Biology subjects

Williams, J. W.

Publications and source records attributed to Williams, J. W..

16 recordsLinked to original sources

bioRxiv2026

TREM2 encodes plaque macrophage plasticity to mediate atherosclerosis regression

Cholesterol lowering therapies stabilize atherosclerotic plaque and reduce ischemic events, but the molecular mechanisms governing plaque remodeling or regression remain poorly defined. The lipid sensor TREM2 is a key modulator of plaque-associated foam cell development and was upregulated by plaque macrophages in atherosclerosis regression. We examined macrophage- or monocyte-specific Trem2 deletion during regression in mice and found that TREM2 expression on plaque macrophages, not newly recruited monocytes, was required for plaque regression. Trem2 deletion impeded necrotic core resolution, leading us to interrogate the efferocytic capacity of TREM2+ cells during lipid lowering. An in vitro model of cholesterol-experienced ex-lipid associated macrophages (Ex-LAMs) demonstrated that prior lipid priming enhanced efferocytic ability after unloading lipids and maintained expression of lysosomal and cytoskeletal remodeling genes. Augmented TREM2 signaling through genetic models or agonist treatment accelerated efferocytic ability in vitro and plaque regression in vivo. Thus, we posit that a TREM2-dependent ExLAM programming drives atherosclerosis resolution and facilitates beneficial plaque remodeling through enhanced efferocytosis. Overall, targeting the TREM2 pathway may be a viable strategy for stabilizing atherosclerotic plaques in patients treated with aggressive cholesterol control.

immunology↗

bioRxiv2026

Adrenal Gland Macrophage-derived TGF-β Governs Vascular Permeability to Drive Monocyte Recruitment during Stress

The adrenal glands are central regulators of systemic stress responses through tightly controlled glucocorticoid production. Yet, the contribution of local immune-vascular interactions to adrenal stress adaptation remains poorly understood. Here, we investigated the role of adrenal gland macrophages in coordinating stress-induced immune remodeling and vascular function. By integrating single-cell RNA sequencing datasets across four distinct stress models, including acute cold exposure, chronic social defeat, chronic inflammation, and systemic Candida albicans infection, we identified a conserved increase in monocyte recruitment to the adrenal gland, accompanied by dynamic macrophage transitions. Comparative transcriptomic and ligand-receptor analyses identified transforming growth factor-{beta} (TGF{beta}) as a dominant macrophage-derived signal targeting adrenal endothelial cells across all stress conditions. Pharmacological blockade of TGF{beta} receptor signaling reduced endothelial activation, vascular permeability, and monocyte infiltration into the adrenal gland following stress, without directly altering resident macrophage numbers. Using genetic fate-mapping and conditional knockout models, we demonstrate that macrophage-derived, but not endothelial-derived, TGF{beta} is required to promote enhanced endothelial adhesion molecule expression, vascular fenestration, permeability, and efficient monocyte recruitment. Loss of macrophage TGF{beta} production also led to exacerbated systemic stress hormone levels. Together, these findings uncover a previously unrecognized macrophage-endothelial axis in the adrenal gland, whereby macrophage-derived TGF{beta} regulates vascular properties to support immune cell recruitment and stress adaptation. This immune-vascular crosstalk provides new mechanistic insights into adrenal homeostasis and suggests potential therapeutic avenues for disorders associated with dysregulated chronic stress.

immunology↗

bioRxiv2026

Complement 3a Receptor mediates high fat diet induced hypothalamic accumulation of lipid associated microglia to regulate neuroinflammation and obesity

