Immunometabolism最新文献

Although there has been a recent renaissance in the availability of new therapeutic options for patients with acute myeloid leukemia (AML), survival rates remain low coupled with a high incidence of relapse. Enhancing T cell and immune function has become an effective therapeutic approach in hematological malignancies. However, AML cells can modulate the bone marrow microenvironment by changing extracellular nutrient and biochemical availability which can metabolically regulate immune function. Here we review the findings by Uhl et al. showing that T cell metabolism and function can be boosted by treatment with sodium bicarbonate to counteract the metabolic changes induced by lactic acid produced by leukemia cells.

Background: Vascular smooth muscle cells (VSMC) exhibit phenotypic plasticity in atherosclerotic plaques, and among other approaches, has been modeled in vitro by cholesterol loading.

Methods: Meta-analysis of scRNA-seq data from VSMC lineage traced cells across five experiments of murine atherosclerosis was performed. In vivo expression profiles were compared to three in vitro datasets of VSMCs loaded with cholesterol and three datasets of polarized macrophages.

Results: We identified 24 cell clusters in the meta-analysis of single cells from mouse atherosclerotic lesions with notable heterogeneity across studies, especially for macrophage populations. Trajectory analysis of VSMC lineage positive cells revealed several possible paths of state transitions with one traversing from contractile VSMC to macrophages by way of a proliferative cell cluster. Transcriptome comparisons between in vivo and in vitro states underscored that data from three in vitro cholesterol-treated VSMC experiments did not mirror cell state transitions observed in vivo. However, all in vitro macrophage profiles analyzed (M1, M2, and oxLDL) were more similar to in vivo profiles of macrophages than in vitro VSMCs were to in vivo profiles of VSMCs. oxLDL loaded macrophages showed the most similarity to in vivo states. In contrast to the in vitro data, comparison between mouse and human in vivo data showed many similarities.

Conclusions: Identification of the sources of variation across single cell datasets in atherosclerosis will be an important step towards understanding VSMC fate transitions in vivo. Also, we conclude that cholesterol-loading in vitro is insufficient to model the VSMC cell state transitions observed in vivo, which underscores the need to develop better cell models. Mouse models, however, appear to reproduce a number of the features of VSMCs in human plaques.

Metabolism is a common cellular feature. Cancer creates a suppressive microenvironment resulting in inactivation of antigen-specific T cells by metabolic reprogramming. Development of approaches that enhance and sustain physiologic properties of T cell metabolism to prevent T cell inactivation and promote effector function in the tumor microenvironment is an urgent need for improvement of cell-based cancer immunotherapies.

Billions of cells undergo apoptosis daily and are swiftly removed by macrophages through an evolutionarily conserved program termed "efferocytosis". Consequently, macromolecules within an apoptotic cell significantly burden a phagocyte with nutrients, such as lipids, oligonucleotides, and amino acids. In response to this nutrient overload, metabolic reprogramming must occur for the process of efferocytosis to remain non-phlogistic and to execute successive rounds of efferocytosis. The inability to undergo metabolic reprogramming after efferocytosis drives inflammation and impairs its resolution, often promoting many chronic inflammatory diseases. This is particularly evident for atherosclerosis, as metabolic reprogramming alters macrophage function in every stage of atherosclerosis, from the early formation of benign lesions to the progression of clinically relevant atheromas and during atherosclerosis regression upon aggressive lipid-lowering. This Review focuses on the metabolic pathways utilized upon apoptotic cell ingestion, the consequences of these metabolic pathways in macrophage function thereafter, and the role of metabolic reprogramming during atherosclerosis. Due to the growing interest in this new field, I introduce a new term, "efferotabolism", as a means to define the process by which macrophages break down, metabolize, and respond to AC-derived macromolecules. Understanding these aspects of efferotabolism will shed light on novel strategies to combat atherosclerosis and compromised inflammation resolution.

A large and growing body of evidence supports functions of enzymes that regulate or effect cellular metabolism in governing the development, survival, and effector functions of immune cells-especially T cells, macrophages, and dendritic cells. Among these proteins, adenosine monophosphate-activated protein kinase (AMPK) is a conserved ATP and nutrient sensor that regulates multiple metabolic pathways to promote energy homeostasis. Although AMPK had been shown to regulate aspects of CD4⁺ and CD8⁺ T cell biology, its function in B lymphocytes has been less clear. Here, we review recent advances in our understanding of the role of AMPK in the metabolism, function, and maintenance of the B lineage.

CD4⁺ Foxp3⁺ T regulatory cells (Tregs) residing in the visceral adipose tissues (VAT) have profound effects on local and systemic metabolism. Although many of the molecular characteristics of VAT resident Tregs have been identified, how these cells promote metabolic homeostasis is still unclear. Several new publications help to illuminate the molecular mechanisms that underpin VAT resident Treg function and will be discussed here.

Despite the advances in immunotherapies, effective against some types of cancer, progression of several types of carcinoma remains uncurable. Recent studies indicate that changes in lipid metabolism, aggravated by obesity, disable anti-tumor immune response. In the July issue of Immunity, Xu et al. use mouse models to demonstrate that certain types of oxidized lipids, transported by CD36, suppress the capacity of CD8⁺ T lymphocytes to secrete cytotoxic molecules. This study sheds light on how lipid modifications in the tumor microenvironment make killer T cells incapable of inhibiting tumor growth.

Recent advancements in the field of B cell immunometabolism have provided mechanistic insights to B cell activation and fate determination. Here, in this short article, I will explain the main principles of our novel metabolic clock model and how it may reshape our perspective on longstanding immunological questions related to pathologies arising from out of context B cell activation.

Cellular metabolism is critical for generating energy and macromolecules for cell growth and survival. In recent years, the importance of metabolism in mediating T cell differentiation, proliferation, and function has been a hot topic of investigation. However, very little is known about metabolic regulation in invariant natural killer T (iNKT) cells. In this viewpoint, we will discuss what is currently known about immunometabolism in iNKT cells and how these findings relate to CD4 T cells.

One of the most fascinating aspects of mitochondria is their remarkable ability to accumulate and store large amounts of calcium in the presence of phosphate leading to mitochondrial calcification. In this paper, we briefly address the mechanisms that regulate mitochondrial calcium homeostasis followed by the extensive review on the formation and characterization of intramitochondrial calcium phosphate granules leading to mitochondrial calcification and its relevance to physiological and pathological calcifications of body tissues.