Biology subjects

MacNamara, K. C.

Publications and source records attributed to MacNamara, K. C..

6 recordsLinked to original sources

bioRxiv2025

Lipid lowering alone fails to limit atherosclerosis progression and neutrophilic inflammation in middle-aged mice

While cholesterol lowering remains the cornerstone therapy for atherosclerosis and prevention of major adverse cardiovascular events, 33-50% of individuals on lipid-lowering therapy continue to exhibit elevated inflammation. Middle age (MA) represents a critical window for disease acceleration, underscoring a need to better understand non-resolving inflammation in this time frame. We rendered young (2 months) and MA mice (10 months) hypercholesterolemic with an AAV8-PCSK9 virus and fed a western diet (WD). Following 20 weeks on a WD, mice were switched to chow for 6 weeks to mimic lipid-lowering therapy. We found that MA atherosclerotic mice had increased plaque necrosis with increased circulating and bone marrow PMN compared to young mice. Upon lipid lowering, unlike in young mice, MA mice had increased necrosis, and reduced remodeling as well as increased circulating white blood cells and bone marrow hematopoietic stem cell progenitors (HSPCs). Circulating neutrophils correlated with necrosis in MA mice whereas young mice exhibited no correlation. Lipid lowered MA atherosclerotic mice had bone marrow HSPCs and neutrophils that exhibited a more activated phenotype relative to young. Elevated neutrophil-endothelial contacts were observed in the hippocampal vasculature of MA lipid lowered mice. While lipid lowering restrains atheroprogression in young, it is inadequate in MA, failing to reduce systemic inflammation and indicating the need for complementary therapies during this time frame.

immunology↗

bioRxiv2025

Endothelial Cells retain inflammatory memory through chromatin remodeling

Sepsis survivors face a heightened risk of secondary infections and chronic vascular dysfunction despite clinical recovery, yet the underlying mechanisms remain poorly defined. Our study identifies a novel mechanism of endothelial inflammatory memory, wherein transient inflammatory exposure induces durable chromatin remodeling, priming endothelial cells for exaggerated responses to subsequent inflammatory insults. Utilizing a clinically relevant two-hit mouse model, cecal ligation and puncture (CLP) followed by secondary Streptococcus pneumoniae (SP) infection, we reveal persistent transcriptional activation in endothelial cells (ECs), characterized by amplified expression of inflammatory cytokines, adhesion molecules (e.g., ICAM-1), complement factors, and interferon-stimulated genes. Genome-wide ATAC-seq analyses demonstrated stable chromatin accessibility at key inflammatory loci, indicative of epigenetic priming. Mechanistically, we uncovered a critical role for the AP-1 transcription factor JunB in mediating this epigenetic remodeling. JunB knockdown attenuated chromatin accessibility and subsequent transcriptional amplification upon secondary challenge, pinpointing JunB-driven chromatin modifications as central to endothelial reprogramming. Our findings offer mechanistic insights into how transient inflammation creates lasting epigenetic states within the endothelium, highlighting JunB as a potential therapeutic target to mitigate chronic endothelial dysfunction and increased susceptibility to secondary infections post-sepsis.

cell biology↗

bioRxiv2023

Impaired inflammation resolution in murine bone marrow failure is rescued by Resolvin E1 treatment

Current treatments for severe aplastic anemia (SAA) rely on hematopoietic stem cell (HSC) transplantation and immunosuppressive therapies, however these treatments are not always effective. While immune-mediated destruction and inflammation are known drivers of SAA, the underlying mechanisms that lead to persistent inflammation are unknown. Using an established mouse model of SAA, we observed a significant increase in apoptotic cells within the bone marrow (BM) and demonstrate impaired efferocytosis in SAA mice, as compared to radiation controls. Single-cell transcriptomic analysis revealed heterogeneity among BM monocytes and unique populations emerged during SAA characterized by increased inflammatory signatures and significantly increased expression of Sirpa and Cd47. CD47, a "dont eat me" signal, was increased on both live and apoptotic BM cells, concurrent with markedly increased expression of signal regulatory protein alpha (SIRP) on monocytes. Functionally, SIRP blockade improved cell clearance and reduced accumulation of CD47-positive apoptotic cells. Lipidomic analysis revealed a reduction in the precursors of specialized pro-resolving lipid mediators (SPMs) and increased prostaglandins in the BM during SAA, indicative of impaired inflammation resolution. Specifically, 18-HEPE, a precursor of E-series resolvins, was significantly reduced in SAA-induced mice relative to radiation controls. Treatment of SAA mice with Resolvin E1 (RvE1) improved efferocytic function, BM cellularity, platelet output, and survival. Our data suggest that impaired efferocytosis and inflammation resolution contributes to SAA progression and demonstrate that SPMs, such as RvE1, offer new and/or complementary treatments for SAA that do not rely on immune suppression. Key Points- IFN{gamma} impairs efferocytosis in SAA, correlating with increased SIRPahi monocytes and increased CD47 expression - Pro-inflammatory and pro-resolving lipid mediators are imbalanced in SAA, and RvE1 treatment improved efferocytosis and disease outcomes

immunology↗

bioRxiv2023

The Resolvin D2-GPR18 Axis Enhances Bone Marrow Function and Limits Hepatic Fibrosis in Aging

