Biology subjects

Zahr, T.

Publications and source records attributed to Zahr, T..

3 recordsLinked to original sources

bioRxiv2026

IgG Propels Atherosclerosis by Noncanonically Activating Macrophages

Despite being a central component of adaptive immunity and a highly abundant serum protein, the contribution of IgG to the milieu of atherosclerosis remains unappreciated. Here, we identify a pro-atherogenic role for IgG as it activates an innate immune cascade, independent of its classical antigen-neutralizing function. Analyses of human coronary artery plaques reveal a positive correlation between IgG and cardiovascular and cerebrovascular disease severity. Integrated single-cell plaque analyses localize IgG, coinciding with its recycling receptor FcRn, to pro-inflammatory and foamy macrophages. Genetic ablation of FcRn in myeloid cells prevents IgG from accumulating in mouse atherosclerotic lesions, diminishing plaque size and inflammation. Mechanistically, IgG acts as an endogenous ligand for TLR4, triggering NF-{kappa}B-NLRP3 inflammasome signaling without requiring its antigen-binding domain. Additionally, IgG accelerates macrophage foam cell formation through upregulation of downstream effector LCN2. Our work uncovers a role for previously overlooked adaptive immune molecules in the pathogenesis of atherosclerosis through a noncanonical mechanism linked with innate immunity.

immunology↗

bioRxiv2025

Ischemic Injury Drives Tumor Growth via Accelerated Hematopoietic Aging

BackgroundPatients with peripheral artery disease have increased risk of cancer development. Aging-associated changes in hematopoietic stem and progenitor cells (HSPCs), including inflammation and increased myelopoiesis, are implicated in both cardiovascular disease (CVD) and cancer, but their contributions to CVD-driven tumor progression are unclear. ObjectivesTo study cancer growth following peripheral ischemia and consequent changes within the HSPC bone marrow compartment to uncover mechanisms through which altered hematopoiesis promotes oncogenesis. MethodsMammary cancer cell (E0771) growth was monitored in C57BL/6J mice after hind limb ischemia (HLI) or sham surgery. The tumor immune microenvironment, circulatory immune cells, and HSPC compartment were assessed by flow cytometry. Next-generation single-cell RNA and ATAC sequencing of HSPCs was performed to assess transcriptomic and epigenetic changes. The functional impact on tumor progression and persistence of ischemia-induced epigenetic reprogramming of HSPCs and their myeloid progeny was examined by bone marrow transplantation. ResultsPeripheral ischemia increased monocyte and neutrophil output at the expense of lymphocytes, driven by a shift toward CD150hi myeloid-biased hematopoietic stem cells (HSCs). This was associated with accelerated breast cancer growth and increased accumulation of tumoral immunosuppressive regulatory T cells and monocytes. Increased myelopoiesis was also supported by multiomic analyses showing HLI-induced transcriptional and epigenetic enrichment for inflammatory (NLRP3 inflammasome) and aging-associated (Neogenin-1, Thrombospondin-1) signatures in subsets of monocyte/dendritic progenitors. HLI-accelerated tumor growth and myeloid-skewing was transmissible via bone marrow transplantation, indicating long-term reprogramming of innate immune responses. ConclusionsPeripheral ischemia promotes inflammaging of HSCs and long-lasting alterations to anti-tumoral immunity, accelerating breast tumor growth.

immunology↗

bioRxiv2020

Transcriptional regulation of ACSL1 by CHREBP and NF-kappa B in macrophages during hyperglycemia and inflammation

Acyl-CoA synthetase 1 (ACSL1) is an enzyme that converts fatty acids to acyl-CoA-derivatives for use in both lipid catabolism and lipid synthesis, including of arachidonic acid mediators that promote inflammation. ACSL1 has also been linked to the pro-atherosclerotic effects of diabetes in mice. ACSL1 expression has been reported to be upregulated in monocytes and macrophages by hyperglycemia, as well as enhanced by inflammatory stimuli, yet surprisingly little is known about the mechanisms underlying its transcriptional regulation. Here we show that increased Acsl1 mRNA expression in mouse macrophages by hyperglycemia is via transcription initiation such that nascent ACSL1 RNA and Acsl1 promoter activity are increased. We further demonstrate that the hyperglycemic-dependent induction of Acsl1 mRNA is governed by the glucose-sensing transcription factor, Carbohydrate Response Element Binding Protein (CHREBP), since the hyperglycemic upregulation of Acsl1 mRNA is lost in mouse bone marrow derived macrophages (BMDMs) from Chrebp knock out mice. In addition, we show that LPS treatment of mouse BMDMs increased Acsl1 mRNA, and this is attenuated by an NF-kappa B inhibitor that blocks p65 subunit binding to DNA. We further show that LPS treatment increased ACSL1 protein abundance and stimulated ACSL1 protein localization to membranes where it likely exerts its activity. Using an ACSL1 reporter gene containing the promoter and 1.6 Kb of upstream regulatory region, which contain multiple predicted CHREBP and NF-kappa B (RELA) binding sites conserved between the human and mouse ACSL1 gene, we found a synergistic increase of ACSL1 promoter activity when CHREBP and RELA were co-expressed. Thus, we have identified pathways controlling the expression of ACSL1 by hyperglycemia and inflammation through CHREBP and NF-kappa B.

molecular biology↗