Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke

Liu, Jing; Shen, Danmin; Wei, Chao; Wu, Weihua; Luo, Zhaoli; Hu, Liye; Xiao, Zhongnan; Hu, Tingting; Sun, Qingyu; Wang, Xiaotong; Ding, Yumeng; Li, Meng; Pang, Miaoyi; Gai, Kaiyuan; Ma, Yiran; Tian, Yongchao; Yu, Yan; Wang, Peipei; Guan, Yun; Xu, Meng; Yang, Fei; Li, Qian

doi:10.1016/j.isci.2022.105527

Cited by 5 publications

(7 citation statements)

References 76 publications

(89 reference statements)

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“…However, AMPK has also been shown to attenuate inflammation by inhibiting STAT1 expression and signaling (He et al, 2015;Meares et al, 2013), consistent with the increased STAT1 expression levels reported in VASP-deficient macrophages (Laban et al, 2018). As AMPK activation enhances the phagocytic capacity of macrophages and neutrophils (Bae et al, 2011;Gregoire et al, 2018;He et al, 2019;Liu et al, 2022;Mounier et al, 2013), the phagocytic capacity of VASP-deficient macrophages was assessed. Wild-type and VASP -/bone marrowderived macrophages were incubated with pH-sensitive fluorogenic bioparticles and relative fluorescence intensity was measured using live cell imaging.…”

Section: Resultsmentioning

confidence: 58%

Impaired AMPK activity contributes to the inflammatory phenotype and the reduced phagocytosis capacity of VASP-deficient macrophages

Laban

Froemel

Fleming

et al. 2023

Preprint

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Macrophage polarization plays an important role in tissue regeneration. Numerous factors and signaling molecules affect polarization processes. Here we investigated the consequences of the genetic deletion of vasodilator-stimulated phosphoprotein (VASP), which increases macrophage M1 polarization through augmented signal transducer and activator of transcription 1 (STAT1) signaling, and AMP-activated protein kinase (AMPK), which attenuates inflammation by inhibiting STAT1 expression and signaling. While a basal activity of AMPK (phosphorylation on Thr172) was detected in macrophages from wild-type mice, AMPK phosphorylation was significantly reduced in VASP-deficient M1 macrophages in vitro and the expression of the pro-inflammatory cytokines TNFα and IL-1β was increased in these cells. Consistent with the role of AMPK in macrophage phagocytosis, VASP-/- macrophage phagocytosis was also significantly impaired. Interestingly, impaired phagocytosis could be rescued by exogenous activation of AMPK. Mechanistically, we found that VASP binds directly to protein phosphatase 1 regulatory subunit 6 (PP1-R6) and we hypothesize that VASP-binding to PP1-R6/PP1 limits the PP1-dependent de-phosphorylation of AMPK in wild-type cells. Conversely, AMPK dephosphorylation by the PP1-R6/PP1 complex is enhanced in the absence of VASP. In summary, we have identified a link between VASP and AMP-activated protein kinase (AMPK) activity, which may contribute to the pro-inflammatory phenotype of VASP-deficient macrophages.

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Section: Resultsmentioning

confidence: 58%

Impaired AMPK activity contributes to the inflammatory phenotype and the reduced phagocytosis capacity of VASP-deficient macrophages

Laban

Froemel

Fleming

et al. 2023

Preprint

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“…Peroxisome proliferator-activated receptor (PPAR)-γ and nuclear factor erythroid 2-related factor 2 (Nrf2) are the most studied phagocytosis-related transcription factors. 42 , 49 , 50 Kyoto Encyclopedia of Genes and Genomes (KEGG) and violin plot analyses showed that both PPAR and Nrf2 signaling pathway-related genes were enriched in the 4-OI-treated cells (n = 3, Supplemental Fig. S3 a–c).…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, the direct transcription of Cd36 by Nrf2 is consistent with previous findings generated by our own lab and others. 42 , 82 , 90 We next mutated two potential itaconation sites on Keap1 (cysteine 151 and 288) to explore the molecular mechanism of Irg1/itaconate axis-enhanced phagocytosis. Itaconate covalent modifies the cysteine 151 (C151) on Keap1 to promote the anti-inflammation and anti-oxidative effects of Nrf2, 13 , 53 , 54 , 55 and cysteine 288 (C288) on Keap1 was identified as a potential itaconation site in a high throughput screening study and hasn't been well studied.…”

Section: Discussionmentioning

confidence: 99%

“…For in vitro experiments, briefly, 42 pH-sensitive latex beads, pH-sensitive Escherichia coli ( E. coli ; P35361, Invitrogen), PKH26-labeled RBCs, or propidium iodide (PI)-labeled dying cancer cells were incubated with cells for 20 min, respectively. Phagocytes were washed and fixed with 4% paraformaldehyde (PFA; P1110, Solarbio), washed, and immunostained.…”

Section: Methodsmentioning

confidence: 99%

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Targeted macrophage phagocytosis by Irg1/itaconate axis improves the prognosis of intracerebral hemorrhagic stroke and peritonitis

Luo,

Sheng,

et al. 2024

eBioMedicine

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“…Given that AMPK activation enhances the phagocytic capacity of macrophages and neutrophils [ 176 , 177 , 178 ], the phagocytic capacity of VASP-deficient macrophages was assessed. VASP −/− macrophages displayed significantly reduced phagocytic capacity compared to wild-type controls.…”

Section: Role Of Vasp In Leukocyte Infiltration Polarization and Vasc...mentioning

confidence: 99%

Cardiovascular Functions of Ena/VASP Proteins: Past, Present and Beyond

Benz

Frömel

Laban

et al. 2023

Cells

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Actin binding proteins are of crucial importance for the spatiotemporal regulation of actin cytoskeletal dynamics, thereby mediating a tremendous range of cellular processes. Since their initial discovery more than 30 years ago, the enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) family has evolved as one of the most fascinating and versatile family of actin regulating proteins. The proteins directly enhance actin filament assembly, but they also organize higher order actin networks and link kinase signaling pathways to actin filament assembly. Thereby, Ena/VASP proteins regulate dynamic cellular processes ranging from membrane protrusions and trafficking, and cell-cell and cell-matrix adhesions, to the generation of mechanical tension and contractile force. Important insights have been gained into the physiological functions of Ena/VASP proteins in platelets, leukocytes, endothelial cells, smooth muscle cells and cardiomyocytes. In this review, we summarize the unique and redundant functions of Ena/VASP proteins in cardiovascular cells and discuss the underlying molecular mechanisms.

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Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke

Cited by 5 publications

References 76 publications

Impaired AMPK activity contributes to the inflammatory phenotype and the reduced phagocytosis capacity of VASP-deficient macrophages

Impaired AMPK activity contributes to the inflammatory phenotype and the reduced phagocytosis capacity of VASP-deficient macrophages

Targeted macrophage phagocytosis by Irg1/itaconate axis improves the prognosis of intracerebral hemorrhagic stroke and peritonitis

Cardiovascular Functions of Ena/VASP Proteins: Past, Present and Beyond

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