Terminally differentiated effector memory T cells associate with cognitive and AD-related biomarkers in an aging-based community cohort.

Background And Purpose: The immune response changes during aging and the progression of Alzheimer's disease (AD) and related dementia (ADRD). Terminally differentiated effector memory T cells (called T) are important during aging and AD due to their cytotoxic phenotype and association with cognitive decline. However, it is not clear if the changes seen in T are specific to AD-related cognitive decline specifically or are more generally correlated with cognitive decline.

Fasting and Glucose Metabolism Differentially Impact Peripheral Inflammation in Human Type 2 Diabetes.

Cytokines produced by peripheral T-helper 1/17 cells disproportionately contribute to the inflammation (i.e., metaflammation) that fuels type 2 diabetes (T2D) pathogenesis.

T cells in obesity-associated inflammation: The devil is in the details.

Obesity presents a significant health challenge, affecting 41% of adults and 19.7% of children in the United States. One of the associated health challenges of obesity is chronic low-grade inflammation.

Everolimus alleviates CD4 T cell inflammation by regulating autophagy and cellular redox homeostasis.

Aging is associated with the onset and progression of multiple diseases, which limit health span. Chronic low-grade inflammation in the absence of overt infection is considered the simmering source that triggers age-associated diseases. Failure of many cellular processes during aging is mechanistically linked to inflammation; however, the overall decline in the cellular homeostasis mechanism of autophagy has emerged as one of the top and significant inducers of inflammation during aging, frequently known as inflammaging.

MITOCHONDRIA-ASSOCIATED MEMBRANES ARE NOT ALTERED IN IMMUNE CELLS IN T2D.

Metabolism research is increasingly recognizing the contributions of organelle crosstalk to metabolic regulation. Mitochondria-associated membranes (MAMs), which are structures connecting the mitochondria and endoplasmic reticulum (ER), are critical in a myriad of cellular functions linked to cellular metabolism. MAMs control calcium signaling, mitochondrial transport, redox balance, protein folding/degradation, and in some studies, metabolic health.

Terminally differentiated effector memory T cells associate with cognitive and AD-related biomarkers in an aging-based community cohort.

Background And Purpose: The immune response changes during aging and the progression of Alzheimer's disease (AD) and related dementia (ADRD). Terminally differentiated effector memory T cells (called TEMRA) are important during aging and AD due to their cytotoxic phenotype and association with cognitive decline. However, it is not clear if the changes seen in T are specific to AD-related cognitive decline specifically or are more generally correlated with cognitive decline.

STAT3 modulates CD4 T mitochondrial dynamics and function in aging.

Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and T-cell cytokine production. Mechanistically, mitoSTAT3 increased the activity of aging T-cell mitochondria by increasing complex II.

T cells dominate peripheral inflammation in a cross-sectional analysis of obesity-associated diabetes.

Objective: Myeloid cells dominate metabolic disease-associated inflammation (metaflammation) in mouse obesity, but the contributions of myeloid cells to the peripheral inflammation that fuels sequelae of human obesity are untested. This study used unbiased approaches to rank contributions of myeloid and T cells to peripheral inflammation in people with obesity across the spectrum of metabolic health.

Methods: Peripheral blood mononuclear cells (PBMCs) from people with obesity with or without prediabetes or type 2 diabetes were stimulated with T cell-targeting CD3/CD28 or myeloid-targeting lipopolysaccharide for 20 to 72 hours to assess cytokine production using Bio-Plex.

T-cell Metabolism as Interpreted in Obesity-associated Inflammation.

The appreciation of metabolic regulation of T-cell function has exploded over the past decade, as has our understanding of how inflammation fuels comorbidities of obesity, including type 2 diabetes. The likelihood that obesity fundamentally alters T-cell metabolism and thus chronic obesity-associated inflammation is high, but studies testing causal relationships remain underrepresented. We searched PubMed for key words including mitochondria, obesity, T cell, type 2 diabetes, cristae, fission, fusion, redox, and reactive oxygen species to identify foundational and more recent studies that address these topics or cite foundational work.

Obesity and Fatty Acids Promote Mitochondrial Translocation of STAT3 Through ROS-Dependent Mechanisms.

Obesity promotes the onset and progression of metabolic and inflammatory diseases such as type 2 diabetes. The chronic low-grade inflammation that occurs during obesity triggers multiple signaling mechanisms that negatively affect organismal health. One such mechanism is the persistent activation and mitochondrial translocation of STAT3, which is implicated in inflammatory pathologies and many types of cancers.

Early life stress exacerbates obesity in adult female mice via mineralocorticoid receptor-dependent increases in adipocyte triglyceride and glycerol content.

Previously, we have shown that Maternal Separation and Early Weaning (MSEW) exacerbates high fat diet (HF)-induced visceral obesity in female offspring compared to normally reared female mice. Stress hormones such as glucocorticoids and mineralocorticoids are critical mediators in the process of fat expansion, and both can activate the mineralocorticoid receptor (MR) in the adipocyte. Therefore, this study aimed to, comprehend the specific effects of MSEW on adipose tissue basic homeostatic function, and investigate whether female MSEW mice show an exacerbated obesogenic response mediated by MR.

Obesity alters pathology and treatment response in inflammatory disease.

Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses.

