Immunometabolism最新文献

Background: The prevalence of obesity is rising and leads to increased morbidity and mortality. Adipose tissue inflammation, due to accumulation and activation of adipose tissue macrophages (ATMs), is a key driver of this phenomenon. Macrophages are heterogeneous cells, adapting quickly to the microenvironment, resulting in so-called M1 or M2 macrophages. In this study, we describe the dynamics and inflammatory properties of a newly identified ATM subset in obese mice.

Methods: LDLR^-/- mice received a high fat diet (HFD) for 5 weeks or 16 weeks to induce obesity. Adipose tissues were isolated and immune cell subsets were analyzed with flow cytometry or microarray analysis. Bone marrow transplantation (BMT) using CD45.1 and CD45.2 LDLR^-/- mice was performed to determine ATM origin.

Results: Upon HFD, there is a massive increase of ATM subsets in the adipose tissue. CD11c^-M2 ATMs could be subdivided based on their MHC2 expression into CD11c^-MHC2^high ATMs and previously unidentified CD11c^-MHC2^low ATMs. CD11c^-MHC2^low ATMs accumulated very rapidly after 10 days of HFD, after which they increased even further with prolonged HFD. Microarray data showed that CD11c^-MHC2^low ATMs resembled CD11c^-MHC2^high ATMs in the steady state, but became more inflammatory during development of obesity. In vitro stimulation of bone marrow-derived macrophages with palmitate, abundantly present in HFD, resulted in the induction of the CD11c^-MHC2^low phenotype.

Conclusions: Among M2 macrophages, a novel pro-inflammatory subset of macrophages was found based on their low level of MHC2 expression. This subset may play a role in the development of adipose tissue inflammation.

Monocytes are circulating innate immune cells that are functionally dysregulated during aging. However, while metabolic regulation of innate immune cell function is now well-established, only a handful of studies have examined this in the context of aging. In a recent article published in Aging Cell, Saare et al. observe comprehensive metabolic reprogramming of otherwise unstimulated monocytes isolated from older adults. These cells display increased glucose uptake and dysregulation of mitochondrial function, concomitant with activation of signaling pathways contributing to increased inflammation. These findings suggest a mechanism whereby metabolic reprogramming in aged monocytes contributes to chronic low-grade inflammation and open new avenues of investigation into the biological underpinning of inflammaging.

Aging is a complex process that involves dysfunction on multiple levels, all of which seem to converge on inflammation. Macrophages are intimately involved in initiating and resolving inflammation, and their dysregulation with age is a primary contributor to inflammaging-a state of chronic, low-grade inflammation that develops during aging. Among the age-related changes that occur to macrophages are a heightened state of basal inflammation and diminished or hyperactive inflammatory responses, which seem to be driven by metabolic-dependent epigenetic changes. In this review article we provide a brief overview of mitochondrial functions and age-related changes that occur to macrophages, with an emphasis on how the inflammaging environment, senescence, and NAD decline can affect their metabolism, promote dysregulation, and contribute to inflammaging and age-related pathologies.

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are relatively common autoimmune diseases, often considered prototypic examples for how protective immunity switches to destructive immunity. The autoantigens recognized in RA and SLE are distinct, clinical manifestations are partially overlapping. A shared feature is the propensity of the adaptive immune system to respond inappropriately, with T cell hyper-responsiveness a pinnacle pathogenic defect. Upon antigen recognition, T cells mobilize a multi-pranged metabolic program, enabling them to massively expand and turn into highly mobile effector cells. Current evidence supports that T cells from patients with RA or SLE adopt metabolic programs different from healthy T cells, in line with the concept that autoimmune effector functions rely on specified pathways of energy sensing, energy generation and energy utilization. Due to misrouting of the energy sensor AMPK, RA T cells have a defect in balancing catabolic and anabolic processes and deviate towards a cell-building program. They supply biosynthetic precursors by shunting glucose away from glycolytic breakdown towards the pentose phosphate pathway and upregulate lipogenesis, enabling cellular motility and tissue invasiveness. Conversely, T cells from SLE patients are committed to high glycolytic flux, overusing the mitochondrial machinery and imposing oxidative stress. Typically, disease-relevant effector functions in SLE are associated with inappropriate activation of the key metabolic regulator mTORC1. Taken together, disease-specific metabolic signatures in RA and SLE represent vulnerabilities that are therapeutically targetable to suppress pathogenic immune responses.

LC3-associated phagocytosis, a distinct form of autophagy, plays a key role in antigen presentation. Autophagy itself plays a central role in the regulation of cellular metabolism. Proteins that regulate autophagy include the AMPK which senses high levels of AMP, and mTOR, which integrates amino acid and fatty acid metabolism with autophagy. More recently, autophagy has been demonstrated to regulate tumor cell immunogenicity via the degradation of histone deacetylase proteins. Individual drugs and drug combinations that activate the ATM-AMPK pathway and inactivate mTOR, cause autophagosome formation. The maturation of autophagosomes into autolysosomes causes the autophagic degradation of histone deacetylase proteins who regulate the transcription of PD-L1, Class I MHCA, ODC and IDO1. Indeed, drug combinations that do not contain an HDAC inhibitor can nevertheless act as de facto HDAC inhibitors, via autophagic degradation of HDAC proteins. Such drug combinations simultaneously kill tumor cells via immunogenic autophagy and in parallel opsonize tumor cells to checkpoint inhibitor immunotherapies via reduced expression of PD-L1, ODC and IDO1, and increased expression of Class I MHCA.

Objective: EZH2 is overexpressed in CD4⁺ T cells from patients with systemic lupus erythematosus (SLE). Increased disease activity in SLE patients is associated with a proinflammatory epigenetic shift in naïve CD4⁺ T cells, likely mediated by EZH2. Here we aim to understand the upstream mechanisms underlying EZH2 overexpression in SLE CD4⁺ T cells.

