Biology subjects

Berg, A. H.

Publications and source records attributed to Berg, A. H..

3 recordsLinked to original sources

bioRxiv2025

The Role of Supraoptic Hypothalamic Arginine Vasopressin Neurons in Aging-Associated Water Balance and Thermoregulatory Deficits

Aging disrupts physiological homeostasis, impairing thermoregulation, metabolism, and water balance, but the underlying neural mechanisms remain unclear. Here, we identify arginine vasopressin (AVP) neurons in the supraoptic nucleus (SON) of the hypothalamus as a critical driver of these changes. Using single-nucleus RNA-sequencing of the anterior hypothalamus in young and aged mice, we found Avp to be one of the most upregulated neuronal transcripts with age. Aged SONAVP neurons displayed enlarged size and heightened excitability, features consistent with hyperactivity. Functionally, chemogenetic activation of SONAVP neurons in young mice reproduced aging-associated phenotypes including hypothermia, reduced energy expenditure, and suppressed water intake. Conversely, knockdown of Avp in the SON of aged mice restored water balance, partially improved thermoregulation and systemic metabolism. Pharmacological inhibition of AVP receptors revealed that neuroendocrine release of AVP drives homeostatic deficits, with distinct roles for V1A and V2 receptors. Senolytic drug treatment improved systemic metabolism and reduced inflammaging but does not rescue hypothalamic AVP dysfunction, underscoring a brain autonomous mechanism of age-related physiological failure. Together, our findings establish SONAVP neuronal hyperactivity as a driver of impaired homeostasis with age and suggest that targeted modulation of neuroendocrine AVP signaling may offer a therapeutic strategy to alleviate age-associated water balance defects.

physiology↗

bioRxiv2025

Quinolinic acid metabolism may mitigate AKI to CKD transition

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a significant clinical problem with unclear underlying mechanisms. Emerging evidence suggests that alterations in tryptophan metabolism, particularly in the production of downstream metabolites such as quinolinic acid (QA), play a role in renal pathophysiology. QA is a NAD biosynthesis intermediate metabolized by the enzyme quinolinate phosphoribosyltransferase (QPRT). In this study, we investigated the role of QA in the AKI-to-CKD transition using experimental mouse models and clinical observations and leveraging multiple omics approaches. Systematic metabolomic profiling identified endogenous QA as one of the most significantly elevated metabolites following folic acid-(FA) induced injury. Exogenous QA exacerbated FA-induced kidney dysfunction. Conversely, aged mice deficient in QPRT showed worsened expression of kidney fibrosis markers even in absence of kidney injury, while younger littermates exhibited worsened induced kidney injury. Mice lacking QA-producing enzymes resisted experimental AKI and AKI-to-CKD progression. Multimodal spatial metabolomics analysis of human AKI kidney biopsies revealed QA accumulation in regions of inflammatory infiltration. Finally, children with CKD exhibited higher urinary QA levels compared to healthy controls. These findings underscore QA as a potential mediator of kidney injury and a therapeutic target for preventing the progression from AKI to CKD. One Sentence SummaryQuinolinic acid promotes kidney damage and fibrosis, suggesting it as a contributor of AKI-to-CKD progression and a potential therapeutic target.

pathology↗

bioRxiv2024

Butyrophilin 2A2 promotes T cell immunoregulation by enhancing CD45 phosphatase activity within the immune synapse

B7 costimulatory family member Butyrophilin 2A2 (BTN2A2) is predominantly expressed by antigen presenting cells and regulates T cell immunity, but molecular mechanisms are unclear. Using immunoblots analyzing TCR-initiated signaling intermediaries, co-immunoprecipitation studies, confocal microscopy, structural modeling-guided mutational analyses, and microscale thermophoresis, we demonstrate that BTN2A2 directly interacts with CD45RO, resulting in CD45 retention within the immune synapse during TCR activation. Recombinant BTN2A2 increased murine CD4+Foxp3+ regulatory T cells (Treg) and reduced T helper 17 (Th17) cells in vitro through mechanisms dependent on CD45 phosphatase activity. BTN2A2 treatment reduced clinical expression of two murine autoimmune disease models and increased Treg/Th17 ratios. Analyses of BTN2A2-deficient animals showed exacerbated disease associated with reduced Treg/Th17 ratios. Addition of BTN2A2 to human mixed lymphocyte responses similarly enhanced human Treg and suppressed Th17 cells and was CD45 phosphatase dependent. Together, our studies identify BTN2A2 as a physiological CD45RO ligand that enhances CD45 phosphatase activity in murine and human T cells, providing mechanisms for BTN2A2-mediated amelioration of autoimmunity. SummaryButyrophilin 2A2 ameliorates autoimmunity by binding to CD45RO on activated T cell surfaces leading to dampened TCR signaling which in turn leads to expansion of T regulatory cells and reduction of Th17 differentiation.

immunology↗