Microglia, the resident macrophages of the central nervous system, are recognized for their heterogeneity and integral role in brain function and diseases. In the context of high fat diet (HFD) feeding and obesity, microglia become overactive, acquiring a prevailing lipid associated microglial phenotype (also known as LAM). Yet, how microgliosis is induced and regulated remains unclear. Here we report a key role for the Complement 3a Receptor (C3aR), on HFD-induced hypothalamic gliosis and weight gain in mice. HFD consumption leads to elevated microglial expression of C3aR, which parallels widespread accumulation of reactive microglia, selectively in the hypothalamus. Conditional microglial C3aR deletion protects mice from HFD-induced hypothalamic reactive microgliosis. C3aR deletion or pharmacological antagonism opposes HFD-induced weight gain in male but not female mice. Mechanistically, we demonstrated that C3aR is essential for lipid-induced lipid droplet formation, and acquisition of a LAM molecular signature. In summary, we uncovered a previously unknown role for C3aR in the acquisition of a LAM signature driving diet-induced gliosis, identifying this receptor as a new viable therapeutic candidate for conditions associated with hypothalamic neuroinflammation.

immunology↗

bioRxiv2025

CSF1R regulates monocyte subset differentiation and intracellular metabolism.

Monocytes are key circulating effectors of vascular homeostasis, innate immunity and inflammation. Following their generation in mouse bone marrow, classical (Ly6Chigh) monocytes are mobilized into the blood circulation where they mature into non-classical (Ly6Clow) patrolling monocytes or are recruited into peripheral tissues where they differentiate into tissue resident or inflammatory macrophages. Monocytes and macrophages express CSF1R (CD115), the receptor for lineage-specific growth factors CSF1 and IL34. Here, we report that acute CSF1R blockade or genetic deletion negatively interferes with monocyte intracellular metabolism and reduces blood Ly6Clow monocytes in part by blunting differentiation of Ly6Chigh monocytes. Based upon lineage-specific deletion of GFPT1 (Glutamine-Fructose-6-Phosphate Transaminase 1), the hexosamine biosynthetic pathway (HBP) is identified as a novel regulator of CSF1R expression and monocyte subset diversity. Our findings provide new insights into the link between CSF1R signaling, metabolic regulation, and monocyte survival and differentiation.

immunology↗

bioRxiv2024

CD226+ adipose tissue macrophages arise from MDP-derived monocytes and regulate lipid metabolism.

Macrophages are innate immune cells present in all tissues, in which they participate in immune responses and maintenance of tissue homeostasis. They develop either from embryonic precursors or from circulating monocytes, and their origin impacts their functions. We previously observed robust recruitment of monocytes to brown adipose tissue in which they could differentiation into two distinct macrophage subsets identifiable by CD206 or CD226 expression. In the present study, we investigated monocyte differentiation pathways in brown adipose tissue and the function of monocyte-derived macrophages. Fate mapping analysis revealed a low contribution of GMP- and a high contribution of MDP-derived monocytes to the CD226high macrophage subset. Importantly, adoptive transfer experiments demonstrate that MDP- but not GMP-derived monocytes are pre-conditioned to give rise to CD226high macrophages. We found that MDP-derived CD226high macrophages were also present in other tissues including peritoneal cavity, adrenal glands and all adipose depots. CD226high macrophages were regulated by both GM-CSF and CSF1R. Genetic depletion of CD226high macrophages caused increased BAT and plasma triglyceride content. We thus identify CD226high MDP-derived macrophages as a new myeloid cell type conserved across tissues and tied to lipid metabolism homeostasis.

immunology↗

bioRxiv2024

Identification of conserved and tissue-restricted transcriptional profiles for lipid associated macrophages (LAMs)

