Biology subjects

Trzeciak, A.

Publications and source records attributed to Trzeciak, A..

3 recordsLinked to original sources

bioRxiv2023

Early life high fructose exposure disrupts microglia function and impedes neurodevelopment

Despite the success of fructose as a low-cost food additive, recent epidemiological evidence suggests that high fructose consumption by pregnant mothers or during adolescence is associated with disrupted neurodevelopment1-7. An essential step in appropriate mammalian neurodevelopment is the synaptic pruning and elimination of newly-formed neurons by microglia, the central nervous systems (CNS) resident professional phagocyte8-10. Whether early life high fructose consumption affects microglia function and if this directly impacts neurodevelopment remains unknown. Here, we show that both offspring born to dams fed a high fructose diet and neonates exposed to high fructose exhibit decreased microglial density, increased uncleared apoptotic cells, and decreased synaptic pruning in vivo. Importantly, deletion of the high affinity fructose transporter SLC2A5 (GLUT5) in neonates completely reversed microglia dysfunction, suggesting that high fructose directly affects neonatal development. Mechanistically, we found that high fructose treatment of both mouse and human microglia suppresses synaptic pruning and phagocytosis capacity which is fully reversed in GLUT5-deficient microglia. Using a combination of in vivo and in vitro nuclear magnetic resonance- and mass spectrometry-based fructose tracing, we found that high fructose drives significant GLUT5-dependent fructose uptake and catabolism, rewiring microglia metabolism towards a hypo-phagocytic state. Importantly, mice exposed to high fructose as neonates exhibited cognitive defects and developed anxiety-like behavior which were rescued in GLUT5-deficient animals. Our findings provide a mechanistic explanation for the epidemiological observation that early life high fructose exposure is associated with increased prevalence of adolescent anxiety disorders.

immunology↗

bioRxiv2022

A microbiota-derived metabolite instructs peripheral efferocytosis

The phagocytic clearance of dying cells, termed efferocytosis, is essential for both tissue homeostasis and tissue health during cell death-inducing treatments. Failure to efficiently clear dying cells augments the risk of pathological inflammation and has been linked to a myriad of autoimmune and inflammatory diseases. Although past studies have elucidated local molecular signals that regulate efferocytosis in a tissue, whether signals arising distally also regulate efferocytosis remains elusive. Interestingly, clinical evidence suggests that prolonged use of antibiotics is associated with an increased risk of autoimmune or inflammatory disease development. We therefore hypothesized that intestinal microbes produce molecular signals that regulate efferocytotic ability in peripheral tissue phagocytes. Here, we find that macrophages, the bodys professional phagocyte, display impaired efferocytosis in peripheral tissues in both antibiotic-treated and germ-free mice in vivo, which could be rescued by fecal microbiota transplantation. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosted efferocytosis efficiency and capacity in mouse and human macrophages, with both intestinal and local delivery of butyrate capable of rescuing antibiotic-induced peripheral efferocytosis defects. Bulk mRNA sequencing of primary macrophages treated with butyrate in vitro and single cell mRNA sequencing of macrophages isolated from antibiotic-treated and butyrate-rescued mice revealed specific regulation of phagocytosis-associated transcriptional programs, in particular the induction of programs involved in or supportive of efferocytosis. Surprisingly, the effect of butyrate on efferocytosis was not mediated through G protein-coupled receptor signaling, but instead acted by inhibition of histone deacetylase 3. Strikingly, peripheral efferocytosis was impaired well-beyond withdrawal of antibiotics and, importantly, antibiotic-treated mice exhibited a poorer response to a sterile efferocytosis-dependent inflammation model. Collectively, our results demonstrate that a process essential for tissue homeostasis, efferocytosis, relies on distal molecular signals, and suggest that a defect in peripheral efferocytosis may contribute to the clinically-observed link between broad-spectrum antibiotics use and inflammatory disease.

immunology↗

bioRxiv2022

Novel adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments

Apoptotic cell clearance (efferocytosis), a process essential for organismal homeostasis, is performed by phagocytes that inhabit a wide range of environments, including physiologic hypoxia. Here, we find macrophages, the predominant tissue-resident phagocyte, display enhanced efferocytosis under prolonged (chronic) physiological hypoxia, characterized by increased internalization and accelerated degradation of apoptotic cells. Analysis of mRNA and protein programs revealed that chronic physiological hypoxia induces two distinct but complimentary states in macrophages. The first, primed state consists of concomitant induction of transcriptional and translational programs broadly associated with metabolism in apoptotic cell-naive macrophages that persist during efferocytosis. The second, poised state consists of transcription, but not translation, of phagocyte function programs in apoptotic cell-naive macrophages that are subsequently translated during efferocytosis. Importantly, we discovered that both states are necessary for enhanced continual efferocytosis. Mechanistically, we find that one such primed state consists of the efficient flux of glucose into a noncanonical pentose phosphate pathway (PPP) loop, whereby PPP-derived intermediates cycle back through the PPP to enhance production of NADPH. Furthermore, we found that PPP-derived NADPH directly supports enhanced continual efferocytosis under chronic physiological hypoxia via its role in phagolysosomal maturation and maintenance of cellular redox homeostasis. Thus, macrophages residing under chronic physiological hypoxia adopt states that both support cell fitness and ensure ability to perform essential homeostatic functions rapidly and safely. Highlights- Macrophages residing in chronic physiological hypoxia have enhanced apoptotic cell uptake and degradation - Chronic physiological hypoxia induces both primed and poised states in macrophages - Both primed and poised state programs directly support enhanced continual efferocytosis - A noncanonical PPP loop, a unique primed state, directly supports enhanced efferocytosis and maintains redox homeostasis

immunology↗