Biology subjects

Bains, A.

Publications and source records attributed to Bains, A..

5 recordsLinked to original sources

bioRxiv2026

Osteoprotegerin-Enabled Immune Evasion by Pathological Adipose Stromal Cells Drives Metabolic Dysfunction in Obesity

Diet-induced obesity (DIO) promotes the accumulation of stromal cells with senescent characteristics in the adipose tissue (AT). Selectively clearing these cells--either through chemical senolytics or activation of invariant natural killer T (iNKT) cells--improves glucose homeostasis in obese mice, however the identity of the responsible stromal population remains unknown. Here, we use transcriptional profiling of AT stromal cells coupled with C12FDG-based enrichment of senescent populations in mice with DIO and healthy controls to identify a distinct subset of adipose progenitor cells (APCs) with robust senescence signatures that accumulate in DIO across multiple AT depots. We show that these cells, which we term senescent APCs (sAPCs), are not merely passive markers of metabolic stress but are instead active stromal organizers, accumulating in parallel with the emergence of lipid-associated macrophages (LAMs) and the diminution of multipotent mesenchymal progenitors. sAPCs promoted CCR2-dependent macrophage chemotaxis, directly linking stromal senescence to chemokine-mediated remodeling of the AT immune niche. Comparative transcriptional analysis revealed a remarkable similarity between sAPCs and inflammatory cancer-associated fibroblasts (iCAFs), including the strong induction of periostin (POSTN) and the production of osteoprotegerin (OPG), a decoy receptor for RANKL and TRAIL that enables tumoral immune evasion. Indeed, OPG production by AT stromal cells was induced by DIO across AT depots. Exogenous OPG inhibited the ability of iNKT cells to kill senescent APCs in vitro, whereas antibody-mediated OPG neutralization reciprocally enhanced such cytotoxic killing. In vivo, systemic OPG neutralization both reduced sAPC accumulation in AT and normalized glucose homeostasis in obese mice. Together, these findings identify sAPCs as a pathological stromal population that expands in obesity through elaboration of immunomodulatory factors. In particular, secreted OPG enables sAPCs to evade iNKT-mediated immune surveillance and contributes to metabolic dysfunction, highlighting OPG and sAPCs as promising therapeutic targets for restoring AT immune and metabolic homeostasis.

immunology↗

bioRxiv2025

Blocking Osteoprotegerin Reprograms Cancer Associated Fibroblast to Promotes Immune Infiltration into the Tumor Microenvironment

AbstractThe stromal compartment of many solid tumors plays a critical role in shaping an immunosuppressive microenvironment that limits the effectiveness of immune-based therapies1. Among stromal constituents, cancer-associated fibroblasts (CAFs) have emerged as key regulators of antitumor immunity2-5. Here, we identify a distinct subset of CAFs in both murine and human stroma-rich cancers that secrete osteoprotegerin (OPG)-- a soluble decoy receptor that neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL), both of which are involved in T cell function. In vitro, OPG directly impairs CD8 T cell-mediated killing of target cells. In murine models of pancreatic and breast cancer, antibody-mediated blockade of OPG promotes robust immune infiltration into the tumor microenvironment, leading to significant tumor regression. Stromal profiling revealed that OPG blockade induces a shift in CAF cells--reducing immunosuppressive OPG fibroblasts while expanding interferon-responsive fibroblasts, thus recalibrating the tumor stroma toward a pro-immunogenic landscape. These findings uncover a previously unrecognized mechanism of stromal immune suppression and highlight OPG as a stromal immune checkpoint controlling CD8 T cell infiltration. Targeting OPG may offer a novel therapeutic strategy to convert immunologically "cold" tumors into T cell-infiltrated, tumor microenvironment.

cancer biology↗

bioRxiv2022

L-norepinephrine induces ROS formation but alters microbial community composition by altering cellular metabolism

