Biology subjects

Frey, J. M.

Publications and source records attributed to Frey, J. M..

4 recordsLinked to original sources

bioRxiv2026

Transient efferocytosis-induced activation of IKKβ reprograms macrophages to promote tissue resolution

The clearance of apoptotic cells by macrophages, termed efferocytosis, reprograms macrophages to a resolution/repair phenotype, and pathologic defects in efferocytosis drive many chronic inflammatory diseases. Previous studies have elucidated numerous downstream pro-resolving pathways activated by efferocytosis, but whether there exists a common upstream trigger of these pathways remains unknown. Here, we report that efferocytosing macrophages surprisingly use a signaling module typically associated with inflammation to carry out this key initiating role in tissue resolution. The binding of apoptotic cells to the MerTK receptor triggers a rapid and transient activation of inhibitor of nuclear factor (NF) kappa-B kinase subunit beta (IKK{beta}), leading to NF{kappa}B and p38-signal transducer and activator of transcription 3 (STAT3) signaling and then activation of several key downstream pro-resolving pathways, including interleukin-10 (IL-10) production, continuing efferocytosis, and regulatory T (Treg) cell expansion. The upstream IKK{beta} pathway and the downstream resolution pathways are linked through several intermediary molecules, including the transcription factor Myc, the epigenetic modifier ten-eleven translocation-2 (TET2), and the immune checkpoint protein programmed cell death ligand 1 (PD-L1). Deletion of macrophage IKK{beta} in vivo blocks the above resolution pathways and compromises tissue repair in two efferocytosis-mediated repair settings: resolution of thymic injury after dexamethasone-induced thymocyte apoptosis; and, most importantly, atherosclerosis regression induced by low-density lipoprotein (LDL)-lowering, which is highly relevant to the prevention of cardiovascular disease in humans. These findings illustrate the existence of a unifying upstream signal for efferocytosis-induced resolution, which could suggest new therapeutic strategies to enhance multiple tissue resolution pathways and to optimize anti-inflammatory therapies by avoiding blocking IKK{beta}-NF{kappa}B/p38-mediated resolution.

immunology↗

bioRxiv2025

Ablation of microglial estrogen receptor alpha predisposes to diet-induced obesity in male mice

Estrogen receptor alpha (ER) signaling has metabolic and anti-inflammatory properties in addition to its impact on reproductive function. In male but not female mice, inflammatory activation of microglia, the resident macrophages of the brain, has been implicated in the pathogenesis of diet-induced obesity (DIO), raising the possibility that differences in microglial estrogen signaling may account for the sexual dimorphism. In this study, we assessed metabolic and CNS histopathological properties in a mouse model with inducible microglia-specific ablation of ER (MG-ERKO). Male MG-ERKO mice developed increased weight gain and insulin resistance relative to controls during high-fat diet (HFD) feeding. Indirect calorimetry analysis revealed that reduced energy expenditure was the main driver of the obese phenotype. In contrast, female MG-ERKO mice fed HFD developed mild insulin resistance with no change in body weight gain compared to controls. Immunohistochemical analyses of the microglial activation marker IBA1 in the mediobasal hypothalamus (MBH) revealed that female MG-ERKO mice had an increased number of microglia without showing morphological signs of activation. In contrast, MBH microglial number was unchanged in MG-ERKO male mice, but the cells adopted more activated morphological profiles. Finally, HFD-fed MG-ERKO male mice had increased POMC neuron-microglia interactions but fewer overall hypothalamic POMC neurons, suggesting microglia may disrupt POMC neuron integrity to promote DIO. Together, these findings indicate that sex-specific actions of estrogen in microglia limit the metabolic complications of HFD feeding.

neuroscience↗

bioRxiv2022

Microglial inflammatory activation paradoxically improves glucose tolerance during diet-induced obesity

Hypothalamic gliosis associated with high fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain, and is therefore presumed to promote obesity-associated consequences such as glucose intolerance as well. Nevertheless, the body weight-independent contribution of microglial activation to glucose regulation has not been determined. Here we show that reducing microglial NF-{kappa}B signaling via cell-specific IKK{beta} deletion exacerbates HFD-induced glucose intolerance and insulin resistance despite reducing body weight and adiposity. This effect was associated with reduced activity of hypothalamic glucose sensing neurons. Conversely, a genetic approach to increase microglial inflammatory activity improved glucose tolerance independently of diet in lean rodents. To avoid confounding effects due to chronic alterations to microglial signaling pathways from dietary or genetic interventions, we developed an inducible model of microglial activation using DREADD-based chemogenetics. Gq-coupled GPCR activation rapidly increased microglial calcium levels, cytokine gene expression, and morphological hallmarks of inflammatory activation. In both lean and obese rodents, chemogenetic microglial activation caused a marked improvement in glucose tolerance along with increased activation of hypothalamic glucose sensing neurons, effects abrogated by central blockade of TNF signaling. Thus, while diet-induced microglial activation promotes weight gain, it may also serve an adaptive function--to prevent the deterioration of glucose tolerance associated with obesity, an important consideration for immune-modulating metabolic therapies.

neuroscience↗

bioRxiv2021

Prostaglandin PGE2 receptor EP4 regulates microglial phagocytosis and increases susceptibility to diet-induced obesity

BackgroundIn rodents, susceptibility to diet-induced obesity requires microglial activation, but the molecular components of this pathway remain incompletely defined. Prostaglandin E2 (PGE2) levels increase in the mediobasal hypothalamus during high fat diet (HFD) feeding, and the PGE2 receptor EP4 regulates microglial activation state and phagocytic activity, suggesting a potential role for microglial EP4 signaling in obesity pathogenesis. MethodMetabolic phenotyping, as assessed by body weight, energy expenditure, glucose, and insulin tolerance, was performed in microglia-specific EP4 knockout (MG-EP4 KO) mice and littermate controls on HFD. Morphological and gene expression analysis of microglia, and a histological survey of microglia-neuron interactions in the arcuate nucleus was performed. Phagocytosis was assessed using in vivo and in vitro pharmacological techniques. ResultsMicroglial EP4 deletion markedly reduced weight gain and food intake in response to HFD feeding. In correspondence with this lean phenotype, insulin sensitivity was also improved in the HFD-fed MG-EP4 KO mice though glucose tolerance remained surprisingly unaffected. Mechanistically, EP4-deficient microglia showed an attenuated phagocytic state marked by reduced CD68 expression and fewer contacts with POMC neuron soma and processes. These cellular changes observed in the microglial EP4 knockout mice corresponded with an increased density of POMC neurites extending into the paraventricular nucleus. ConclusionThese findings reveal that microglial EP4 signaling promotes body weight gain and insulin resistance during HFD feeding. Furthermore, the data suggest that curbing microglial phagocytic function may preserve POMC cytoarchitecture and PVN input to limit overconsumption during diet-induced obesity.

physiology↗