Recent studies indicate an intimate link between immunity and metabolism, spawning the now
burgeoning field of immunometabolism. What is the rationale for such a link? On the one hand,
immune responses are energetically very demanding. Clonal expansion of T and B cells, increased
production of inflammatory cytokines and antibodies by activated macrophages and plasma cells,
and recruitment of immune cells to the site of an infection are all thought to impose a high
metabolic and energetic demand. This may explain why cellular metabolism regulates the
activation/differentiation and proliferation of T and B cells, as well as the effector functions of all
immune cells. On the other hand, immune cells play a fundamental role in regulating metabolism
and homeostasis. Maintenance of homeostasis is necessary to life and health, and in many respects,
metabolism can be considered a first line of defense in such maintenance, for example, sustaining
nutrient and energy homeostasis in response to the nutrient influx and nutrient deprivation.
Immunity can be considered a second line of defense in the maintenance of homeostasis and is
called into action when metabolism is insufficient to do the job. For example, if adipocytes are not
able to handle nutrient surplus or deficiency in a cell-autonomous manner, adipose tissue-resident
immune cells can be engaged to help adipocytes do so. Therefore, immunity and metabolism are
inextricably linked in coordinating homeostasis and health, while dysregulation of such a link
predisposes to chronic diseases, many of which are the most common diseases of the twenty-first
century.
Jordana B Freemantle, D Grahame Hardie·22 Jun 2023
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The AMP-activated protein kinase (AMPK) is known to maintain the integrity of cellular mitochondrial networks by (i) promoting fission; (ii) inhibiting fusion; (iii) promoting recycling of damaged components via mitophagy; (iv) enhancing lysosomal biogenesis to support mitophagy; and (v) promoting biogenesis of new mitochondrial components. While the AMPK targets underlying the first three of these effects are known, a recent paper suggests that direct phosphorylation of the folliculin-interacting protein 1 (FNIP1) by AMPK may be involved in the remaining two.
Strategies for effective entrainment of the circadian clock by external cues are continuously being refined to circumvent dysfunctional cellular metabolism that may cause metabolic disease. The efficacy of daytime-restricted feeding was recently investigated in mice and shown to dramatically improve exercise capacity through a mechanism involving Plin5.
Gregory J Anderson, David M Frazer·27 Jul 2023
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The key metabolic intermediate lactate can increase expression of the liver-derived peptide hepcidin, the central regulator of body iron homeostasis. A new paper by Liu et al. shows that lactate achieves this by binding to and activating soluble adenylyl cyclase, thereby increasing cellular cyclic adenosine monophosphate (cAMP) (cAMP) and enhancing signaling through the bone morphogenetic protein (BMP) pathway to modulate hepcidin expression.
Changhong Li, Yi Zhang, Li Chen, Xiaoying Li·13 Jul 2023
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Glucokinase (GK) plays a pivotal role in glucose homeostasis as the glucose sensor in the pancreas and liver. Loss of function of GK results in hyperglycemia, and gain of function causes congenital hyperinsulinemic hypoglycemia. We speculate that the progressive loss of GK at both mRNA and protein levels in the islets and liver would be the key mechanism for type 2 diabetes pathogenesis. The development of GK activator (GKA) as an anti-diabetic drug has been endeavored for several decades. The failure of the early development of GKAs is due to the limitation of understanding the mode of GKA action. The success of dorzagliatin in the treatment of type 2 diabetes has brought new hope for GK in setting a good model for repairing the underlying defects in the pancreatic islets and liver of T2D patients.
Alessio Bevilacqua, Ping-Chih Ho, Fabien Franco·28 Jun 2023
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Aging represents an emerging challenge for public health due to the declined immune responses against pathogens, weakened vaccination efficacy, and disturbed tissue homeostasis. Metabolic alterations in cellular and systemic levels are also known to be cardinal features of aging. Moreover, cellular metabolism has emerged to provide regulations to guide immune cell behavior via modulations on signaling cascades and epigenetic landscape, and aberrant aging process in immune cells can lead to inflammaging, a chronic and low-grade inflammation that facilitates aging by perturbing homeostasis in tissues and organs. Here, we review how metabolic program in T cells is influenced by aging process and how aged T cells modulate inflammaging. In addition, we discuss the potential approaches to reverse or ameliorate aging by rewiring metabolic programming of immune cells.
Na Wang, Tiange Yao, Chenfei Luo, Ling Sun, Yuetong Wang, Steven X Hou·06 Sep 2023
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Tumor immunotherapy has achieved breakthroughs in a variety of tumors. However, the systemic absence of T cells in tumors and immunosuppression tumor microenvironment so far limits the efficacy of immunotherapy to a small population of patients. Therefore, novel agents to increase T cell tumor infiltration are urgently needed in the clinic. We recently found that inhibition of the ADP-ribosylation factor 1 (Arf1)-mediated lipid metabolism not only kills cancer stem cells (CSCs) but also elicits an anti-tumor immune response. In this study, we revealed a mechanism that targeting Arf1 promotes the infiltration of cytotoxic T lymphocytes (CTLs) into tumors through the CCL5 (C-C chemokine ligand 5)-CCR5 (C-C chemokine receptor type 5) pathway. We found that blockage of Arf1 induces the production of the unsaturated fatty acid (PE 18:1) that binds and sequestrates peroxisome proliferator-activated receptor gamma (PPARγ) from the PPARγ-nuclear factor kappa NF-κB cytoplasmic complex. The released NF-κB was then phosphorylated and translocated into the nucleus to regulate the transcription of chemokine CCL5. The CCL5 promoted infiltration of CTLs for tumor regression. Furthermore, the combination of the Arf1 inhibitor and programmed cell death protein 1 (PD-1) blockade induced an even stronger anti-tumor immunity. Therefore, targeting Arf1 represents a novel anti-tumor immune approach by provoking T cell tumor infiltration and may provide a new strategy for tumor immunotherapy.
