AMPK activation during myocardial ischemia. Furthermore, a ligand of Notch1 Jagged1 can significantly reduce cardiac damage caused by ischemia via activation of AMPK signaling pathway and modulation of glucose oxidation and fatty acid oxidation during ischemia and reperfusion. But Jagged1 did not have any cardioprotections on AMPK kinase dead transgenic hearts. Taken together, the results indicate that the cardioprotective effect of Notch1 against ischemic damage is mediated by AMPK signaling via an interaction with upstream LKB1.

Interleukin(IL)-33 is a member of the IL-1 cytokine family that has been attributed T helper (Th) type 2 immunity-promoting capacity. However, new studies indicate that IL-33 is a multifunctional protein that acts as transcriptional/signaling repressor, functions as an alarmin alerting the immune system to necrosis, as well as serves as a cytokine that targets cells expressing ST2, the IL-33 receptor. Interestingly, IL-33 is also emerging as a pleiotropic cytokine. Depending on the innate or adaptive immune cells targeted by IL-33, it can not only promote type 2, but also IFN-γ dominated type 1 immunity. In addition, IL-33 expands regulatory T cells. In this review, we assimilate the current knowledge of IL-33 immunobiology and discuss how IL-33 may mediate such diverse roles in the immune response to pathogens and development of immune-mediated pathologies. The function of IL-33 in shaping alloimmune responses to transplanted organs is poorly explored, but a particularly beneficial role of IL-33 in experimental heart transplant models is summarized. Finally, given the implication of IL-33 in pathologies of the lung and intestine, we discuss how IL-33 may contribute to the comparatively poor outcomes following transplantation of these two organs.

Our study indicates that the treatment of fibrous dysplasia patients should be tailored according to patient and disease characteristics. The main surgical procedure is the endoscopic approach, and the effect is good. Although the recurrence rate is low, follow-up is necessary.

Considering the ATP-driven (SERCA) pump flux as function of glucose concentration and the calcium flux from the endoplasmic reticulum (ER) through the IP(3)R channel, the calcium-based phantom bursting model (PBM) of beta-cells (Bertram and Sherman in Bull Math Biol 66:1313, 2004) is theoretically extended to discuss the effects of glucose and inositol 1,4,5-trisphosphate (IP(3)) concentration on the membrane potential activities. When IP(3) concentration is fixed, it is found that there is a critical glucose concentration at which electrical bursting oscillations transfer into spiking, and the critical concentration of glucose is increased with the increasing of IP(3) concentration. To get the bursting oscillations in beta-cells, our theoretical results show that the stimulatory glucose concentration should be more than 10 mM, which is consistent with the normal physiological IP(3) level. When the stochastic opening and closing of IP(3)R channels are considered, it is shown that the membrane potential oscillation transfers from spiking to bursting with the channel number decreasing, and the average cytosolic free Ca(2+) concentration is increased with the increase of glucose concentration.