Macrophages are essential immune cells present in all tissues, and are vital for maintaining tissue homeostasis, immune surveillance, and immune responses. Considerable efforts have identified shared and tissue-specific gene programs for macrophages across organs during homeostasis. This information has dramatically enhanced our understanding of tissue-restricted macrophage programming and function. However, few studies have addressed the overlapping and tissue-specific responses of macrophage subsets following inflammatory responses. One subset of macrophages that has been observed across several studies, lipid-associated macrophages (LAMs), have gained interest due to their unique role in lipid metabolism and potential as a therapeutic target. LAMs have been associated with regulating disease outcomes in metabolically related disorders including atherosclerosis, obesity, and nonalcoholic fatty liver disease (NAFLD). In this study, we utilized single-cell RNA sequencing (scRNAseq) data to profile LAMs across multiple tissues and sterile inflammatory conditions in mice and humans. Integration of data from various disease models revealed that LAMs share a set of conserved transcriptional profiles, including Trem2 and Lpl, but also identified key sets of tissue-specific LAM gene programs. Importantly, the shared LAM markers were highly conserved with human LAM populations that also emerge in chronic inflammatory settings. Overall, this analysis provides a detailed transcriptional landscape of tissue-restricted and shared LAM gene programs and offers insights into their roles in metabolic and chronic inflammatory diseases. These data may help instruct appropriate targets for broad or tissue-restricted therapeutic interventions to modulate LAM populations in disease.

immunology↗

bioRxiv2024

MACanalyzeR: scRNA-seq Analysis Tool Reveals PPARγHI Lipid-Associated Macrophages Facilitate Thermogenic Expansion in BAT

Macrophages in brown adipose tissue (BAT) play a complex role in regulating its activity. However, the role of macrophages in regulating BAT activation/deactivation has not yet been comprehensively characterized. To elucidate this, we developed MACanalyzeR, a scRNAseq-based tool specifically designed to explore the macrophage features at molecular and metabolic level. MACanalyzeR was applied in scRNA-seq datasets obtained from BAT with thermogenic loss (db/db mice) and activation (High Fat Diet, HFD). Our computational approach revealed that macrophages accumulating in BAT upon these conditions resemble lipid-associated macrophages (LAMs) with foaming-like features. BAT LAMs also show a significant enrichment of genes associated with mitochondria and lysosomes. Interestingly, LAMs identified in BAT from HFD mice positively correlate with thermogenic genes and exhibit an enrichment in PPAR{gamma} signaling pathway, with an activated mitochondrial metabolism. Cell dynamic strategy, revealed that LAM with high Pparg expression levels (PpargHIGH) progressively accumulate during skeletal muscle regeneration, suggesting a potential role for this LAM subcluster in maintaining tissue homeostasis. Our findings suggest PpargHIGH LAMs as a subclass of macrophages potentially contributing in preserving tissue homeostasis associated with high energy demand conditions such as thermogenic and regenerative stimuli.

physiology↗

bioRxiv2023

Loss of TREM2 exacerbates parenchymal amyloid pathology but diminishes CAA in Tg-SwDI mice

Alzheimers disease (AD) is a progressive neurodegenerative disease, and it is the most common cause of dementia worldwide. Recent genome-wide association studies (GWAS) identified TREM2 (triggering receptor expressed on myeloid cells 2) as one of the major risk factors for AD. TREM2 is a surface receptor expressed on microglia and largely mediates microglial functions and immune homeostasis in the brain. The functions of TREM2 in AD pathogenesis, including in the formation of the key pathology parenchymal amyloid-{beta} (A{beta}) plaques, have been investigated by introducing Trem2 deficiency in AD mouse models. However, the role of TREM2 in cerebrovascular amyloidosis, in particular cerebral amyloid angiopathy (CAA) remains unexplored. CAA features A{beta} deposition along the cerebral vessels, signifying an intersection between AD and vascular dysfunction. Using a well-characterized CAA-prone, transgenic mouse model of AD, Tg-SwDI (SwDI), we found that loss of TREM2 led to a marked increase in overall A{beta} load in the brain, but a dramatic decrease in CAA in microvessel-rich regions, along with reduced microglial association with CAA. Transcriptomic analysis revealed that in the absence of Trem2, microglia were activated but trapped in transition to the fully reactive state. Like microglia, perivascular macrophages were activated with upregulation of cell junction related pathways in Trem2-deficient SwDI mice. In addition, vascular mural cells and astrocytes exhibited distinct responses to Trem2 deficiency, contributing to the pathological changes in the brain of Trem2-null SwDI mice. Our study provides the first evidence that TREM2 differentially modulates parenchymal and vascular A{beta} pathologies, which may have significant implications for both TREM2- and A{beta}-targeting therapies for AD.

