Immunometabolism (Cobham (Surrey, England))最新文献

Post-traumatic osteoarthritis (PTOA) is a multifactorial disease of the cartilage, synovium, and subchondral bone resulting from direct joint trauma and altered joint mechanics after traumatic injury. There are no current disease-modifying therapies for PTOA, and early surgical interventions focused on stabilizing the joint do not halt disease progression. Chronic pain and functional disability negatively affect the quality of life and take an economic toll on affected patients. While multiple mechanisms are at play in disease progression, joint inflammation is a key contributor. Impact-induced mitochondrial dysfunction and cell death or altered joint mechanics after trauma culminate in inflammatory cytokine release from synoviocytes and chondrocytes, cartilage catabolism, suppression of cartilage anabolism, synovitis, and subchondral bone disease, highlighting the complexity of the disease. Current understanding of the cellular and molecular mechanisms underlying the disease pathology has allowed for the investigation of a variety of therapeutic strategies that target unique apoptotic and/or inflammatory processes in the joint. This review provides a concise overview of the inflammatory and apoptotic mechanisms underlying PTOA pathogenesis and identifies potential therapeutic targets to mitigate disease progression. We highlight Ca²⁺/calmodulin-dependent protein kinase kinase 2 (CaMKK2), a serine/threonine protein kinase that was recently identified to play a role in murine and human osteoarthritis pathogenesis by coordinating chondrocyte inflammatory responses and apoptosis. Given its additional effects in regulating macrophage inflammatory signaling and bone remodeling, CaMKK2 emerges as a promising disease-modifying therapeutic target against PTOA.

Macrophages play fundamental roles in atherosclerotic plaque formation, growth, and regression. These cells are extremely plastic and perform different immune functions depending on the stimuli they receive. Initial in vitro studies have identified specific metabolic pathways that are crucial for the proper function of pro-inflammatory and pro-resolving macrophages. However, the plaque microenvironment, especially in the context of insulin resistance and type 2 diabetes, constantly challenges macrophages with several simultaneous inflammatory and metabolic stimuli, which may explain why atherosclerosis is accelerated in diabetic patients. In this mini review, we discuss how macrophage mitochondrial function and metabolism of carbohydrates, lipids, and amino acids may be affected by this complex plaque microenvironment and how risk factors associated with type 2 diabetes alter the metabolic rewiring of macrophages and disease progression. We also briefly discuss current challenges in assessing macrophage metabolism and identify future tools and possible strategies to alter macrophage metabolism to improve treatment options for diabetes-associated atherosclerosis.

There is an increasing prevalence of alcohol-associated liver disease (ALD) worldwide. In addition to excessive alcohol consumption, other nutritional factors have been shown to affect the initiation and progression of ALD. The emerging role of cholesterol in exacerbating ALD has been reported recently and the underlying mechanisms are discussed. In addition, the interplay between dietary cholesterol and alcohol on cholesterol metabolism is reviewed. Furthermore, we highlight the therapeutic potential of cholesterol-lowering drugs in managing the onset and severity of ALD. Finally, we suggest the future mechanistic investigation of the effect of cholesterol on insulin resistance and intestinal inflammation in the exacerbation of alcohol-induced cellular and systemic dysfunction.

The activation and function of T cells is fundamental for the control of infectious diseases and cancer, and conversely can mediate several autoimmune diseases. Among the signaling pathways leading to T cell activation and function, the sensing of extracellular adenosine triphosphate (eATP) has been recently appreciated as an important component. Through a plethora of purinergic receptors, most prominently P2RX7, eATP sensing can induce a wide variety of processes in T cells, such as proliferation, subset differentiation, survival, or cell death. The downstream roles of eATP sensing can vary according to (a) the T cell subset, (b) the tissue where T cells are, and (c) the time after antigen exposure. In this mini-review, we revisit the recent findings on how eATP signaling pathways regulate T-cell immune responses and posit important unanswered questions on this field.

Bacterial cell wall peptidoglycan is composed of innate immune ligands and, due to its important structural role, also regulates access to many other innate immune ligands contained within the bacteria. There is a growing body of literature demonstrating how innate immune recognition impacts the metabolic functions of immune cells and how metabolic changes are not only important to inflammatory responses but are often essential. Peptidoglycan is primarily sensed in the context of the whole bacteria during lysosomal degradation; consequently, the innate immune receptors for peptidoglycan are primarily intracellular cytosolic innate immune sensors. However, during bacterial growth, peptidoglycan fragments are shed and can be found in the bloodstream of humans and mice, not only during infection but also derived from the abundant bacterial component of the gut microbiota. These peptidoglycan fragments influence cells throughout the body and are important for regulating inflammation and whole-body metabolic function. Therefore, it is important to understand how peptidoglycan-induced signals in innate immune cells and cells throughout the body interact to regulate how the body responds to both pathogenic and nonpathogenic bacteria. This mini-review will highlight key research regarding how cellular metabolism shifts in response to peptidoglycan and how systemic peptidoglycan sensing impacts whole-body metabolic function.

