Biology subjects

Moore, B. B.

Publications and source records attributed to Moore, B. B..

8 recordsLinked to original sources

bioRxiv2026

Cell-Specific Modulation of the Aryl Hydrocarbon Receptor by Kynurenine in Pulmonary Fibrosis Requires Microenvironmental Crosstalk

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, chronic lung disease with limited therapeutic options. Tryptophan metabolism is significantly dysregulated during lung fibrogenesis, with the metabolite kynurenine (kyn) accumulating in lung tissue and driving pathology via the aryl hydrocarbon receptor (AHR). This study evaluates the cell-specific contributions of kyn-mediated AHR signaling across different pulmonary cell types to clarify its role in disease progression. MethodsUsing a murine model of bleomycin-induced pulmonary fibrosis, lung tryptophan metabolites were profiled via liquid chromatography-mass spectrometry. The functional and transcriptomic impacts of kyn administration and AHR modulation were subsequently characterized across three distinct cellular compartments: CD103+ dendritic cells (DCs), fibroblasts, and alveolar epithelial cells (AECs). ResultsKyn levels were elevated in fibrotic lungs, and exogenous kyn selectively exacerbated collagen deposition during the fibrogenic phase rather than altering acute injury. In vitro monocultures of primary lung fibroblasts and AECs revealed negligible functional responses to kyn or AHR inhibition regarding myofibroblast differentiation, migration, or epithelial barrier disruption. Intriguingly, primary tissue-resident CD103+ DCs exhibited a hyperinflammatory, non-canonical AHR signaling profile in vivo. While ex vivo monoculture rapidly reverted these DCs to an anti-inflammatory, canonical AHR state, directly co-culturing DCs with fibrotic primary lung fibroblasts successfully restored the pathogenic, non-canonical signaling phenotype characterized by augmented IL-6 production and suppressed canonical targets. ConclusionsPathogenic AHR signaling in pulmonary fibrosis is highly cell-context dependent and driven by complex cell-cell interactions. Reductionist monocultures fail to replicate tissue- level dendritic cell phenotypes, highlighting the necessity of co-culture models and providing a cautionary note for the systemic clinical use of AHR-targeted therapeutics.

immunology↗

bioRxiv2025

Immunomodulatory nanoparticles elicit antifibrotic monocyte activation to resolve murine pulmonary fibrosis

Organ fibrosis presents a substantial disease burden with few therapeutic options. Innate immunity mediates fibrinogenesis, but also plays a major role in fibrinolysis. Here, we show that immunomodulatory nanoparticles (NPs) can harness this endogenous antifibrotic capacity by catalyzing monocyte activation leading to resolution of bleomycin-induced pulmonary fibrosis in vivo. Cargo-free NPs comprised of the degradable biopolymer poly(lactide-co-glycolide) (PLG) induce a transcriptional shift toward antifibrotic immune activation in profibrotic M2 macrophages (M{Phi}s) in vitro. NPs stimulate M2 M{Phi}s toward a glycolytic, rather than fatty acid oxidative, metabolism; suppress canonical M2 markers like arginase-1 (Arg1) and periostin (Postn); and upregulate collagenases, hyaluronidases and immunoregulatory factors. When delivered intravenously in vivo, NPs reverse established bleomycin-induced pulmonary fibrosis and invert the trajectory of over 1,000 genes from pre- to post-treatment according to bulk RNA-sequencing. NPs also suppress profibrotic signaling and increase expression of repair-associated pathways like peroxisome proliferator-activated receptor gamma (PPAR-{gamma}), nuclear retinoic acid receptor (RAR), vascular endothelial growth factor (VEGF), and sphingolipid signaling in fibrotic lungs. Flow cytometry confirms that NPs induce monocyte recruitment to fibrotic lungs via enhanced integrin expression. Altogether, NPs induce a robust pro-regenerative signature comprised of ECM degradation, inflammation resolution, and tissue repair pathways, concomitant with increased NP+ monocyte recruitment to fibrotic lungs. This work demonstrates that monocytes are not intrinsically profibrotic, but rather, their effects are context-dependent, and they retain a capacity for fibrotic resolution under conditions that can be induced by materials with translational potential. Significance StatementOrgan fibrosis can follow from tissue injury and substantially impairs organ function, but it is incurable and has limited therapeutic options. Myeloid immune cells drive fibrosis onset and progression, but they can also mediate fibrosis resolution. We used polymeric NPs made from clinically translatable biomaterials to harness the antifibrotic capacity of immune cells as a fibrosis therapy. We found that intravenous NPs can reprogram myeloid cells to acquire an antifibrotic phenotype in a mouse model of pulmonary fibrosis. NPs increased myeloid activation and pulmonary recruitment while decreasing fibrosis, showing that directed immune activation, instead of suppression, could be an effective therapeutic strategy for fibrosis.

bioengineering↗

bioRxiv2025

Long-term Reprogramming and Altered Ontogeny of Classical Monocytes Mediates Enhanced Lung Injury in Sepsis Survivor Mice

