Biology subjects

Febbraio, M.

Publications and source records attributed to Febbraio, M..

4 recordsLinked to original sources

bioRxiv2026

Gp130 Orchestrates a Bidirectional Neuron-Microglia Circuit for neuroprotection

Acquired central nervous system (CNS) injury is one of the most common neurological conditions globally, yet effective treatment options are lacking. As the main tissue-resident macrophages of the CNS, microglia have emerged as key functional regulators of CNS repair. However, means to induce neuroprotective microglia and harness their intrinsic repair capabilities have remained elusive. Here we identify gp130 as a key receptor molecule for facilitating bidirectional microglia-neuron communication that improves outcomes from CNS injury. We show that activation of gp130 in CNS-resident microglia triggers the secretion of leukemia inhibitory factor (LIF), a neurotrophic cytokine. LIF induces neuronal IL-6 secretion that then acts back onto the microglial gp130 receptor, thus creating a neuroprotective loop. We demonstrate the broad therapeutic potential of acute gp130 activation across multiple models, including traumatic brain injury, stroke, and spinal cord injury, and that this pathway can be leveraged therapeutically with designer cytokines.

neuroscience↗

bioRxiv2024

Remote ischemic conditioning attenuates transneuronal degeneration and promotes stroke recovery via CD36-mediated efferocytosis.

BACKGROUNDRemote ischemic limb conditioning (RIC) has been implicated in cross-organ protection in cerebrovascular disease, including stroke. However, the lack of a consensus protocol and controversy over the clinical therapeutic outcomes of RIC suggest inadequate mechanistic understanding of RIC. The current study identifies RIC-induced molecular and cellular events in the blood that enhance long-term functional recovery in experimental cerebral ischemia METHODSNaive mice or mice subjected to transient ischemic stroke were randomly selected to receive sham conditioning or RIC in the hind limb at 2 h post-stroke. At 3d post-stroke, monocyte composition in the blood was analyzed, and brain tissue was examined for monocyte-derived macrophages (M{varphi}), levels of efferocytosis, and CD36 expression. Mouse with conditional deletion of CD36 in M{varphi} (cKOMM{varphi}) was used to establish the role of CD36 in RIC-mediated modulation of efferocytosis, transneuronal degeneration, and recovery following stroke. RESULTSRIC applied 2h after stroke increased entry of monocytes into the injured brain. In the post-ischemic brain, M{varphi} had increased levels of CD36 expression and efferocytosis. These changes in brain M{varphi} were derived from RIC-induced changes in circulating monocytes. In the blood, RIC increased CD36 expression in circulating monocytes and shifted monocytes to a proinflammatory LY6CHigh state. Conditional deletion of CD36 in M{varphi} abrogated the RIC-induced monocyte shift in the blood and efferocytosis in the brain. During the recovery phase of stroke, RIC rescued the loss of the volume and of tyrosine hydroxylase+ neurons in substantia nigra (SN) as well as behavioral deficits in WT mice, but not in cKOMM{varphi} mice. CONCLUSIONSRIC induces a shift in monocytes to a proinflammatory state with elevated CD36 levels, and this is associated with CD36-dependent efferocytosis in M{varphi}s that rescues delayed transneuronal degeneration in the post-ischemic brain and promotes stroke recovery. Together, these findings provide novel insight into our mechanistic understanding of how RIC improves in post-stroke recovery. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIInfiltrated monocyte-derived macrophages (M{varphi}) into the post-ischemic brain cause neural inflammation, but they also engage in efferocytosis that promotes tissue repair in the injured CNS. C_LIO_LIRemote ischemic limb conditioning (RIC) changes monocyte composition and enhances functional recovery in experimental brain ischemia. C_LIO_LIThe application of RIC is safe, feasible, and tolerable in stroke patients, but clinical outcomes remain inconsistent. C_LI What New Information Does This Article Contribute?O_LIWe provide experimental evidence that RIC modifies peripheral monocyte composition and molecular expression, and leads to favorable changes in debris clearance, structure integrity, transneuronal degeneration, and behavior following stroke. C_LIO_LIProtective effects of RIC disappear in the absence of CD36 in M{varphi}, suggesting an essential mechanistic role for CD36 in RIC-induced endogenous protective outcomes. C_LIO_LIThe current study demonstrates that immune-mediated RIC mechanisms facilitate inflammatory and recovery processes in the injured CNS. Given the challenges in directly manipulating the brain after stroke, the study suggests that RIC is a promising alternative strategy by inducing changes in peripheral monocytes that can influence injury progression and recovery. Moreover, RIC-induced peripheral changes uncovered by this study may serve as biomarkers to establish an optimal RIC protocol. C_LI

neuroscience↗

bioRxiv2023

Endothelial stiffening induced by CD36-mediated lipid uptake leads to endothelial barrier disruption and contributes to atherosclerotic lesions

BackgroundTo determine the impact of endothelial stiffening induced by CD36-mediated lipid uptake in the disruption of aortic endothelial barrier and development of atherosclerosis in mouse models of obesity and hypercholesterolemia. Approach and ResultsEndothelial-specific inducible downregulation of CD36 results in abrogating the stiffening of aortic endothelium induced by a short-term (6-8 weeks) high-fat Western diet in intact freshly isolated mouse aortas of Cdh5.CreERT2CD36fl/fl mice, as assessed by atomic force microscopy. No effect was observed on the stiffness of aortic vascular wall assessed in the same groups of mice by echocardiography. Prevention of WD-induced endothelial stiffening by the downregulation of endothelial CD36 was associated with a protective effect against endothelial barrier disruption, assessed by morphological analysis of VE-cadherin junctions and penetration of Evans blue dye into the aortic wall. These protective effects were independent of the changes in the serum lipid profiles. Furthermore, endothelial specific downregulation of CD36 in hypercholesterolemic Cdh5.CreERT2CD36fl/flLDLR-/- mice also led to significant decrease in endothelial stiffening after 4-5 months of high fat diet and a significant decrease in the areas of atherosclerotic lesion. In both models, significant endothelial stiffening was observed specifically in male mice, while female mice exhibited less endothelial stiffening and less severe atherosclerosic phenotype, consistent with endothelial stiffening playing an important role in aortic vascular disease in a sex-dependent way. Mechanistically, we show in vitro that CD36-mdiated uptake of long chain saturated fatty acids, particularly palmitic acid, induces endothelial stiffening via activation of RhoA/ROCK pathway. Moreover, palmitic acid-induced endothelial stiffening critically depends on the expression of a RhoA inhibitory protein, Rho-GDI-1. ConclusionsWe conclude that stiffening of the aortic endothelium by CD36-mediated uptake of fatty acids contributes significantly to WD-induced vascular dysfunction and atherosclerosis. We further propose that fatty acids may activate RhoA by inducing its dissociation from Rho-GDI-1.

cell biology↗

bioRxiv2022

Class IIa HDACs reprogram mitochondrial metabolism to inhibit apoptosis and ferroptosis in response to lipotoxicity

Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle, resulting in increased non-oxidative glucose metabolism. This metabolic reprogramming was also associated with impaired apoptosis and ferroptosis responses, and preserved muscle cell viability in response to lipotoxicity. Mechanistically, increased HDAC4 and 5 decreased acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis. Redox drivers of ferroptosis derived from oxidative metabolism were also reduced. The relevance of this pathway was demonstrated by overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice, which enhanced oxidative metabolic capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of skeletal muscle oxidative metabolism, which is linked to inhibition of cell death pathways and preservation of muscle integrity in response to lipotoxicity.

cell biology↗