Aging is associated with non-resolving inflammation and tissue dysfunction. Resolvin D2 (RvD2) is a pro-resolving ligand that acts through the G-protein coupled receptor (GPCR) called GRP18. Using an unbiased screen, we report increased Gpr18 expression in macrophages from old mice and in livers from elderly humans that is associated with increased steatosis and fibrosis in middle-aged (MA) and old mice. MA mice that lack GPR18 on myeloid cells had exacerbated steatosis and hepatic fibrosis, which was associated with a decline in Mac2+ macrophages. Treatment of MA mice with RvD2 reduced steatosis and decreased hepatic fibrosis, correlating with increased Mac2+ macrophages, monocyte-derived macrophages and elevated numbers of monocytes in the liver, blood, and bone marrow. RvD2 acted directly upon the bone marrow to increase monocyte-macrophage progenitors. Using a transplantation assay we further demonstrated that bone marrow from old mice facilitated hepatic collagen accumulation in young mice, and transient RvD2 treatment to mice transplanted with bone marrow from old mice prevented hepatic collagen accumulation. Together, our study demonstrates that RvD2-GPR18 signaling controls steatosis and fibrosis and provides a mechanistic-based therapy for promoting liver repair in aging.

physiology↗

bioRxiv2022

Co-infection of Ehrlichia with B. burgdorferi drives emergency myelopoiesis and promotes Lyme arthritis

Lyme disease is caused by the extracellular pathogen Borrelia burgdorferi (Bb), transmitted by the Ixodes scapularis tick. Approximately one-third of infected individuals develop arthritis of weight-bearing joints, though it is unclear why some patients develop arthritis and severe systemic disease while others do not. C57BL/6 (B6) mice are susceptible to Bb infection but do not develop arthritis, providing an in vivo model to evaluate mechanisms regulating development of Lyme arthritis. We demonstrate here that co-infection of B6 mice with the tick-borne pathogens Bb and Ehrlichia muris (Em) induced significant arthritis. Although co-infection did not impact bacterial burden or growth of either pathogen, the resultant Lyme arthritis in co-infected mice correlated with significant hematologic disturbances. Whereas single Bb infection elicited no overt hematologic changes, Em infection resulted in thrombocytopenia, lymphopenia, monocytosis, and granulocytosis, which was consistently observed in mice co-infected with both Bb and Em. Hematologic changes correlated with profound changes to the hematopoietic stem and progenitor cell (HSPC) populations in Em-infected mice. Most notable were dramatic reductions in populations of HSPCs committed to myeloid-biased differentiation. Co-infection resulted in persistent hematologic changes and bone marrow inflammation. Our data demonstrate for the first time that B6 mice, resistant to developing Lyme arthritis, exhibit severe joint pathology in the presence of a second pathogen, correlating with persistent emergency myelopoiesis. Our data support the conclusion that pathogen burden is not sufficient for disease and specific inflammatory signals and cells regulate the development of Lyme arthritis. ImportanceTick-borne illnesses, historically relegated to specific geographic areas, are increasing in prevalence and distribution. Borrelia burgdorferi causes Lyme disease, the most common tick-borne illness in North America, characterized by debilitating arthritis, carditis, and neurologic complications. It remains unclear why certain infected individuals develop severe disease while others are only mildly symptomatic. Human monocytic ehrlichiosis (HME) is another tick-borne disease that often results in profound illness and severe hematological disturbances. We show here that co-infection of B6 mice, resistant to Lyme arthritis, with Borrelia burgdorferi and Ehrlichia muris, used to model HME, results in the development of severe arthritis and emergency myelopoiesis. Our work suggests that immune activation driven by co-infection contributes to the development of Lyme arthritis.

immunology↗

bioRxiv2021

Sub-lethal radiation-induced senescence impairs resolution programs and drives cardiovascular inflammation

Radiation is associated with tissue damage and increased risk of atherosclerosis but there are currently no treatments and a very limited mechanistic understanding of how radiation impacts tissue repair mechanisms. We uncovered that radiation significantly delayed temporal resolution programs that was associated with decreased efferocytosis in vivo. Resolvin D1 (RvD1), a known pro-resolving ligand, promoted swift resolution and restored efferocytosis in sub-lethally irradiated mice. Irradiated macrophages exhibited several features of senescence, including increased expression of p16INK4A and p21, heightened levels of SA-{beta}-gal, COX-2, and oxidative stress (OS) in vitro, and when transferred to mice exacerbated inflammation in vivo. Mechanistically, heightened OS in senescent macrophages led to impairment in their ability to carry out efficient efferocytosis and treatment with RvD1 reduced OS and improved efferocytosis. Sub-lethally irradiated Ldlr-/- mice exhibited increased plaque necrosis and p16INK4A cells compared with non-irradiated controls and treatment with RvD1 significantly reduced these endpoints. Removal of p16INK4A hematopoietic cells during advanced atherosclerosis with p16-3MR mice reduced plaque necrosis and increased production of key intraplaque resolving mediators. Our results demonstrate that sub-lethal radiation drives macrophage senescence and efferocytosis defects and suggest that RvD1 may be a new therapeutic strategy to limit radiation-induced tissue damage.

immunology↗