Biology subjects

Sturgill, J. L.

Publications and source records attributed to Sturgill, J. L..

3 recordsLinked to original sources

bioRxiv2026

CNS-resident B cells develop locally into a pro-inflammatory age-associated phenotype during aging and after stroke

Aging and age-related diseases like ischemic stroke induce chronic lymphocyte recruitment into the central nervous system (CNS). Conflicting effects on post-stroke functional recovery, however, are secondary to the differences in responding lymphocyte populations that shift immunophenotype with both ischemic injury and age. To better define CNS-localized B cell subsets, we used flow cytometry, single-cell RNA sequencing, and B cell receptor sequencing on B cells isolated from uninjured and post-stroke brains of aged male and female mice. We identified a novel B1b cell progenitor pool distinct from canonical pleural and peritoneal B1 niches. Trajectory analysis showed B1b progenitors transition into age-associated B cell (ABC) subsets, and clonal expansion of IgM+ ABCs (ABC/B1b) and plasma cells following ischemic stroke. We also confirmed analogous ABCs and developing B cell populations in post-mortem human parenchymal tissue isolated from aged brain donors. These studies reveal unique B cell populations that proliferate within the aging CNS and are associated with impaired post-stroke functional recovery in mice. Identification of inflammatory, CNS-resident ABC/B1b cells that are conserved across species is critical as they have the potential to be sequestered from peripheral immunotherapies and/or contribute to age-related neurodegenerative diseases.

neuroscience↗

bioRxiv2025

mTORC1-Dependent Regulation of the CCL24-CCR3 Axis Controls Granuloma Formation and Maintenance in Sarcoidosis

Sarcoidosis is a chronic granulomatous disease marked by persistent inflammation and immune cell aggregation, yet its molecular underpinnings remain incompletely understood, hindering the development of effective targeted therapies. Here, we report that deletion of TSC1 or TSC2 in mice using a Fsp1-Cre leads to spontaneous formation of sarcoid-like granulomas, driven by hyperactivation of the mTORC1 pathway in fibroblasts and interstitial macrophages. Through inflammatory cytokine/chemokine array, we identified CCL24, a chemokine ligand for CCR3, as a key immunoregulatory molecule downregulated in both our murine model and sarcoid cohort plasma. Mechanistically, mTORC1 suppresses CCL24 expression via aberrant STAT3 signaling in fibroblasts and promotes CCR3 expression in interstitial macrophages, uncovering a novel regulatory axis in granuloma formation and maintenance. Pharmacological inhibition using rapamycin and azithromycin markedly attenuated granuloma burden and normalized CCL24-CCR3 signaling, underscoring the therapeutic relevance of this axis. Together, our study establishes a mechanistic link between mTORC1 activation, CCL24-CCR3 dysregulation, and granuloma persistence, offering not only a new insight into molecular mechanisms in sarcoidosis but also identifying promising targets for clinical intervention.

immunology↗

bioRxiv2024

Unfolded Von Willebrand Factor Binds Protein S and Reduces Anticoagulant Activity

Protein S (PS), the critical plasma cofactor for the anticoagulants tissue factor (TF) pathway inhibitor (TFPI) and activated protein C (APC), circulates in two functionally distinct pools: free (anticoagulant) or bound to complement component 4b-binding protein (C4BP) (anti-inflammatory). Acquired free PS deficiency is detected in several viral infections, but its cause is unclear. Here, we identified a shear-dependent interaction between PS and von Willebrand Factor (VWF) by mass spectrometry. Consistently, plasma PS and VWF comigrated in both native and agarose gel electrophoresis. The PS/VWF interaction was blocked by TFPI but not APC, suggesting an interaction with the C-terminal sex hormone binding globulin (SHBG) region of PS. Microfluidic systems, mimicking arterial laminar flow or disrupted turbulent flow, demonstrated that PS stably binds VWF as VWF unfolds under turbulent flow. PS/VWF complexes also localized to platelet thrombi under laminar arterial flow. In thrombin generation-based assays, shearing plasma decreased PS activity, an effect not seen in the absence of VWF. Finally, free PS deficiency in COVID-19 patients, measured using an antibody that binds near the C4BP binding site in SHBG, correlated with changes in VWF, but not C4BP, and with thrombin generation. Our data suggest that PS binds to a shear-exposed site on VWF, thus sequestering free PS and decreasing its anticoagulant activity, which would account for the increased thrombin generation potential. As many viral infections present with free PS deficiency, elevated circulating VWF, and increased vascular shear, we propose that the PS/VWF interaction reported here is a likely contributor to virus-associated thrombotic risk. Key PointsO_LIVon Willebrand Factor (VWF) binds Protein S (PS) in a shear-dependent manner, reducing the free PS pool and its anticoagulant activity. C_LIO_LIThe PS/VWF complex forms under turbulent flow conditions, is stable in whole blood, and localizes to growing platelet thrombi. C_LI

biochemistry↗