LC3-associated phagocytosis protects against inflammation and liver fibrosis via immunoreceptor inhibitory signaling

Wan, Jinghong; Weiss, Emmanuel; Mkaddem, Sanae Ben; Mabire, Morgane; Choinier, Pierre‐Marie; Picq, Olivia; Thibault-Sogorb, Tristan; Hegde, Pushpa; Pishvaie, Dorsa; Bens, Marcelle; Broer, Linda; Gilgenkrantz, Hélène; Moreau, Richard; Saveanu, Loredana; Codogno, Patrice; Monteiro, Renato C.; Lotersztajn, Sophie

doi:10.1126/scitranslmed.aaw8523

Cited by 56 publications

(54 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The autophagosome formation results in LC3 cleavage into LC3-I, which may be later transformed into a lipidated form by conjugation to phosphatidylethanolamine (L3-II). The LC3-II incorporated into autophagosomes is a clear indicator of autophagy, which may lead to the late stage of autophagy, including autophagosome fusion with lysosomes and/or lysosomal degradation [ 24 ]. CQ resulted in late autophagic inhibition by impairing autophagosome–lysosome fusion, similar to bafilomycin A 1 [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

Chloroquine-Induced Accumulation of Autophagosomes and Lipids in the Endothelium

Bik

Mateuszuk

Orleanska

et al. 2021

IJMS

View full text Add to dashboard Cite

Chloroquine (CQ) is an antimalarial drug known to inhibit autophagy flux by impairing autophagosome–lysosome fusion. We hypothesized that autophagy flux altered by CQ has a considerable influence on the lipid composition of endothelial cells. Thus, we investigated endothelial responses induced by CQ on human microvascular endothelial cells (HMEC-1). HMEC-1 cells after CQ exposure were measured using a combined methodology based on label-free Raman and fluorescence imaging. Raman spectroscopy was applied to characterize subtle chemical changes in lipid contents and their distribution in the cells, while the fluorescence staining (LipidTox, LysoTracker and LC3) was used as a reference method. The results showed that CQ was not toxic to endothelial cells and did not result in the endothelial inflammation at concentrations of 1- 30 µM. Notwithstanding, it yielded an increased intensity of LipidTox, LysoTracker, and LC3 staining, suggesting changes in the content of neutral lipids, lysosomotropism, and autophagy inhibition, respectively. The CQ-induced endothelial response was associated with lipid accumulation and was characterized by Raman spectroscopy. CQ-induced autophagosome accumulation in the endothelium is featured by a pronounced alteration in the lipid profile, but not in the endothelial inflammation. Raman-based assessment of CQ-induced biochemical changes offers a better understanding of the autophagy mechanism in the endothelial cells.

show abstract

Section: Resultsmentioning

confidence: 99%

Chloroquine-Induced Accumulation of Autophagosomes and Lipids in the Endothelium

Bik

Mateuszuk

Orleanska

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Recent studies on monocyte/macrophages revealed that LAP has a significant role in phenotype differentiation, particularly on the anti-inflammatory phenotype [96]. In addition to its role in regulating autoimmune response [97], LAP-mediated protective response against hepatic and systemic inflammation are also documented [98].…”

Section: Resultsmentioning

confidence: 99%

Progress and Challenges in the Use of MAP1LC3 as a Legitimate Marker for Measuring Dynamic Autophagy In Vivo

Bonam

Bayry

Tschan

et al. 2020

Cells

View full text Add to dashboard Cite

Tremendous efforts have been made these last decades to increase our knowledge of intracellular degradative systems, especially in the field of autophagy. The role of autophagy in the maintenance of cell homeostasis is well documented and the existence of defects in the autophagic machinery has been largely described in diseases and aging. Determining the alterations occurring in the many forms of autophagy that coexist in cells and tissues remains complicated, as this cellular process is highly dynamic in nature and can vary from organ to organ in the same individual. Although autophagy is extensively studied, its functioning in different tissues and its links with other biological processes is still poorly understood. Several assays have been developed to monitor autophagy activity in vitro, ex vivo, and in vivo, based on different markers, the use of various inhibitors and activators, and distinct techniques. This review emphasizes the methods applied to measure (macro-)autophagy in tissue samples and in vivo via a protein, which centrally intervenes in the autophagy pathway, the microtubule-associated protein 1A/1B-light chain 3 (MAP1LC3), which is the most widely used marker and the first identified to associate with autophagosomal structures. These approaches are presented and discussed in terms of pros and cons. Some recommendations are provided to improve the reliability of the interpretation of results.

