Adipocyte CD1d Gene Transfer Induces T Cell Expansion and Adipocyte Inflammation in CD1d Knockout Mice.

CD1d, a lipid Ag-presenting molecule for invariant NKT (iNKT) cells, is abundantly expressed on adipocytes and regulates adipose homeostasis through iNKT cells. CD1d gene expression was restored in visceral adipose tissue adipocytes of CD1d knockout (KO) mice to investigate the interactions between adipocytes and immune cells within adipose tissue. We developed an adipocyte-specific targeting recombinant adeno-associated viral vector, with minimal off-target transgene expression in the liver, to rescue CD1d gene expression in visceral adipose tissue adipocytes of CD1d KO mice, followed by assessment of immune cell alternations in adipose tissue and elucidation of the underlying mechanisms of alteration. We report that adeno-associated virus-mediated gene transfer of CD1d to adipocytes in CD1d KO mice fails to rescue iNKT cells but leads to massive and selective expansion of T cells within adipose tissue, particularly CD8+ T effector cells, that is associated with adipocyte NLRP3 inflammasome activation, dysregulation of adipocyte functional genes, and upregulation of apoptotic pathway proteins. An NLRP3 inhibitor has no effect on T cell phenotypes whereas depletion of CD8+ T cells significantly attenuates inflammasome activation and abolishes the dysregulation of adipocyte functional genes induced by adipocyte CD1d. In contrast, adipocyte overexpression of CD1d fails to induce T cell activation in wild-type mice or in invariant TCR α-chain Jα18 KO mice that have a normal lymphocyte repertoire except for iNKT cells. Our studies uncover an adipocyte CD1d → CD8+ T cell → adipocyte inflammasome cascade, in which CD8+ T cells function as a key mediator of adipocyte inflammation likely induced by an allogeneic response against the CD1d molecule.

Attitudes Toward Euthanasia: A Longitudinal Analysis of the Role of Economic, Cultural, and Health-Related Factors.

CONTEXT: It is crucial that physicians understand differing attitudes toward euthanasia and which factors to consider when discussing end-of-life decisions with patients and families from diverse backgrounds. OBJECTIVES: To investigate how attitudes toward euthanasia differ among countries, how they change, and how economic, religious, and health-related factors affect these attitudes. METHODS: We analyzed attitudes toward euthanasia and economic, religious, and health-related indicators using longitudinal (1981-2018) World Values Survey (WVS) data. They included 62 countries with at least a 15-year, three-wave, time series (total n = 389,243 participants). Each national survey interviewed representative samples of adults (mean = 1405). RESULTS: In the latest wave, The Netherlands had the most favorable views of euthanasia (10-point scale with 1 = least justifiable: mean = 7.47) and Jordan the least (mean = 1.50). Residents of 23 of 24 high-income countries came to view euthanasia as more justifiable, while residents of 12 of 38 middle- and low-income countries came to view it as less justifiable over time. The higher GDP per-capita at the time of survey, the more euthanasia was accepted (r = 0.703; P< 0.0001); the more important respondents viewed religion as being, the less euthanasia was accepted (r = -0.834; P< 0.0001); the higher life expectancy and the lower infant mortality were, the more euthanasia was accepted (r = 0.669; P< 0.0001/r = -0.716; P< 0.0001). CONCLUSION: Euthanasia-related attitudes differ widely depending on the cultural context; changes over time varied in both directions; euthanasia-related attitudes were associated with economic, religious and health-related factors. With globalization increasing cultural diversity, these findings can inform physicians' communication about end-of-life decisions with patients and families from diverse backgrounds.

Regulation of aging and cancer by enhanced environmental activation of a hypothalamic-sympathoneural-adipocyte axis.

Social and environmental factors impact cancer and energy balance profoundly. Years ago, our lab established the existence of a novel brain-fat interaction we termed the "hypothalamic-sympathoneural-adipocyte (HSA) axis", through which complex environmental stimuli provided by an enriched environment regulate body composition, energy balance, and development of cancer. We have spent a significant portion of the past decade to further characterize the broad health benefits of an enriched environment (for example, leanness, enhanced immune function, and cancer resistance), and to identify mediators in the brain and periphery along the HSA axis. This review summarizes our recent work regarding the interface between endocrinology, immunology, cancer biology, aging, and neuroscience. We will discuss the interplay between these systemic phenomena and how the HSA axis can be targeted for regulation of cancer and aging.

Improvements to Healthspan Through Environmental Enrichment and Lifestyle Interventions: Where Are We Now?

