In this issue of Cell Reports, Redford et al.1 uncouple the role of CD4+ and CD8+ T cells in controlling anorexia and wasting of muscle and adipose tissue during chronic parasitic infections. These ...results shed light on the impact of adaptive immune cells on organ catabolism.
In this issue of Cell Reports, Redford et al.1 uncouple the role of CD4+ and CD8+ T cells in controlling anorexia, and wasting of muscle and adipose tissue during chronic parasitic infections. These results shed light on the impact of adaptive immune cells on organ catabolism.
Summary
Immune cell differentiation and function depend on metabolic changes for the provision of energy and metabolites. Consequently, cellular metabolism relies on the availability of ...micronutrients such as vitamins and energy‐rich sources including amino acids and fatty acids. The bone marrow controls the continuous production of blood cells and is thereby reliant on the sophisticated interplay of progenitor and mature immune cells with its stromal microenvironment. The significance of stromal subsets in immunopoiesis is undisputed; however, our current knowledge is limited to their role in the production and secretion of a variety of soluble proteins such as cytokines. In contrast, the role of the haematopoietic niche in controlling and providing nutrients such as fatty acids, amino acids and vitamins, which are required for immune cell differentiation and function, remains largely elusive. In this review, we summarize the current understanding of local nutritional exchange and control between immune and stromal cells in peripheral tissue and, when it is known, in the bone marrow. The parallels found between peripheral tissues and bone marrow stroma raises the question of how local metabolism is capable of influencing haematopoiesis and immunopoiesis. A better understanding of the local exchange of nutrients in the bone marrow can be used to improve immune cell formation during ageing, after haematopoietic stem cell transplantation and during immune challenge.
Immune cell differentiation and function depend on metabolic changes for the provision of energy and metabolites. Consequently, cellular metabolism relies on the availability of micronutrients such as vitamins and energy‐rich sources including amino acids and fatty acids. In this review, we summarize the current understanding of local nutritional exchange and control between immune and stromal cells in peripheral tissue and when it is known in the bone marrow.
Vaccines are powerful tools to develop immune memory to infectious diseases and prevent excess mortality. In older adults, however vaccines are generally less efficacious and the molecular mechanisms ...that underpin this remain largely unknown. Autophagy, a process known to prevent aging, is critical for the maintenance of immune memory in mice. Here, we show that autophagy is specifically induced in vaccine-induced antigen-specific CD8+ T cells in healthy human volunteers. In addition, reduced IFNγ secretion by RSV-induced T cells in older vaccinees correlates with low autophagy levels. We demonstrate that levels of the endogenous autophagy-inducing metabolite spermidine fall in human T cells with age. Spermidine supplementation in T cells from old donors recovers their autophagy level and function, similar to young donors' cells, in which spermidine biosynthesis has been inhibited. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB. In summary, we have provided evidence for the importance of autophagy in vaccine immunogenicity in older humans and uncovered two novel drug targets that may increase vaccination efficiency in the aging context.
Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a ...lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte‐specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti‐inflammatory energy substrates. Instead, Atg7‐deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2‐mediated upregulation of Ephx1. This shift reduced secretion of IL‐10 from adipose tissues, which was dependent on the cytochrome P450‐EPHX pathway, and lowered circulating levels of IL‐10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat‐gut crosstalk through an autophagy‐dependent regulation of anti‐inflammatory oxylipins via the cytochrome P450‐EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation.
Synopsis
Cell‐extrinsic effects of autophagy on inflammation remain poorly understood. This study identifies adipocyte autophagy as an important contributor to an adipose‐driven anti‐inflammatory response to intestinal inflammation.
Adipocyte autophagy is induced by DSS‐induced colitis in mice and in Crohn's disease patients.
Loss of autophagy in mature adipocytes results in an exacerbation of DSS‐induced intestinal inflammation.
Augmented DSS‐induced intestinal inflammation upon adipocyte‐specific autophagy inhibition was not due to reduced adipose tissue lipolysis.
Adipocyte‐specific autophagy loss resulted in altered oxylipin metabolism via activation of the cytochrome P450‐EPHX pathway.
Oxylipin imbalance impaired IL‐10 secretion from adipose tissues of DSS‐treated mice.
Gut inflammation modulates autophagy‐dependent oxylipin metabolism in distant fat cells to trigger the release of anti‐inflammatory signals.
The microRNA-34a is a well-studied tumor suppressor microRNA (miRNA) and a direct downstream target of TP53 with roles in several pathways associated with oncogenesis, such as proliferation, cellular ...growth, and differentiation. Due to its broad tumor suppressive activity, it is not surprising that miR34a expression is altered in a wide variety of solid tumors and hematological malignancies. However, the mechanisms by which miR34a is regulated in these cancers is largely unknown. In this study, we find that a long noncoding RNA transcribed antisense to the miR34a host gene, is critical for miR34a expression and mediation of its cellular functions in multiple types of human cancer. We name this long noncoding RNA lncTAM34a, and characterize its ability to facilitate miR34a expression under different types of cellular stress in both TP53-deficient and wild-type settings.
The role of macroautophagy/autophagy, a conserved lysosomal degradation pathway, during cellular differentiation has been well studied over the last decade. In particular, evidence for its role ...during immune cell differentiation is growing. Despite the description of a variety of dramatic immune phenotypes in tissue-specific autophagy knockout models, the underlying mechanisms are still under debate. One of the proposed mechanisms is the impact of autophagy on the altered metabolic states during immune cell differentiation. This concept is strengthened through novel molecular insights into how AMPK and MTOR signaling cascades affect both autophagy and metabolism. In this review, we discuss direct and indirect evidence linking autophagy, metabolic pathways and immune cell differentiation including T, B, and innate lymphocytes as well as in myeloid cells that are direct mediators of inflammation. Herein, we propose a model for autophagy-driven immunometabolism controlling immune cell differentiation.
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