Biology subjects

Spite, M.

Publications and source records attributed to Spite, M..

6 recordsLinked to original sources

bioRxiv2026

Multi-Omic Analyses of Dietary Fatty Acid-Microbe-Host Interactions Reveal Metaorganismal Lipid Metabolic Crosstalk Impacting Cardiometabolic Disease

Following a meal, our gut microbiome and human cells collaborate via metaorganismal metabolic circuits to produce diverse nutrient metabolites that systemically circulate to influence health and disease. Although there are now several examples of bacterial fiber-, amino acid-, and micronutrient-derived metabolites impacting cardiometabolic disease, very little is known in regards to how diet-microbe-host interactions impact lipid homeostasis. Here we address this by defining dietary fatty acid substrate availability in germ-free versus conventionally-raised mice coupled to deep multi-omic metabolic phenotyping. Our data demonstrate that the effects of dietary saturated (SFA), monounsaturated (MUFA), and polyunsaturated fatty acids (PUFA) on the host lipidome, transcriptome, proteome and metabolome are uniquely impacted by resident microbiota. Also, the hepatic levels of both pro-inflammatory and pro-resolving lipid mediators are strongly influenced by dietary fatty acid-microbe interactions. This study presents a unique resource to the nutrition and metabolism research community to advance our understanding of metaorganismal lipid metabolism. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/705588v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@4fc7e3org.highwire.dtl.DTLVardef@1cc1dc8org.highwire.dtl.DTLVardef@1b7648dorg.highwire.dtl.DTLVardef@12a8088_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG

biochemistry↗

bioRxiv2024

Improving Functional Muscle Regeneration in Volumetric Muscle Loss Injuries by Shifting the Balance of Inflammatory and Pro-Resolving Lipid Mediators

Severe tissue loss resulting from extremity trauma, such as volumetric muscle loss (VML), poses significant clinical challenges for both general and military populations. VML disrupts the endogenous tissue repair mechanisms, resulting in acute and unresolved chronic inflammation and immune cell presence, impaired muscle healing, scar tissue formation, persistent pain, and permanent functional deficits. The aberrant healing response is preceded by acute inflammation and immune cell infiltration which does not resolve. We analyzed the biosynthesis of inflammatory and specialized pro-resolving lipid mediators (SPMs) after VML injury in two different models; muscle with critical-sized defects had a decreased capacity to biosynthesize SPMs, leading to dysregulated and persistent inflammation. We developed a modular poly(ethylene glycol)-maleimide hydrogel platform to locally release a stable isomer of Resolvin D1 (AT-RvD1) and promote endogenous pathways of inflammation resolution in the two muscle models. The local delivery of AT-RvD1 enhanced muscle regeneration, improved muscle function, and reduced pain sensitivity after VML by promoting molecular and cellular resolution of inflammation. These findings provide new insights into the pathogenesis of VML and establish a pro-resolving hydrogel therapeutic as a promising strategy for promoting functional muscle regeneration after traumatic injury.

bioengineering↗

bioRxiv2024

Exercise-stimulated Resolvin Biosynthesis in Adipose Tissue is Abrogated by High Fat Diet-induced Adrenergic Deficiency

ObjectiveDiet-induced white adipose tissue inflammation is associated with insulin resistance and metabolic perturbations. Conversely, exercise (Exe) protects against the development of chronic inflammation and insulin resistance independent of changes in weight; however, the mechanisms remain largely unknown. We have recently shown that, through adrenergic stimulation of macrophages, exercise promotes resolution of acute peritoneal inflammation by enhancing the biosynthesis of specialized pro-resolving lipid mediators (SPMs). In this study, we sought to determine if exercise stimulates pro-resolving pathways in adipose tissue and whether this response is modified by diet. Specifically, we hypothesized that high fat diet feeding disrupts exercise-stimulated resolution by inhibiting adrenergic signaling, priming the development of chronic inflammation in adipose tissue (AT). Approach and ResultsTo explore the dietary dependence of the pro-resolving effects of Exe, mice were fed either a control or high-fat diet (HFD) for 2 weeks prior to, and throughout, a 4 wk period of daily treadmill running. Glucose handling, body weight and composition, and exercise performance were evaluated at the end of the feeding and exercise interventions. Likewise, catecholamines and their biosynthetic enzymes were measured along with AT SPM biosynthesis and macrophage phenotype and abundance. When compared with sedentary controls (Sed), macrophages isolated from mice exposed to 4 wk of exercise display elevated expression of the SPM biosynthetic enzyme Alox15, while whole AT SPM levels and anti-inflammatory CD301+ M2 macrophages increased. These changes were dependent upon diet as 6 wk of feeding with HFD abrogated the pro-resolving effect of exercise when compared with control diet-fed animals. Interestingly, exercise-induced epinephrine production was inhibited by HFD, which diminished expression of the epinephrine biosynthetic enzyme phenylethanolamine N-methyltransferase (PNMT) in adrenal glands. ConclusionTaken together, these results suggest that a diet high in fat diminishes the pro-resolving effects of exercise in adipose tissue via decreasing the biosynthesis of catecholamines. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/608014v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1b508e7org.highwire.dtl.DTLVardef@5b9d8corg.highwire.dtl.DTLVardef@c46707org.highwire.dtl.DTLVardef@48083e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Resolvin D2-GPR18 Signaling on Myeloid Cells Limits Plaque Necrosis

Introduction/ObjectiveDysregulated inflammation-resolution programs are associated with atherosclerosis progression. Inflammation-resolution is in part mediated by Resolvins, including Resolvin D2 (RvD2). RvD2, which activates a G-protein coupled receptor (GPCR) called GPR18, limits plaque progression. Cellular targets of RvD2 are not known. Approach and ResultsHere we developed humanized GPR18 floxed ("fl/fl") and a myeloid (Lysozyme M Cre) GPR18 knockout (mKO) mouse. We functionally validated this model by assessing efferocytosis in bone marrow derived macrophages (BMDMs) and found that RvD2 enhanced efferocytosis in the fl/fl, but not in the mKO BMDMs. We employed two different models to evaluate the role of GPR18 in atherosclerosis. We first used the PCSK9-gain of function approach and found increased necrosis in the plaques of the mKO mice compared with fl/fl mice. Next, we performed a bone marrow transfer of fl/fl or mKO bone marrow into Ldlr-/- recipients. For these experiments, we treated each genotype with either Veh or RvD2 (25 ng/mouse, 3 times/week for 3 weeks). Myeloid loss of GPR18 resulted in significantly more necrosis and cleaved caspase-3+ cells compared with fl/fl transplanted mice. RvD2 treatment decreased plaques necrosis and cleaved caspase-3+ cells in fl/fl, but not in the mKO transplanted mice. ConclusionsThese results are the first to suggest a causative role for endogenous RvD2 signaling on myeloid cells in limiting plaque necrosis. Moreover, these results provide a mechanistic basis for RvD2 as a therapy limiting plaque necrosis.

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↗

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↗