Patients who survive sepsis are predisposed to new hospitalizations for respiratory failure, but the underlying mechanisms are unknown. Using a murine model in which prior sepsis predisposes to enhanced lung injury, we previously discovered that classical monocytes persist in the lungs after long-term recovery from sepsis and exhibit enhanced cytokine expression after secondary challenge with intra-nasal lipopolysaccharide. Here, we hypothesized that immune reprogramming of post-sepsis monocytes and altered ontogeny predispose to enhanced lung injury. Monocyte depletion and/or adoptive transfer was performed three weeks and three months after sepsis. Monocytes from post-sepsis mice were necessary and sufficient for enhanced LPS-induced lung injury and promoted neutrophil degranulation. Prior sepsis enhanced JAK-STAT signaling and AP-1 binding in monocytes and shifted monocytes toward the neutrophil-like monocyte lineage. In human sepsis and/or pneumonia survivors, monocytes were predictive of 90-day mortality and exhibit transcriptional and proteomic neutrophil-like signatures. We conclude that sepsis reprograms monocytes into a pro-inflammatory phenotype and skews bone marrow progenitors and monocytes toward the neutrophil-like lineage, predisposing to neutrophil degranulation and lung injury.

immunology↗

bioRxiv2025

Toxoplasma induced cytokine release syndrome is critically dependent on the expression of pore-forming Perforin-Like Protein-1

Acute virulence in Toxoplasma gondii is linked to an excessive proinflammatory cytokine cascade during laboratory murine infection. Previous work showed that T. gondii secretes a pore forming protein, PLP1, that is required for efficient cytolytic egress from host cells. Deletion of the PLP1 gene results in defective egress from infected culture cells and a marked reduction in parasite virulence. The goal of the present study was to gain insight into the nature of the attenuated virulence observed in PLP1 knockout compared to wild type (WT) RH parasites. Using in vivo bioluminescence imaging, we show that parasites lacking PLP1 establish an acute infection and disseminate throughout the infected mice. Histological tissue analysis indicates that parasites cause severe pathology, even in the absence of PLP1. However, mice infected with{Delta} plp1 parasites evoke a protective inflammatory response, demonstrated by mouse survival and control of infection. Flow cytometric analysis was used to determine cellular changes occurring during both WT and {Delta}plp1 parasite infection. Parasite control in the{Delta} plp1 infection was associated with earlier activation of myeloid cells and a moderate neutrophil response that, by comparison, becomes the dominant infiltrating cell type of WT infection. Positive disease outcome during{Delta} plp1 parasite infection is also associated with regulated induction of proinflammatory cytokines, including IFN-{gamma} and TNF-, and an earlier IL-10 regulatory response that is dysregulated during WT infection. Together these findings suggest a key role for Toxoplasma PLP1 in promoting a lethal inflammatory immune response during acute infection with a virulent strain of the parasite. Author SummaryPore-forming proteins are virulence determinants expressed by multiple different pathogens, with varied roles including cellular invasion and escape, immune cell destruction, and the hijack of host cell defenses. The pathogen, Toxoplasma gondii, expresses a pore-forming protein PLP1, that is required for cell lysis and acute virulence in mice. Here, we investigate the potential mechanisms by which this pore-forming protein promotes parasite virulence; from parasite replication and dissemination to immunologic outcomes after infection. In vivo infections demonstrate that parasites replicate, disseminate, and stimulate a protective immune response when PLP1 is not expressed. We show that PLP1 expression induces a parasite driven dysregulation of cell populations and cytokine/chemokine responses, resulting in cytokine release syndrome. In a broader context, Toxoplasmas PLP1 is comparable to other pathogen pore-forming proteins that function as virulence determinants by their ability to alter host immune responses.

microbiology↗

bioRxiv2024

Lung Microbiome Intervention Attenuates Herpesvirus-Induced Post-HCT Pulmonary Fibrosis Through PD-L1 Upregulation on Dendritic Cells

Alterations in the lung microbiome frequently accompany adverse pulmonary outcomes. Hematopoietic cell transplantation (HCT) markedly affects the lung microbiome corresponding with a high incidence of post-HCT pulmonary complications. In a preclinical mouse model of HCT, we observed a reduction in Lactobacillus johnsonii within the lung microbiome following transplantation. Intranasal administration of live or heat-killed (HK) L. johnsonii at low doses reduced gammaherpesvirus-induced pulmonary fibrosis in HCT mice, in which IL-17A plays an essential role. HK L. johnsonii treatment of HCT mice suppressed inflammatory cytokine production by lung macrophages and decreased Il17a expression in T helper 17 (Th17) cells. HK L. johnsonii increased PD-L1 expression on the surface of type II conventional dendritic cells (cDC2) in HCT mice and in vitro in bone marrow-derived dendritic cells (BMDCs). HK L. johnsonii-exposed BMDCs also inhibited IL-17A secretion from co-cultured Th17 cells in a PD-1-dependent manner. Notably, when HK L. johnsonii was administered to HCT mice reconstituted with bone marrow cells from PD-1 knockout (KO) mice, which lack a PD-L1 mediated response, HK L. johnsonii-mediated reduction of pulmonary fibrosis was negated. Collectively, our findings demonstrate that HK L. johnsonii mitigates herpesvirus-induced pulmonary fibrosis in HCT mice by modulating cDC2 surface expression of PD-L1, which subsequently suppresses Il17a expression in Th17 cells, pointing towards a potential postbiotic-based strategy for immunomodulation to address pulmonary complications of HCT.

