Blocking glycosphingolipid production alters autophagy in osteoclasts and improves myeloma bone disease.

Glycosphingolipids (GSLs) are key constituents of membrane bilayers playing a role in structural integrity, cell signalling in microdomains, endosomes and lysosomes, and cell death pathways. Conversion of ceramide into GSLs is controlled by GCS (glucosylceramide synthase) and inhibitors of this enzyme for the treatment of lipid storage disorders and specific cancers. With a diverse range of functions attributed to GSLs, the ability of the GSC inhibitor, eliglustat, to reduce myeloma bone disease was investigated.

Proteostasis in T cell aging.

Aging leads to a decline in immune cell function, which leaves the organism vulnerable to infections and age-related multimorbidities. One major player of the adaptive immune response are T cells, and recent studies argue for a major role of disturbed proteostasis contributing to reduced function of these cells upon aging. Proteostasis refers to the state of a healthy, balanced proteome in the cell and is influenced by synthesis (translation), maintenance and quality control of proteins, as well as degradation of damaged or unwanted proteins by the proteasome, autophagy, lysosome and cytoplasmic enzymes.

Autophagy preserves hematopoietic stem cells by restraining MTORC1-mediated cellular anabolism.

Adult stem cells are long-lived and quiescent with unique metabolic requirements. Macroautophagy/autophagy is a fundamental survival mechanism that allows cells to adapt to metabolic changes by degrading and recycling intracellular components. Here we address why autophagy depletion leads to a drastic loss of the stem cell compartment.

Autophagy orchestrates the crosstalk between cells and organs.

Over the recent years, it has become apparent that a deeper understanding of cell-to-cell and organ-to-organ communication is necessary to fully comprehend both homeostatic and pathological states. Autophagy is indispensable for cellular development, function, and homeostasis. A crucial aspect is that autophagy can also mediate these processes through its secretory role.

The central role of DNA damage in immunosenescence.

Ageing is the biggest risk factor for the development of multiple chronic diseases as well as increased infection susceptibility and severity of diseases such as influenza and COVID-19. This increased disease risk is linked to changes in immune function during ageing termed immunosenescence. Age-related loss of immune function, particularly in adaptive responses against pathogens and immunosurveillance against cancer, is accompanied by a paradoxical gain of function of some aspects of immunity such as elevated inflammation and increased incidence of autoimmunity.

Mechanisms of spermidine-induced autophagy and geroprotection.

Aging involves the systemic deterioration of all known cell types in most eukaryotes. Several recently discovered compounds that extend the healthspan and lifespan of model organisms decelerate pathways that govern the aging process. Among these geroprotectors, spermidine, a natural polyamine ubiquitously found in organisms from all kingdoms, prolongs the lifespan of fungi, nematodes, insects and rodents.

Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL-10.

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.

Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease.

Patients with multiple myeloma, an incurable malignancy of plasma cells, frequently develop osteolytic bone lesions that severely impact quality of life and clinical outcomes. Eliglustat, a U.S.

Age-related mechanisms in the context of rheumatic disease.

Ageing is characterized by a progressive loss of cellular function that leads to a decline in tissue homeostasis, increased vulnerability and adverse health outcomes. Important advances in ageing research have now identified a set of nine candidate hallmarks that are generally considered to contribute to the ageing process and that together determine the ageing phenotype, which is the clinical manifestation of age-related dysfunction in chronic diseases. Although most rheumatic diseases are not yet considered to be age related, available evidence increasingly emphasizes the prevalence of ageing hallmarks in these chronic diseases.

Mapping autophagosome contents identifies interleukin-7 receptor-α as a key cargo modulating CD4+ T cell proliferation.

CD4+ T cells are pivotal cells playing roles in the orchestration of humoral and cytotoxic immune responses. It is known that CD4+ T cell proliferation relies on autophagy, but identification of the autophagosomal cargo involved is missing. Here we create a transgenic mouse model, to enable direct mapping of the proteinaceous content of autophagosomes in primary cells by LC3 proximity labelling.

GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans.

Inborn errors of immunity (IEIs) unveil regulatory pathways of human immunity. We describe a new IEI caused by mutations in the GTPase of the immune-associated protein 6 (GIMAP6) gene in patients with infections, lymphoproliferation, autoimmunity, and multiorgan vasculitis. Patients and Gimap6-/- mice show defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)-containing lipids.

Autophagy takes it all - autophagy inducers target immune aging.

Autophagy, as the key nutrient recycling pathway, enables eukaryotic cells to adapt to surging cellular stress during aging and, thereby, delays age-associated deterioration. Autophagic flux declines with age and, in turn, decreases in autophagy contribute to the aging process itself and promote senescence. Here, we outline how autophagy regulates immune aging and discuss autophagy-inducing interventions that target senescent immune cells, which are major drivers of systemic aging.

Autophagy in healthy aging and disease.

Autophagy is a fundamental cellular process that eliminates molecules and subcellular elements, including nucleic acids, proteins, lipids and organelles, via lysosome-mediated degradation to promote homeostasis, differentiation, development and survival. While autophagy is intimately linked to health, the intricate relationship among autophagy, aging and disease remains unclear. This Review examines several emerging features of autophagy and postulates how they may be linked to aging as well as to the development and progression of disease.

Autophagy in major human diseases.

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies.

EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells.

Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be explored. Here, we identify that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in helper T (Th) cells.

Asymmetric cell division shapes naive and virtual memory T-cell immunity during ageing.

Efficient immune responses rely on heterogeneity, which in CD8 T cells, amongst other mechanisms, is achieved by asymmetric cell division (ACD). Here we find that ageing, known to negatively impact immune responses, impairs ACD in murine CD8 T cells, and that this phenotype can be rescued by transient mTOR inhibition. Increased ACD rates in mitotic cells from aged mice restore the expansion and memory potential of their cellular progenies.

Hallmarks and detection techniques of cellular senescence and cellular ageing in immune cells.

The ageing of the global population brings about unprecedented challenges. Chronic age-related diseases in an increasing number of people represent an enormous burden for health and social care. The immune system deteriorates during ageing and contributes to many of these age-associated diseases due to its pivotal role in pathogen clearance, tissue homeostasis and maintenance.

Regulating T-cell differentiation through the polyamine spermidine.

Background: The cross-talk between the host and its microbiota plays a key role in the promotion of health. The production of metabolites such as polyamines by intestinal-resident bacteria is part of this symbiosis shaping host immunity. The polyamines putrescine, spermine, and spermidine are abundant within the gastrointestinal tract and might substantially contribute to gut immunity.