Biology subjects

Rubio-Ponce, A.

Publications and source records attributed to Rubio-Ponce, A..

3 recordsLinked to original sources

bioRxiv2026

Microglial AhR Drives Sex-Biased Amyloid Pathology

Microglia integrate local and systemic signals that can modify their response to amyloid-{beta} (A{beta}), but the molecular pathways connecting these signals to Alzheimer's disease (AD) pathology remain incompletely understood. Here, we identify the aryl hydrocarbon receptor (AhR), a sensor of microbiota- and host-derived metabolites, as a microglial regulator of amyloid pathology. Sustained administration of the AhR agonist indoxyl-3-sulfate (I3S) exacerbated cortical A{beta} deposition and plaque-associated neuritic damage in APPNL-F mice. Conversely, constitutive AhR deficiency reduced amyloid burden, promoted plaque compaction, and preserved behavioural performance, whereas inducible deletion of AhR in microglia was sufficient to reduce plaque accumulation. Single-cell RNA sequencing revealed that AhR loss reprogrammed microglia toward phagolysosomal and A{beta}-recognition states and enhanced microglial A{beta} uptake, with markedly stronger effects in females. APPNL-F mice also exhibited sex-dependent remodelling of the gut microbiota and tryptophan-derived metabolites. Circulating indole-3-aldehyde (IAld) robustly activated AhR and was associated with cortical amyloid pathology. AhR-activating bioactivity was increased in mouse serum, cortex and faecal extracts and was higher in serum from the COGNIBIO12 analytical subcohort than in independently recruited cognitively unimpaired H2H participants. Among amyloid-positive patients, higher serum AhR bioactivity was associated with lower CSF A{beta}42 concentrations. Together, these findings identify microglial AhR as a metabolically responsive regulator linking systemic ligand availability, biological sex, and microglial control of amyloid pathology.

immunology↗

bioRxiv2025

CIRCADIAN MODULATION OF NEUTROPHIL FUNCTION DETERMINES COLLATERAL PERFUSION AND OUTCOME AFTER ISCHEMIC STROKE

Stroke is a leading cause of mortality and disability, driven by complex and time-dependent mechanisms that aggravate ischemic damage. Among them, collateral perfusion determines the initial size of the ischemic core, the rate of its expansion, and the extent of the penumbra both at stroke onset and over time. Insufficiency of collaterals may occur due to genetic factors or other determinants, such as aging or cardiovascular risk factors, which reduce the number of collaterals or the diameter of those that remain. But aspects of less structural nature could also affect the effectiveness of these pathways by decreasing their patency. We hereby show that diurnal fluctuations in infarct volume in ischemic stroke mouse models are neutrophil phenotype-dependent, since differences in infarct volumes were abolished by depleting neutrophils or blocking their circadian clock, and linked to the collateral circulation: during the inactive phase of mice (daytime), collateral perfusion in the ipsilesional hemisphere was reduced, coinciding with an increase in intravascular neutrophil accumulation, suggestive of microvascular stalling. Single-cell transcriptomics, ex vivo functional assays and in vivo pharmacological and genetic strategies confirmed enhanced neutrophil extracellular traps (NETs) formation at this time. Importantly, in a cohort of human stroke patients, we identified diurnal oscillations in neutrophil and NET-related biomarkers, peaking during the human inactive phase (evening/night), and similarly associated with reduced collateral flow and poorer clinical outcomes. These findings underscore the critical role of neutrophils, their circadian dynamics and NET release in driving collateral insufficiency and ischemic brain damage, suggesting novel personalized therapeutic strategies based on circadian rhythms for the treatment of stroke.

immunology↗

bioRxiv2024

Zfp263 is a transcriptional checkpoint of neutrophil development

During development neutrophils undergo extensive changes in nuclear morphology, gene expression programmes, and acquire specific effector functions. However, molecular mechanisms controlling neutrophil development remain largely unknown. Here we systematically analysed changes in gene expression and chromatin landscape across stages of neutrophil differentiation, to construct a network of transcription factors, predicted to control neutrophil development and acquisition of functions. Zinc finger protein 263 (Zfp263) emerged at the apex of this network. Neutrophil maturation ex vivo and in vivo was blocked in cells lacking Zfp263 and accelerated if its levels were induced. Mechanistically, Zfp263 acts as a direct transcriptional repressor of the ERK1/2 pathway, that supports the proliferative capacity of neutrophil progenitors and limits their differentiation into mature cells. Blocking ERK1/2 signalling in the Zfp263 deficient cells using chemical inhibitors, rescues neutrophil differentiation. Other targets of Zfp263 include genes involved in neutrophil migration, cytokine and chemokine expression, reactive oxygen species and formation of neutrophil extracellular traps. Thus, our study outlines a framework for modulation of neutrophil development and / or function, aimed at neutrophil-mediated diseases.

genomics↗