immunology↗

bioRxiv2024

Dendritic Cell - Fibroblast Crosstalk via TLR9 and AHR Signaling Drives Lung Fibrogenesis

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients succumb to the disease within 2-5 years. The molecular pathogenesis of IPF regarding the immunologic changes that occur is poorly understood. We characterize a role for non-canonical aryl-hydrocarbon receptor signaling (ncAHR) in dendritic cells (DCs) that leads to production of IL-6 and IL-17, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2 which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing floxed AHR exon-2 deletion mice (AHR{Delta}ex2) with mice harboring a CD11c-Cre. Bleomycin was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex-vivo with relevant TLR agonists and AHR modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis, however, AHR{Delta}ex2 mice treated with bleomycin developed more fibrosis and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2. Study of human samples corroborate the relevance of these findings in IPF patients. We also, for the first time, identify that AHR exon-2 floxed mice retain capacity for ncAHR signaling.

immunology↗

bioRxiv2024

Cellular heterogeneity and dynamics of the human uterus in healthy premenopausal women

The human uterus is a complex and dynamic organ whose lining grows, remodels, and regenerates in every menstrual cycle or upon tissue damage. Here we applied single-cell RNA sequencing to profile more the 50,000 uterine cells from both the endometrium and myometrium of 5 healthy premenopausal individuals, and jointly analyzed the data with a previously published dataset from 15 subjects. The resulting normal uterus cell atlas contains more than 167K cells representing the lymphatic endothelium, blood endothelium, stromal, ciliated epithelium, unciliated epithelium, and immune cell populations. Focused analyses within each major cell type and comparisons with subtype labels from prior studies allowed us to document supporting evidence, resolve naming conflicts, and to propose a consensus annotation system of 39 subtypes. We release their gene expression centroids, differentially expressed genes, and mRNA patterns of literature-based markers as a shared community resource. We find many subtypes show dynamic changes over different phases of the cycle and identify multiple potential progenitor cells: compartment-wide progenitors for each major cell type, transitional cells that are upstream of other subtypes, and potential cross-lineage multipotent stromal progenitors that may be capable of replenishing the epithelial, stromal, and endothelial compartments. When compared to the healthy premenopausal samples, a postpartum and a postmenopausal uterus sample revealed substantially altered tissue composition, involving the rise or fall of stromal, endothelial, and immune cells. The cell taxonomy and molecular markers we report here are expected to inform studies of both basic biology of uterine function and its disorders. SIGNIFICANCEWe present single-cell RNA sequencing data from seven individuals (five healthy pre-menopausal women, one post-menopausal woman, and one postpartum) and perform an integrated analysis of this data alongside 15 previously published scRNA-seq datasets. We identified 39 distinct cell subtypes across four major cell types in the uterus. By using RNA velocity analysis and centroid-centroid comparisons we identify multiple computationally predicted progenitor populations for each of the major cell compartments, as well as potential cross-compartment, multi-potent progenitors. While the function and interactions of these cell populations remain to be validated through future experiments, the markers and their "dual characteristics" that we describe will serve as a rich resource to the scientific community. Importantly, we address a significant challenge in the field: reconciling multiple uterine cell taxonomies being proposed. To achieve this, we focused on integrating historical and contemporary knowledge across multiple studies. By providing detailed evidence used for cell classification we lay the groundwork for establishing a stable, consensus cell atlas of the human uterus.

cell biology↗

bioRxiv2020

Microengineered 3D pulmonary interstitial mimetics highlight a critical role for matrix degradation in idiopathic pulmonary fibrosis

Fibrosis is often untreatable and is characterized by aberrant tissue scarring from activated myofibroblasts. Although the extracellular matrix becomes increasingly stiff and fibrous during disease progression, how these physical cues impact myofibroblast differentiation in 3D is poorly understood. Here we describe a multicomponent hydrogel that recapitulates the 3D fibrous structure hallmark to the interstitial tissue regions where idiopathic pulmonary fibrosis (IPF) initiates. In contrast to findings on 2D hydrogels, myofibroblast differentiation in 3D was inversely correlated with hydrogel stiffness, but positively correlated with matrix fiber density. Employing a multi-step bioinformatics analysis of IPF patient transcriptomes and in vitro pharmacologic screening, we identify matrix-metalloprotease activity to be essential for 3D but not 2D myofibroblast differentiation. Given our observation that compliant degradable 3D matrices amply support fibrogenesis, these studies demonstrate a departure from the established relationship between stiffness and myofibroblast differentiation in 2D, and provide a new 3D model for studying fibrosis.

bioengineering↗