Biology subjects

Dirain, M. L.

Publications and source records attributed to Dirain, M. L..

3 recordsLinked to original sources

bioRxiv2026

Divergent chromatin remodeling trajectories in CD66b⁺ MDSCs distinguishes recovery from chronic critical illness after sepsis

Sepsis survivors exhibit divergent clinical trajectories, including rapid recovery (RAP) or progression to chronic critical illness (CCI), yet how these outcomes are linked to epigenetic repression remains poorly defined. Here, we applied an optimized Omni-ATAC approach to profile chromatin accessibility in CD66b myeloid-derived suppressor cells (MDSCs) from healthy participants and longitudinally sampled sepsis cohorts stratified by outcome. RAP samples progressively restored healthy chromatin states, whereas CCI samples remained epigenetically fixed in aberrant configurations. Chromatin remodeling exhibited strong pathway specificity: promoters associated with MHC class II antigen presentation were coordinately repressed in CCI, while MHC class I antigen processing and presentation machinery remained preserved. Genome-wide analyses revealed extensive promoter remodeling during recovery in RAP, including immune regulatory loci such as ARG1, CD274, and S100A8/A9, contrasted with broad suppression of immune, metabolic, and chromatin regulatory programs in CCI. These findings define divergent epigenetic trajectories in post-sepsis MDSCs and implicate selective failure of antigen presentation as a mechanism of sepsis-induced immunoparalysis in CCI.

immunology↗

bioRxiv2025

Age- and Sex- Driven Transcriptional and Metabolic Diversity in Myeloid-Derived Suppressor Cells After Mouse Sepsis

Sepsis induces profound immune dysregulation, often resulting in chronic critical illness characterized by persistent immunosuppression and poor outcomes. Myeloid-derived suppressor cells (MDSCs) are central mediators of this immunosuppressive phenotype, yet the influence of age and sex on their transcriptional and metabolic states remain poorly understood. Here, we employed single-cell RNA sequencing of splenic leukocytes from young (3-4 months) and older (18-24 months) adult male and female mice subjected to a clinically relevant murine sepsis model to define age- and sex-specific MDSC phenotypes. We identified significant differences regarding age and sex in MDSC expansion, transcriptome, canonical pathway activation, RNA velocity, mitochondrial metabolism, and predicted cell-cell communication after sepsis. Using drug2cell analysis of total leukocytes we also identified cohort-specific drug target profiles. These findings underscore the importance of age and sex in shaping sepsis-induced MDSC biology and suggest that personalized immunomodulatory strategies targeting MDSCs could improve sepsis outcomes.

immunology↗

bioRxiv2024

Gasdermin D deficiency attenuates development of ascending aortic dissections in a novel mouse model

BackgroundThoracic aortic dissection (TAD) is a silent killer. Approximately two-thirds of the cases occur in the ascending aorta (i.e. type A dissection) and majority of them are unrelated to genetic mutations. However, animal models of spontaneous type A dissection are not widely available. In the present study, a novel mouse TAD model was created. Further, the role of gasdermin D (GSDMD) in TAD development was evaluated. MethodsTADs were created by treating ascending aorta of adult mice (C57BL/6J) with active elastase (40.0 U/ml) and {beta}-aminopropionitrile (Act E+BAPN). The temporal progress of the TAD pathology was rigorously characterized by histological evaluation and scanning electron microscopy, while potential mechanisms explored with bulk RNA sequencing of specimens collected at multiple timepoints. With this novel TAD model, further experiments were performed with Gsdmd-/- mice to evaluate its impact on TAD formation. ResultsThe ascending aorta challenged with Act E+BAPN developed pathology characterized by an early onset of intimomedial tears (complete penetration) and intramural hematoma, followed by progressive medial loss and aortic dilation. Ingenuity Pathway Analysis and functional annotation of differentially expressed genes suggested that a unique inflammatory micro-environment, rather than general inflammation, promoted the onset of TADs by specifically recruiting neutrophils to the aortic wall, while the pathology at the advanced stage was driven by T-cell mediated immune injury. Gsdmd-/- attenuated medial loss, adventitial fibrosis, and dilation of TADs. This protective effect was associated with a reduced number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) positive cells and T-cells in TADs. ConclusionsA novel mouse TAD model was created in the ascending aorta. It produces a unique microenvironment to activate different immune cell subsets, promoting onset and subsequent remodeling of TADs. Consistently, Gsdmd-/- attenuates TAD development, with modulation of cell death and T-cell response likely acting as the underlying mechanism. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/609270v1_ufig1.gif" ALT="Figure 1"> View larger version (91K): org.highwire.dtl.DTLVardef@173a620org.highwire.dtl.DTLVardef@19f8f01org.highwire.dtl.DTLVardef@65bcb9org.highwire.dtl.DTLVardef@1492f88_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