This review summarizes the cellular and molecular underpinnings of autoimmune demyelinating optic neuritis (ADON), a common sequela of multiple sclerosis and other demyelinating diseases. We further present nutritional interventions tested for people with multiple sclerosis focusing on strategies that have shown efficacy or associations with disease course and clinical outcomes. We then close by discuss the potential dietary guidance for preventing and/or ameliorating ADON.

Adipose tissue is a complex organ whose functions go beyond being an energy reservoir to sustain proper body energy homeostasis. Functioning as an endocrine organ, the adipose tissue has an active role in the body's metabolic balance regulation through several secreted factors generally termed as adipokines. Thus, adipose tissue dysregulation in chronic kidney disease (CKD) can have a deep impact in the pathophysiology of diseases associated with metabolic dysregulation including metabolic syndrome, insulin resistance (IR), atherosclerosis, and even cachexia. CKD is a progressive disorder linked to increased morbidity and mortality. Despite being characterized by renal function loss, CKD is accompanied by metabolic disturbances such as dyslipidemia, protein energy wasting, chronic low-grade inflammation, IR, and lipid redistribution. Thus far, the mechanisms by which these changes occur and the role of adipose tissue in CKD development and progression are unclear. Further understanding of how these factors develop could have implications for the management of CKD by helping identify pharmacological targets to improve CKD outcomes.

Atherosclerotic cardiovascular disease is the leading cause of death worldwide. Rupture-prone atheromas that give rise to myocardial infarction and stroke are characterized by the presence of a necrotic core and a thin fibrous cap. During homeostasis, cellular debris and apoptotic cells are cleared quickly through a process termed "efferocytosis". However, clearance of apoptotic cells is significantly compromised in many chronic inflammatory diseases, including atherosclerosis. Emerging evidence suggests that impairments in efferocytosis drive necrotic core formation and contribute significantly to plaque vulnerability. Recently, it has been appreciated that successive rounds of efferocytosis, termed "continual efferocytosis", is mechanistically distinct from single efferocytosis and relies heavily on the metabolism and handling of apoptotic cell-derived cargo. In vivo, selective defects in continual efferocytosis drive secondary necrosis, impair inflammation resolution, and worsen atherosclerosis. This Mini Review focuses on our current understanding of the cellular and molecular mechanisms of continual efferocytosis and how dysregulations in this process mediate nonresolving inflammation. We will also discuss possible strategies to enhance efferocytosis when it fails.

Microglia are a unique population of immune cells resident in the brain that integrate complex signals and dynamically change phenotypes in response to the brain microenvironment. In recent years, single-cell sequencing analyses have revealed profound cellular heterogeneity and context-specific transcriptional plasticity of microglia during brain development, aging, and disease. Emerging evidence suggests that microglia adapt phenotypic plasticity by flexibly reprogramming cellular metabolism to fulfill distinct immune functions. The control of lipid metabolism is central to the appropriate function and homeostasis of the brain. Microglial lipid metabolism regulated by apolipoprotein E (ApoE), a crucial lipid transporter in the brain, has emerged as a critical player in regulating neuroinflammation. The ApoE gene allelic variant, ε4, is associated with a greater risk for neurodegenerative diseases. In this review, we explore novel discoveries in microglial lipid metabolism mediated by ApoE. We elaborate on the functional impact of perturbed microglial lipid metabolism on the underlying pathogenesis of brain aging and disease.

Challenges regarding successful immunotherapy are associated with the heterogeneity of tumors and the complex interactions within the surrounding tumor microenvironment (TME), particularly those between immune and tumor cells. Of interest, T cells receive a myriad of environmental signals to elicit differentiation to effector subtypes, which is accompanied by metabolic reprogramming needed to satisfy the high energy and biosynthetic demands of their activated state. However, T cells are subjected to immunosuppressive signals and areas of oxygen and nutrient depletion in the TME, which causes T-cell exhaustion and helps tumor cells escape immune detection. The cytosolic and mitochondrial branched chain amino transferases, BCATc and BCATm, respectively, are responsible for the first step of the branched chain amino acid (BCAA) degradation, of which, metabolites are shunted into various metabolic processes. In recent years, BCAT isoenzymes have been investigated for their role in a variety of cancers found throughout the body; however, a gap of knowledge exists regarding the role BCAT isoenzymes play within immune cells of the TME. The aim of this review is to summarize recent findings about BCAAs and their catabolism at the BCAT step during T-cell metabolic reprogramming and to discuss the BCAT putative role in the anti-tumor immunity of T cells. Not only does this review acknowledges gaps pertaining to BCAA metabolism in the TME but it also identifies the practical application of BCAA metabolism in T cells in response to cancer and spotlights a potential target for pharmacological intervention.