neuroscience↗

bioRxiv2023

Trem2 Agonist Reprograms Foamy Macrophages to Promote Atherosclerotic Plaque Stability

ObjectiveTrem2, a surface lipid receptor, is expressed on foamy macrophages within atherosclerotic lesions and regulates cell survival, proliferation, and anti-inflammatory responses. Studies examining the role of Trem2 in atherosclerosis have shown that deletion of Trem2 leads to impaired foamy macrophage lipid uptake, proliferation, survival, and cholesterol efflux. Thus, we tested the hypothesis that administration of a validated Trem2 agonist antibody (AL002a) to atherogenic mice could drive macrophage survival and decrease necrotic core formation to improve plaque stability. Approach and ResultsTo model a therapeutic intervention approach, atherosclerosis-prone mice (Ldlr-/-) were fed a high fat diet (HFD) for 8 weeks, then transitioned to treatment with AL002a or isotype control for an additional 8 weeks while continuing on an HFD. AL002a-treated mice had increased lesion size in both the aortic sinus and whole mount aorta, which correlated with an expansion of plaque macrophage area. This expansion was due to increased macrophage survival and proliferation in plaques. Importantly, plaques from AL002a-treated mice showed improved features of plaque stability, including smaller necrotic cores, increased fibrous caps, and greater collagen deposition. Single cell RNA sequencing of whole aorta suspensions from isotype and AL002a-treated atherosclerotic mice revealed that Trem2 agonism dramatically altered foamy macrophage transcriptome. This included upregulation of oxidative phosphorylation and increased expression of collagen genes. In vitro studies validated that Trem2-agonism with AL002a promoted foamy macrophage oxLDL uptake, survival, and cholesterol efflux in culture. ConclusionsTrem2 agonist expands plaque macrophages by promoting cell survival and proliferation but improves features of plaque stability by rewiring foamy macrophage function to enhance collagen deposition.

immunology↗

bioRxiv2023

Hepatic lipid-associated macrophages mediate the protective effects of bariatric surgery against NASH

For patients with obesity and metabolic syndrome, bariatric procedures such as vertical sleeve gastrectomy (VSG) have a clear benefit in ameliorating metabolic dysfunction-associated steatohepatitis (MASH). While the effects of bariatric surgeries have been mainly attributed to nutrient restriction and malabsorption, whether immuno-modulatory mechanisms are involved remains unclear. Here we report that VSG ameliorates MASH progression in a weight loss- independent manner. Single-cell RNA sequencing revealed that hepatic lipid-associated macrophages (LAMs) expressing the triggering receptor expressed on myeloid cells 2 (TREM2) increase their lysosomal activity and repress inflammation in response to VSG. Remarkably, TREM2 deficiency in mice ablates the reparative effects of VSG, suggesting that TREM2 is required for MASH resolution. Mechanistically, TREM2 prevents the inflammatory activation of macrophages and is required for their efferocytotic function. Overall, our findings indicate that bariatric surgery improves MASH through a reparative process driven by hepatic LAMs, providing insights into the mechanisms of disease reversal that may result in new therapies and improved surgical interventions.