Neuroendocrine compounds discharged into wastewater systems represent an emerging challenge at the intersection of human physiology and environmental microbiology. L-norepinephrine (L-NE) L-NE, which has been recognized to potentiate growth of human and animal bacterial pathogens, is discharged in sewage through urine and feces. While extensive pure culture studies have established L-NEs capacity to modulate bacterial virulence through iron acquisition and quorum sensing pathways, its impact on complex microbial communities, where intricate metabolic networks and interspecies interactions dominate, remains largely unexplored. This knowledge gap is particularly critical as urbanization drives increasing neuroendocrine compound loads in wastewater influents in metropolitan areas. Through parallel treatments of L-NE (1x10{square}{square} to 1x10{square}{square} M), dextrose, and H{square}O{square} in municipal and agricultural wastewater communities, we uncovered sophisticated metabolic and regulatory mechanisms that challenge the conventional understanding of microbial substrate utilization. Despite containing 10-fold less carbon, L-NE treatments achieved superior growth (10{square} CFU mL{square}{superscript 1}) while maintaining Pseudomonadaceae-dominated communities. Targeted metaproteomics revealed coordinated upregulation of oxidative stress genes (oxyR, soxRS) and antioxidant enzymes, while proteome-constrained metabolic modeling demonstrated distinct pathway modulation in central carbon and nitrogen metabolism. Notably, when compared to dextrose-supplemented controls representing typical carbon substrate utilization, L-NE treatments showed similar taxonomic profiles without preferential enrichment of known pathogenic families. However, L-NE significantly enhanced autoinducer gene (luxS, qseC) expression, suggesting increased virulence potential through community-level metabolic reprogramming. These findings reveal L-NE as a potent modulator of microbial community dynamics in engineered ecosystems, with important implications for treatment process stability and downstream environmental impacts. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/482069v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1d80968org.highwire.dtl.DTLVardef@51cb63org.highwire.dtl.DTLVardef@b37org.highwire.dtl.DTLVardef@e07503_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOTOC FigureC_FLOATNO C_FIG

microbiology↗

bioRxiv2021

Increasing phagocytosis of microglia through targeting CD33 with liposomes displaying glycan ligands

CD33 is an immunomodulatory receptor expressed on microglia and genetically linked to Alzheimers disease (AD) susceptibility. While antibodies targeting CD33 have entered clinical trials to treat neurodegeneration, it is unknown whether the glycan-binding properties of CD33 can be exploited to modulate microglia. Here, we use liposomes that multivalently display glycan ligands of CD33 (CD33L liposomes) to engage CD33. We find that CD33L liposomes increase phagocytosis of cultured monocytic cells and microglia in a CD33-dependent manner. Enhanced phagocytosis strongly correlates with loss of CD33 from the cell surface and internalization of liposomes. Increased phagocytosis by treatment with CD33L liposomes is dependent on a key intracellular signaling motif on CD33 as well as the glycan-binding ability of CD33. These effects are specific to trans engagement of CD33 by CD33L liposomes, as cis engagement through insertion of lipid-linked CD33L into cells produces the opposite effect on phagocytosis. Moreover, intracerebroventricular injection of CD33L liposomes in mice enhances phagocytosis of microglia in a CD33-dependent manner. These results demonstrate that multivalent engagement of CD33 with glycan ligands can modulate microglial cell function.

immunology↗

bioRxiv2019

Induction of microbial oxidative stress as a new strategy to enhance the enzymatic degradation of organic micropollutants in wastewater

Organic micropollutants (OMPs) are pervasive anthropogenic contaminants of fresh and marine waters with known potential to adversely affect aquatic life (e.g. endocrine disruption). Their ubiquitous environmental occurrence is primarily attributed to wastewater treatment plant discharges following their incomplete removal by common biological treatment processes. This study assesses a new strategy for promoting the degradation of six model OMPs (i.e. sulfamethoxazole, carbamazepine, tylosin, atrazine, naproxen and ibuprofen) by stimulating microbial oxidoreductase production to counter the effects of oxidative stress caused by oxygen perturbation. Microbial cultures from dairy farm wastewater were exposed to a cyclical ON-OFF perturbations of oxygen supply, ranging from 0.16 to 2 cycles per hour (i.e. 2, 1, 0.5, 0.25 and 0.16 cycles/hour), in laboratory bioreactors. The activity and relative abundances of microbial oxidoreductases (such as peroxidases, cytochromes P450) were upregulated by oxygen perturbation. In comparison to controls subjected to constant oxygen levels, OMP concentrations in perturbed cultures decreased by 70{+/-}9% (mean {+/-} SD). A distance-based linear model confirmed strong positive correlations between the relative abundance of the bacterial families, Rhodocyclaceae, Syntrophaceae and Syntrophobacteraceae, and oxygen perturbations. Our results confirm that intentional perturbation of oxygen supply to induce microbial oxidative stress can improve OMP removal efficiencies in wastewater treatment bioreactors.

bioengineering↗