Methods: Naïve CD4⁺ T cells were isolated from SLE patients and then stimulated with anti-CD3/anti-CD28. qPCR and Western blotting were used to measure mRNA and protein expression levels, respectively. 2-Deoxy-d-glucose (2-DG) was used to inhibit glycolysis. mTORC1 signaling was inhibited using rapamycin. Oxidative stress was induced by H₂O₂.

Results: Because glycolysis is increased in SLE CD4⁺ T cells and glycolysis regulates miR-26a and miR-101, which target EZH2, we examined the effect of inhibiting glycolysis on EZH2 expression. 2-DG significantly inhibited EZH2 expression in SLE CD4⁺ T cells. In addition, 2-DG restored the expression of miR-26a and miR-101, suggesting that suppression of EZH2 by 2-DG occurs at the post-transcriptional level. Because mTORC1 is activated in SLE CD4⁺ T cells in part due to increased oxidative stress, and mTORC1 activation increases glycolysis, we hypothesized that mTORC1 mediates increased EZH2 expression. Indeed, inhibiting mTORC1 increased miR-26a and miR-101 and suppressed EZH2 expression in SLE CD4⁺ T cells. Further, H₂O₂ treatment increased EZH2 expression, however, this effect appears to be independent of miR-26a and miR-101.

Conclusion: Increased EZH2 is mediated by activation of mTORC1 and increased glycolysis in SLE CD4⁺ T cells. Therapeutic effects from inhibiting mTOR or glycolysis in SLE might be in part mediated by suppression of EZH2.

Background: Obesity is characterized by visceral adipose tissue (AT) inflammation. Immunosuppressive regulatory T cells (Tregs), phagocytic M2-like macrophages, and innate lymphoid cells type 2 (ILC2) control lean AT inflammation to maintain systemic insulin sensitivity, while the loss of these cells in obesity leads to AT inflammation and insulin resistance (IR).

Objective: The objective of this study was to determine if weight loss following obesity would correct AT inflammation and systemic metabolism.

Results: After six months of high fat diet (HFD) in male C57/Bl6 mice, flow analyses of epidydimal AT stromal vascular fraction (SVF) revealed depleted Tregs by 50%, doubling of CD8⁺ T cells, tripling of pro-inflammatory M1-like macrophages, and an 80% drop in ILC2 cells associated with changes in pro-inflammatory adipocyte and macrophage gene expression. Despite normalization of body weight, fat, and adipocyte size, mice ingesting 3 months of high-fat diet (HFD) followed by 3 months of chow-diet remained more insulin resistant and glucose intolerant than chow-fed animals. Adipocytes, AT Tregs, CD8⁺ T cells, ILC2 cells, and M1-like macrophages all failed to normalize with weight loss.

Conclusions: Persistent AT inflammation contributes to the maintenance of IR despite body weight and fat normalization in previously obese mice. These findings highlight the importance of obesity prevention to avoid the consequences of "obesogenic memory."

Low-grade chronic adipose tissue (AT) inflammation is now recognized as a pivotal driver of the multi-organ dysfunction associated with obesity-related complications; and adipose tissue macrophages (ATMs) are key to the development of this inflammatory milieu. Along with their role in immunosurveillance, ATMs are central regulators of AT iron homeostasis. Under optimal conditions, ATMs maintain a proper homeostatic balance of iron in adipocytes; however, during obesity, this relationship is altered, and iron is repartitioned into adipocytes as opposed to ATMs. This adipocyte iron overload leads to systemic IR and the mechanism for these effects is still under investigation. Here, we comment on the most recent findings addressing the interplay between adipocyte and ATM iron handling, and metabolic dysfunction.

HIV infection is characterized by elevated glycolytic metabolism in CD4 T cells. In their recent study, Valle-Casuso et al. demonstrated that both increased glucose utilization and glutamine metabolism are essential for HIV infectivity and replication in CD4 T cells. Here, we discuss the broader implications of immunometabolism in studies of HIV persistence and their potential to inform new treatment and curative strategies.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. We review the two core MS features, myelin instability, fragmentation, and remyelination failure, and dominance of pathogenic CD4⁺ Th17 cells over protective CD4⁺ Treg cells. To better understand myelin pathology, we describe myelin biosynthesis, structure, and function, then highlight stearoyl-CoA desaturase (SCD) in nervonic acid biosynthesis and nervonic acid's contribution to myelin stability. Noting that vitamin D deficiency decreases SCD in the periphery, we propose it also decreases SCD in oligodendrocytes, disrupting the nervonic acid supply and causing myelin instability and fragmentation. To better understand the distorted Th17/Treg cell balance, we summarize Th17 cell contributions to MS pathogenesis, then highlight how 1,25-dihydroxyvitamin D₃ signaling from microglia to CD4⁺ T cells restores Treg cell dominance. This signaling rapidly increases flux through the methionine cycle, removing homocysteine, replenishing S-adenosyl-methionine, and improving epigenetic marking. Noting that DNA hypomethylation and inappropriate DRB1*1501 expression were observed in MS patient CD4⁺ T cells, we propose that vitamin D deficiency thwarts epigenetic downregulation of DRB1*1501 and Th17 cell signature genes, and upregulation of Treg cell signature genes, causing dysregulation within the CD4⁺ T cell compartment. We explain how obesity reduces vitamin D status, and how estrogen and vitamin D collaborate to promote Treg cell dominance in females. Finally, we discuss the implications of this new knowledge concerning myelin and the Th17/Treg cell balance, and advocate for efforts to address the global epidemics of obesity and vitamin D deficiency in the expectation of reducing the impact of MS.