Regulatory T Cells Control Effector T Cell Inflammation in Human Prediabetes.

A disparate array of plasma/serum markers provides evidence for chronic inflammation in human prediabetes, a condition that is most closely replicated by standard mouse models of obesity and metaflammation. These remain largely nonactionable and contrast with our rich understanding of inflammation in human type 2 diabetes. New data show that inflammatory profiles produced by CD4+ T cells define human prediabetes as a unique inflammatory state.

Adaptive immune cells shape obesity-associated type 2 diabetes mellitus and less prominent comorbidities.

Obesity and type 2 diabetes mellitus (T2DM) are increasing in prevalence owing to decreases in physical activity levels and a shift to diets that include addictive and/or high-calorie foods. These changes are associated with the adoption of modern lifestyles and the presence of an obesogenic environment, which have resulted in alterations to metabolism, adaptive immunity and endocrine regulation. The size and quality of adipose tissue depots in obesity, including the adipose tissue immune compartment, are critical determinants of overall health.

Dysregulation of Systemic Immunity in Aging and Dementia.

Neuroinflammation and the tissue-resident innate immune cells, the microglia, respond and contribute to neurodegenerative pathology. Although microglia have been the focus of work linking neuroinflammation and associated dementias like Alzheimer's Disease, the inflammatory milieu of brain is a conglomerate of cross-talk amongst microglia, systemic immune cells and soluble mediators like cytokines. Age-related changes in the inflammatory profile at the levels of both the brain and periphery are largely orchestrated by immune system cells.

The intersection of metformin and inflammation.

The biguanide metformin is the most commonly used antidiabetic drug. Recent studies show that metformin not only improves chronic inflammation by improving metabolic parameters but also has a direct anti-inflammatory effect. In light of these findings, it is essential to identify the inflammatory pathways targeted by metformin to develop a comprehensive understanding of the mechanisms of action of this drug.

Next steps in mechanisms of inflammaging.

Striking age-related changes occur in the human immune system, beginning in the sixth decade of life. Age is a non-modifiable, universal risk factor that results in the dysregulation of many cellular homeostatic processes. The decline in immune cell macroautophagy/autophagy and the increased generation of proinflammatory cytokines during agingfuels the development of diseases in the elderly.

Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation.

Age is a non-modifiable risk factor for the inflammation that underlies age-associated diseases; thus, anti-inflammaging drugs hold promise for increasing health span. Cytokine profiling and bioinformatic analyses showed that Th17 cytokine production differentiates CD4 T cells from lean, normoglycemic older and younger subjects, and mimics a diabetes-associated Th17 profile. T cells from older compared to younger subjects also had defects in autophagy and mitochondrial bioenergetics that associate with redox imbalance.

Commentary on Camell et al., Aging Induces Nlrp3 Inflammasome Dependent Adipose B Cell Expansion to Impair Metabolic Homeostasis.

The burden of aging and obesity is urging extended investigation into the molecular mechanisms that underlie chronic adipose tissue inflammation. B cell-targeted therapies are emerging as novel tools to modulate the immune system and thereby mitigate aging and obesity-related metabolic complications.

Origin of Th17 Cells in Type 2 Diabetes-Potentiated Periodontal Disease.

New strategies are critically needed to counter uncontrolled periodontal infection and inflammation in obesity-associated type 2 diabetes (T2D). However, mechanisms that explain the relationship between periodontitis (PD) and T2D remain poorly understood. Several lines of evidence indicate that destructive immune responses potentiate periodontitis (PD) in T2D.

Tissue Immune Cells Fuel Obesity-Associated Inflammation in Adipose Tissue and Beyond.

Obesity-associated inflammation stems from a combination of cell-intrinsic changes of individual immune cell subsets and the dynamic crosstalk amongst a broad array of immune cells. Although much of the focus of immune cell contributions to metabolic disease has focused on adipose tissue-associated cells, these potent sources of inflammation inhabit other metabolic regulatory tissues, including liver and gut, and recirculate to promote systemic inflammation and thus obesity comorbidities. Tissue-associated immune cells, especially T cell subpopulations, have become a hotspot of inquiry based on their contributions to obesity, type 2 diabetes, non-alcoholic fatty liver diseases and certain types of cancers.

Fatty Acid Metabolites Combine with Reduced β Oxidation to Activate Th17 Inflammation in Human Type 2 Diabetes.

Mechanisms that regulate metabolites and downstream energy generation are key determinants of T cell cytokine production, but the processes underlying the Th17 profile that predicts the metabolic status of people with obesity are untested. Th17 function requires fatty acid uptake, and our new data show that blockade of CPT1A inhibits Th17-associated cytokine production by cells from people with type 2 diabetes (T2D). A low CACT:CPT1A ratio in immune cells from T2D subjects indicates altered mitochondrial function and coincides with the preference of these cells to generate ATP through glycolysis rather than fatty acid oxidation.

Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent Mechanism.

Circulating fatty acids (FAs) increase with obesity and can drive mitochondrial damage and inflammation. Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial protein that positively regulates nicotinamide adenine dinucleotide phosphate (NADPH), a key mediator of energy transduction and redox homeostasis. The role that NNT-regulated bioenergetics play in the inflammatory response of immune cells in obesity is untested.