physiology↗

bioRxiv2022

Trem2 Promotes Foamy Macrophage Lipid Uptake and Survival in Atherosclerosis

Atherosclerotic plaque formation is driven by the continued expansion of cholesterol loaded foamy macrophages within the arterial intima. Foamy macrophages are primarily derived from newly recruited monocytes, but factors regulating monocyte specification toward foamy macrophage differentiation and prolonged survival in plaque remain poorly understood. We used trajectory analysis of integrated single cell RNA-seq data, along with a genome-wide CRISPR screening approach to identify Triggering Receptor Expressed on Myeloid Cells 2 (Trem2) as a candidate regulator for foamy macrophage specification. Loss of Trem2 led to a reduced ability of foamy macrophages to take up additional oxidized low density lipoprotein (LDL) cholesterol in vitro. Competitive chimera experiments showed that Trem2-deficient macrophages were less competent to form foamy macrophages when competed against Trem2-sufficient macrophages in vivo. In addition, myeloid specific conditional deletion of Trem2 resulted in a dramatic attenuation of plaque progression, even when targeted in established atherosclerotic lesions. This was independent of changes in circulating inflammatory cytokines, monocyte recruitment, or serum cholesterol levels, but due to a reduction in plaque macrophage proliferation and enhanced cell death. Mechanistically, we link Trem2-deficient macrophages with an inability for cells to sense cholesterol loading and failure to upregulate efflux molecules. Accumulation of cholesterol in the endoplasmic reticulum enhanced activation of the ER-stress response that increased susceptibility for cholesterol-toxicity and cell death in foamy Trem2-deficient macrophages. Overall, this study identifies Trem2 as a regulator of foamy macrophage differentiation, atherosclerotic plaque growth, and as a putative therapeutic target for future intervention studies.

immunology↗

bioRxiv2022

Tumor-specific CD4 T cells instruct monocyte differentiation in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to immunotherapy. The pancreatic tumor microenvironment is shaped and maintained by myeloid cells that outnumber tumor cells. Here, using monocyte fate-mapping PDA mouse models and human tumor tissues, we identify monocytes give rise to most heterogeneous macrophage subpopulations in PDA. We show that monocyte differentiation is governed by the local presence of CD4, but not CD8, T cells. We demonstrate that tumor specific CD4 T cells induce monocyte differentiation into antitumor MHCIIhi proinflammatory macrophages dependent on non-redundant IFN{gamma} and CD40 signaling pathways that suppress tumor growth. Pancreatic tissue-resident macrophages exhibit an immunosuppressive pro-tumor state that is refractory to the modulatory effects of antitumor CD4 T cells. Intratumoral monocytes adopt a pro-tumor fate indistinguishable from tissue-resident macrophages following CD4 T cell depletion. Thus, tumor-specific CD4 T cell governance of monocyte fate promotes immune-mediated control of solid tumors. Highlights{blacksquare} Circulating monocytes are progenitors to most heterogeneous macrophage subsets in PDA {blacksquare}Monocyte-derived macrophage acquisition of an MHCIIhi phenotype is dependent on tumor-specific CD4 T cells {blacksquare}In the absence of CD4 T cells, monocyte-derived macrophages acquire tissue resident macrophage traits and tumors rapidly progress {blacksquare}IFN{gamma} and CD40 signaling are nonredundant and critical determinants of intratumoral monocyte fate

immunology↗

bioRxiv2022

Free fatty acid receptor 4 (FFAR4) regulates cardiac oxylipin balance to promote inflammation resolution in a model of heart failure preserved ejection fraction secondary to metabolic syndrome

Free fatty acid receptor 4 (Ffar4) is a G-protein coupled receptor for long-chain fatty acids that improves metabolism and attenuates inflammation. Heart failure preserved ejection fraction (HFpEF) is a complex clinical syndrome, but a predominant subset of patients has meta-bolic syndrome (MetS). Mechanistically, systemic, non-resolving inflammation associated with MetS might promote HFpEF. Interestingly, we recently demonstrated that Ffar4 is cardioprotective in pressure overload. The beneficial effects of Ffar4 on metabolism/inflammation, the high incidence of MetS in HFpEF patients, and the cardioprotective effects of Ffar4 led us to hypothesize that loss of Ffar4 would worsen remodeling in HFpEF secondary to MetS (HFpEF-MetS). To test this, mice with systemic deletion of Ffar4 (Ffar4KO) were fed a high-fat/high-sucrose diet with L-NAME in their water (HFpEF-MetS diet) to induce HFpEF-MetS. In male Ffar4KO mice, the HFpEF-MetS diet induced similar metabolic deficits, but worsened diastolic function and microvascular rarefaction compared to wild-type mice. Conversely, in female Ffar4KO mice, the diet produced greater obesity but no worsening of HFpEF. Loss of Ffar4 in males altered the balance of inflammatory oxylipins in the heart, decreasing the eicosapentaenoic acid derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE), while increasing the arachadonic acid derived, proinflammatory oxylipin 12-hydroxyeicosatetraenoic acid (12-HETE). This increased 12-HETE/18-HEPE ratio, reflecting a more proinflammatory state, was associated with increased macrophage numbers, which in turn correlated with worsened ventricular remodeling in male Ffar4KO hearts. In summary, our data suggest that Ffar4 controls the pro/anti-inflammatory oxylipin balance in the heart to modulate macrophage function and attenuate HFpEF remodeling.