Environmental enrichment (EE) is an experimental paradigm that is used to explore how a complex, stimulating environment can impact overall health. In laboratory animal experiments, EE housing conditions typically include larger-than-standard cages, abundant bedding, running wheels, mazes, toys, and shelters which are rearranged regularly to further increase stimulation. EE has been shown to improve multiple aspects of health, including but not limited to metabolism, learning and cognition, anxiety and depression, and immunocompetence. Recent advances in lifespan have led some researchers to consider aging as a risk factor for disease. As such, there is a pressing need to understand the processes by which healthspan can be increased. The natural and predictable changes during aging can be reversed or decreased through EE and its underlying mechanisms. Here, we review the use of EE in laboratory animals to understand mechanisms involved in aging, and comment on relative areas of strength and weakness in the current literature. We additionally address current efforts toward applying EE-like lifestyle interventions to human health to extend healthspan. Although increasing lifespan is a clear goal of medical research, improving the quality of this added time also deserves significant attention. Despite hurdles in translating experimental results toward clinical application, we argue there is great potential in using features of EE toward improving human healthy life expectancy or healthspan, especially in the context of increased global longevity.

CSF1R inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice.

As the elderly population grows, chronic metabolic dysfunction including obesity and diabetes are becoming increasingly common comorbidities. Hypothalamic inflammation through CNS resident microglia serves as a common pathway between developing obesity and developing systemic aging pathologies. Despite understanding aging as a life-long process involving interactions between individuals and their environment, limited studies address the dynamics of environment interactions with aging or aging therapeutics. We previously demonstrated environmental enrichment (EE) is an effective model for studying improved metabolic health and overall healthspan in mice, which acts through a brain-fat axis. Here we investigated the CSF1R inhibitor PLX5622 (PLX), which depletes microglia, and its effects on metabolic decline in aging in interaction with EE. PLX in combination with EE substantially improved metabolic outcomes in middle-aged female mice over PLX or EE alone. Chronic PLX treatment depleted 75% of microglia from the hypothalamus and reduced markers of inflammation without affecting brain-derived neurotrophic factor levels induced by EE. Adipose tissue remodeling and adipose tissue macrophage modulation were observed in response to CSF1R inhibition, which may contribute to the combined benefits seen in EE with PLX. Our study suggests benefits exist from combined drug and lifestyle interventions in aged animals.

Modulation of immune checkpoint molecule expression in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy for which novel therapeutics with improved efficacy are greatly needed. To provide support for clinical immune checkpoint blockade, we comprehensively evaluated the expression of therapeutically targetable immune checkpoint molecules on primary MCL cells. MCL cells showed constitutive expression of Programmed Death 1 (PD-1) and Programmed Death Ligand 1 (PD-L1), variable CD200, absent PD-L2, Lymphocyte Activation Gene 3 (LAG-3), and Cytotoxic T-cell Associated Protein 4 (CTLA-4). Effector cells from MCL patients expressed PD-1. Co-culture of MCL cells with T-cells induced PD-L1 surface expression, a phenomenon regulated by IFNγ and CD40:CD40L interaction. Induction of PD-L1 was attenuated by concurrent treatment with ibrutinib or duvelisib, suggesting BTK and PI3K are important mediators of PD-L1 expression. Overall, our data provide further insight into the expression of checkpoint molecules in MCL and support the use of PD-L1 blocking antibodies in MCL patients.

PLK1: a promising and previously unexplored target in double-hit lymphoma.

Inhibitors that target specific kinases or oncoproteins have become popular additions to or replacements for cytotoxic chemotherapies to treat many different types of cancer. However, many tumors lack a discernable target kinase and an amplified oncoprotein and/or rely on several cooperating mechanisms for progression. Thus, combinations of targeted therapies are essential for treating many cancers to avoid the rapid emergence of resistance. In this issue of the JCI, Ren et al. use an elegant kinase activity-profiling method and identify activity of the oncogene polo-like kinase-1 (PLK1) as an important driver of double-hit lymphoma (DHL), an aggressive subgroup of B cell lymphoma characterized by chromosomal translocations involving c-MYC and BCL2 or BCL6. Moreover, PLK1 activity was associated with MYC expression and poor prognosis in DHL patients. PLK1 inhibition with volasertib, alone and in combination with the BCL-2 inhibitor venetoclax, was efficacious in multiple DHL models, including mice harboring DHL patient-derived xenografts. Together, these data support PLK1 as a promising prognostic marker and therapeutic target for DHL.