Biology subjects

Samal, J.

Publications and source records attributed to Samal, J..

5 recordsLinked to original sources

bioRxiv2025

High-Dimensional Single-Cell Analysis Reveals Coordinated Age-Dependent Neuroinflammatory Microglia-T cell Circuits in the Brain

Aging and cerebrovascular pathology drive neuroinflammation in vascular dementia (VaD) but immune mechanisms underlying this interplay remain unresolved. Leveraging multi-modal high-dimensional imaging, flow cytometry, and split pool ligation transcriptomic sequencing in a mouse model of VaD, we constructed a brain immune cell atlas spanning young and aged mice in health and disease. We profiled microglia, T cells, macrophages, neutrophils, and B cells and integrated transcriptomics, cell-cell communication, multiplex imaging, and comparative analysis with human microglia. We found striking depletion of Ccr7+ naive T cells and expansion of Gzmk+ cytotoxic Cd8+ effector memory T cells in the aging brain. At the same time, microglia shifted toward a pro-inflammatory state with enhanced activity of major histocompatibility class complex I (MHC-I) to T cell receptor and co-stimulation from CD86 to CD28. These shifts suggest enhanced neuroinflammatory polarization within the aged brain and in VaD. These signals were strongest from activated microglia to Gzmk+ Cd8+ TEM cells, indicating that age-related microglial polarization may sustain cytotoxic T cell activation in the aged brain. Our findings suggest pro-inflammatory microglia and Gzmk+ CD8+ TEM cells are central drivers of immune brain aging and highlights a therapeutic potential to disrupt age-related neuroinflammatory cascades in VaD.

immunology↗

bioRxiv2021

Nef dimerization defect abrogates HIV viremia and associated immune dysregulation in the Bone Marrow-Liver-Thymus-Spleen (BLTS) humanized mouse model

Loss of function mutations in the human immunodeficiency virus (HIV) negative factor (Nef) gene are associated with reduced viremia, robust T cell immune responses, and delayed acquired immunodeficiency syndrome (AIDS) progression in humans. In vitro studies have shown that mutations in the Nef dimerization interface significantly attenuate viral replication and impair host defense. However, in vivo, mechanistic studies on the role of Nef dimerization in HIV infection are lacking. Humanized rodents with human immune cells are robust platforms for investigating the interactions between HIV and the human immune system. The bone marrow-liver-thymus-spleen (BLTS) humanized mouse model carries human immune cells and lymphoid tissues that facilitate anti-viral immune responses. Here, we employed the BLTS-humanized mouse model to demonstrate that preventing Nef dimerization abrogates HIV viremia and the associated immune dysregulation. This suggests that Nef dimerization may be a therapeutic target for future HIV cure strategies.

immunology↗

bioRxiv2019

Development of a novel preclinical glioblastoma mouse model and therapeutic impact of IRE1 inhibition

Glioblastoma multiforme (GBM) is the most severe primary brain cancer. Despite an aggressive treatment comprising surgical resection and radio/chemotherapy patients survival post diagnosis remains short. A limitation for success in finding novel improved therapeutic options for such dismal disease partly lies in the lack of a relevant animal model that accurately recapitulates patient disease and standard of care. In the present study, we have developed a novel immunocompetent GBM model that includes tumor surgery and a radio/chemotherapy regimen resembling the Stupp protocol and we have used this model to test the impact of the pharmacological inhibition of the endoplasmic reticulum (ER) stress sensor IRE1, on treatment efficacy.

cancer biology↗

bioRxiv2019

Constitutive IRE1α signaling maintains glioblastoma cell differentiation

Endoplasmic Reticulum (ER) proteostasis control and the Unfolded Protein Response (UPRER) have been shown to contribute to tumor development and aggressiveness. As such, the UPRER sensor IRE1 (referred to as IRE1 hereafter) is a major regulator of glioblastoma (GBM) development and is an appealing therapeutic target. To document IRE1 suitability as an antineoplastic pharmacological target, we investigated how this protein contributed to GBM cell reprogramming, a property involved in treatment resistance and disease recurrence. Probing the IRE1 activity molecular signature on transcriptome datasets of human tumors, showed that high IRE1 activity correlated with low expression of the main GBM stemness transcription factors SOX2, SALL2, POU3F2 and OLIG2. Henceforth, this phenotype was pharmacologically and genetically recapitulated in immortalized and primary GBM cell lines as well as in mouse models. We demonstrated that constitutive activation of the IRE1/XBP1/miR148a signaling axis repressed the expression of SOX2 and led to maintenance of a differentiation phenotype in GBM cells. Our results describe a novel role for IRE1 signaling in maintaining differentiated tumor cell state and highlight opportunities of informed IRE1 modulation utility in GBM therapy.

cancer biology↗

bioRxiv2019

IRE1-UBE2D3 signaling controls the recruitment of myeloid cells to glioblastoma.

Tumor cells are exposed to intrinsic and environmental challenges that trigger endoplasmic reticulum (ER) homeostasis alteration, in turn leading to ER stress. To cope with this, tumor cells engage an adaptive signaling pathway, the unfolded protein response (UPR) thus promoting the acquisition of malignant features. As such, glioblastoma multiforme (GBM), the most aggressive primary brain tumors, exhibit constitutive UPR signals to sustain growth. Herein, we showed that signaling elicited by one of the UPR sensors, IRE1, promotes GBM tumor invasion, angiogenesis and infiltration by macrophages. Hence, high IRE1 activity in tumors predicts worse outcome. We further dissect IRE1-dependent mechanisms that shape the brain tumor immune microenvironment towards myeloid cells. We identify an IRE1-dependent signaling pathway that directly controls the expression/release of proinflammatory chemokines (CXCL2, IL6, IL8) leading to tumor cell-mediated chemoattraction of neutrophils and macrophages. This pathway requires XBP1 non-conventional mRNA splicing and XBP1s-dependent expression of the E2 ubiquitin enzyme UBE2D3. The latter contributes to the degradation of the NF{kappa}B inhibitor I{kappa}B, leading to the up-regulation of proinflammatory chemokines. Our work identifies a novel IRE1/UBE2D3 proinflammatory signaling axis instrumental to pro-tumoral immune regulation of GBM.

cancer biology↗