physiology↗

bioRxiv2020

Brain activity fluctuations propagate as waves traversing the cortical hierarchy

The brain exhibits highly organized patterns of spontaneous activity as measured by resting-state fMRI fluctuations that are being widely used to assess the brains functional connectivity. Some evidence suggests that spatiotemporally coherent waves are a core feature of spontaneous activity that shapes functional connectivity, though this has been difficult to establish using fMRI given the temporal constraints of the hemodynamic signal. Here we investigated the structure of spontaneous waves in human fMRI and monkey electrocorticography. In both species, we found clear, repeatable, and directionally constrained activity waves coursed along a spatial axis approximately representing cortical hierarchical organization. These cortical propagations were closely associated with activity changes in distinct subcortical structures, particularly those related to arousal regulation, and modulated across different states of vigilance. The findings demonstrate a neural origin of spatiotemporal fMRI wave propagation at rest and link it to the principal gradient of resting-state fMRI connectivity.

neuroscience↗

bioRxiv2020

Patient-derived xenograft culture-transplant system for investigation of human breast cancer metastasis

Metastasis is a fatal disease where research progress has been hindered by a lack of authentic experimental models. Here, we develop a 3D tumor sphere culture-transplant system that facilitates the expansion and engineering of patient-derived xenograft (PDX) tumor cells for functional metastasis assays in vivo. Orthotopic transplantation and RNA sequencing analyses show that PDX tumor spheres maintain tumorigenic potential, and the molecular marker and global transcriptome signatures of native tumor cells. Tumor spheres display robust capacity for lentiviral engineering and dissemination in spontaneous and experimental metastasis assays in vivo. Inhibition of pathways previously reported to attenuate metastasis also inhibit metastasis after sphere culture, validating our approach for authentic investigations of metastasis. Finally, we demonstrate a new role for the metabolic enzyme NME1 in promoting breast cancer metastasis, providing proof-of-principle that our culture-transplant system can be used for authentic propagation and engineering of patient tumor cells for functional studies of metastasis.

cancer biology↗

bioRxiv2019

Statistically-estimated tree biomass, stem density, and basal area for the upper Midwestern United States at the time of Euro-American settlement

We present gridded 8 km-resolution data products of the estimated biomass, basal area, and stem density of tree taxa at the time of Euro-American settlement of the midwestern United States for the states of Minnesota, Wisconsin, Michigan, Illinois, and Indiana. The data come from settlement-era Public Land Survey (PLS) data (ca. 0.8-km resolution) of trees recorded by land surveyors. The surveyor notes have been transcribed, cleaned, and processed to estimate biomass, basal area, and stem density at individual points on the landscape. The point-level data are then aggregated within grid cells and statistically smoothed using a statistical model that accounts for zero-inflated continuous data with smoothing based on generalized additive modeling techniques and approximate Bayesian uncertainty estimates. We expect this data product to be useful for understanding the state of vegetation in the midwestern United States prior to large-scale Euro-American settlement. In addition to specific regional questions, the data product can serve as a baseline against which to investigate how forests and ecosystems change after intensive settlement. The data products (including both raw and statistically smoothed estimates at the 8-km scale) are being made available at the LTER network data portal as version 1.0.

ecology↗