show abstract

“…Moreover, activation of LAP is abolished in monocytes from patients with acute-onchronic liver failure and can be restored by specifically targeting ITAMi signaling with anti-FcγRIIA F(ab') 2 fragments or by intravenous injection of immunoglobulin (IVIg). 195 Together, these studies suggest a possible approach for targeting macrophages to induce anti-inflammatory and antifibrotic effects.…”

Section: Roles Of Macrophages In Resolving Inflammation During Livermentioning

confidence: 96%

“…Recently, LC3-associated phagocytosis (LAP), a noncanonical form of autophagy that triggers the switch of MoMϕs to an antiinflammatory phenotype, was reported in patients with cirrhosis. 195 Studies involving pharmacological inhibition of LAP in monocytes isolated from patients with cirrhosis or genetic disruption of LAP in mice treated with CCl 4 have demonstrated that LAP attenuates inflammation through FcγRIIA-mediated activation of the anti-inflammatory Src homology region 2 domain-containing phosphatase-1 (SHP1)/inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) pathway. 195 In contrast, mice overexpressing human FcγRIIA in myeloid cells show increased LAP activation, resulting in resistance to inflammation and CCl 4 -induced liver fibrosis.…”

Section: Roles Of Macrophages In Resolving Inflammation During Livermentioning

confidence: 99%

“…195 Studies involving pharmacological inhibition of LAP in monocytes isolated from patients with cirrhosis or genetic disruption of LAP in mice treated with CCl 4 have demonstrated that LAP attenuates inflammation through FcγRIIA-mediated activation of the anti-inflammatory Src homology region 2 domain-containing phosphatase-1 (SHP1)/inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) pathway. 195 In contrast, mice overexpressing human FcγRIIA in myeloid cells show increased LAP activation, resulting in resistance to inflammation and CCl 4 -induced liver fibrosis. Moreover, activation of LAP is abolished in monocytes from patients with acute-onchronic liver failure and can be restored by specifically targeting ITAMi signaling with anti-FcγRIIA F(ab') 2 fragments or by intravenous injection of immunoglobulin (IVIg).…”

Section: Roles Of Macrophages In Resolving Inflammation During Livermentioning

confidence: 99%

See 1 more Smart Citation

Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities

et al. 2020

View full text Add to dashboard Cite

Macrophages, which are key cellular components of the liver, have emerged as essential players in the maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases. Upon liver injury, resident Kupffer cells (KCs) sense disturbances in homeostasis, interact with hepatic cell populations and release chemokines to recruit circulating leukocytes, including monocytes, which subsequently differentiate into monocyte-derived macrophages (MoMϕs) in the liver. Both KCs and MoMϕs contribute to both the progression and resolution of tissue inflammation and injury in various liver diseases. The diversity of hepatic macrophage subsets and their plasticity explain their different functional responses in distinct liver diseases. In this review, we highlight novel findings regarding the origins and functions of hepatic macrophages and discuss the potential of targeting macrophages as a therapeutic strategy for liver disease.

show abstract

LC3-associated phagocytosis protects against inflammation and liver fibrosis via immunoreceptor inhibitory signaling

Cited by 56 publications

References 46 publications

Chloroquine-Induced Accumulation of Autophagosomes and Lipids in the Endothelium

Chloroquine-Induced Accumulation of Autophagosomes and Lipids in the Endothelium

Progress and Challenges in the Use of MAP1LC3 as a Legitimate Marker for Measuring Dynamic Autophagy In Vivo

Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities

Contact Info

Product

Resources

About