Lysosomal Cholesterol Hydrolysis Couples Efferocytosis to Anti-Inflammatory Oxysterol Production

Viaud, Manon; Ivanov, Stoyan; Vujić, Nemanja; Duta-Mare, Madalina; Aira, Lazaro E.; Barouillet, Thibault; Garcia, Elsa; Orange, François; Dugail, Isabelle; Hainault, Isabelle; Stehlik, Christian; Marchetti, Sandrine; Boyer, Laurent; Guinamard, Rodolphe; Foufelle, Fabienne; Bochem, Andrea E.; Hovingh, Kees; Thorp, Edward B.; Gautier, Emmanuel L.; Kratky, Dagmar; DaSilva-Jardine, Paul; Yvan‐Charvet, Laurent

doi:10.1161/circresaha.117.312333

Cited by 94 publications

(103 citation statements)

References 54 publications

(88 reference statements)

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“…Along the same line, the ATP-binding cassette transporter (ABCA1), a protein that modulates cholesterol efflux, is upregulated during efferocytosis in a manner dependent on LXR signaling (114). Furthermore, decreased hydrolysis of cholesterol esters and impaired oxysterol production, due to blockade of the enzyme lysosomal acid lipase, negatively affect LXR pathway activation and apoptotic cell removal, resulting in chronic inflammation (115). These studies point to the intimate crosstalk between cholesterol metabolism and nuclear receptor signaling involved in efferocytosis.…”

Section: Metabolic Modulation Of Macrophage Function In the Context Omentioning

confidence: 99%

Phagocytosis of Apoptotic Cells in Resolution of Inflammation

2020

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Efficient inflammation resolution is important not only for the termination of the inflammatory response but also for the restoration of tissue integrity. An integral process to resolution of inflammation is the phagocytosis of dying cells by macrophages, known as efferocytosis. This function is mediated by a complex and well-orchestrated network of interactions amongst specialized phagocytic receptors, bridging molecules, as well as "find-me" and "eat-me" signals. Efferocytosis serves not only as a waste disposal mechanism (clearance of the apoptotic cells) but also promotes a pro-resolving phenotype in efferocytic macrophages and thereby termination of inflammation. Alterations in cellular metabolism are critical for shaping the phenotype and function of efferocytic macrophages, thus, representing an important determinant of macrophage plasticity. Impaired efferocytosis can result in inflammation-associated pathologies or autoimmunity. The present mini review summarizes current knowledge regarding the mechanisms regulating macrophage efferocytosis during clearance of inflammation.

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Section: Metabolic Modulation Of Macrophage Function In the Context Omentioning

confidence: 99%

Phagocytosis of Apoptotic Cells in Resolution of Inflammation

2020

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“…This stands in contrast to F4/80 + and CD68 + macrophages, found at the injury site and the distal nerve ( Scarb2/scavenger receptor class B member 2) ( Figure 6 -figure supplement 6A-6I). The abundance of gene products that protect from cholesterol overloading (Haidar et al, 2006;Viaud et al, 2018;Wu et al, 2018), suggests that this cluster is comprised of cholesterol laden cells.…”

Section: Identification Of Macrophage Subpopulations With Distinct Fumentioning

confidence: 99%

Analysis of the Immune Response to Sciatic Nerve Injury Identifies Efferocytosis as a Key Mechanism of Nerve Debridement

Kalinski

Yoon

Huffman

et al. 2020

Preprint

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Sciatic nerve crush injury triggers sterile inflammation within the distal nerve and axotomized dorsal root ganglia (DRGs). Granulocytes and pro-inflammatory Ly6C high monocytes infiltrate the nerve first, and rapidly give way to Ly6C negative inflammation-resolving macrophages. In axotomized DRGs, few hematogenous leukocytes are detected and resident macrophages acquire a ramified morphology. Single-cell RNA-sequencing of injured sciatic nerve identifies five macrophage subpopulations, repair Schwann cells, and mesenchymal precursor cells. Macrophages at the nerve crush site are molecularly distinct from macrophages associated with Wallerian degeneration. In the injured nerve, macrophages "eat" apoptotic leukocytes, a process called efferocytosis, and thereby promote an anti-inflammatory milieu. Myeloid cells in the injured nerve, but not axotomized DRGs, strongly express receptors for the cytokine GM-CSF. In GM-CSF deficient (Csf2-/-) mice, inflammation resolution is delayed and conditioning-lesion induced regeneration of DRG neuron central axons is abolished. Thus, carefully orchestrated inflammation resolution in the nerve is required for conditioning-lesion induced neurorepair.

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“…LAL-dependent hydrolysis of CE in macrophages provides the substrate for the synthesis of 25-hydroxycholesterol and 27-hydroxycholesterol, both endogenous ligands of LXR, thus promoting cholesterol efflux and contributing to an efficient efferocytosis (a critical process for the phagocytosis of apoptotic cells) (Figure 2b) [40]. Further, the immunometabolic function of LAL also extends to the ability to contribute FFA following CE and TG hydrolysis, for energetic purposes.…”

Section: Role Of Lal In Immune Cell Maturation and Functionmentioning

confidence: 99%

Lysosomal Acid Lipase: From Cellular Lipid Handler to Immunometabolic Target

Gomaraschi

Bonacina

Norata

2019

Trends in Pharmacological Sciences

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Lysosomal acid lipase (LAL) hydrolyzes cholesterol esters and triglycerides to free cholesterol and fatty acids,that are then used for the metabolic purposes in the cell. The process also occurs in immune cells which adapt their metabolic machinery to cope with the different energetic requirements associated to cell activation, proliferation and/or polarization. Deficiency of LAL not only causes severe lipid accumulation, but also impacts the immunometabolic signature in animal models. In humans, LAL deficiency has been recently associated with a peculiar clinical immune phenotype, secondary hemophagocytic lymphohistiocytosis. These observations indicate that LAL represents a critical player for cellular immunometabolic modulation and the availability of an effective enzyme replacement strategy makes LAL an attractive target to rewire the immunometabolic machinery of immune cells beyond its role in controlling cellular lipid metabolism.

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Lysosomal Cholesterol Hydrolysis Couples Efferocytosis to Anti-Inflammatory Oxysterol Production

Abstract: Our findings position lysosomal cholesterol hydrolysis as a critical process that prevents metabolic inflammation by enabling efficient macrophage apoptotic cell clearance.

Cited by 94 publications

References 54 publications

Phagocytosis of Apoptotic Cells in Resolution of Inflammation

Phagocytosis of Apoptotic Cells in Resolution of Inflammation

Analysis of the Immune Response to Sciatic Nerve Injury Identifies Efferocytosis as a Key Mechanism of Nerve Debridement

Lysosomal Acid Lipase: From Cellular Lipid Handler to Immunometabolic Target

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