An anti-inflammatory transcriptional cascade conserved from flies to humans

Pavlidaki, Alexia; Panic, Radmila; Monticelli, Sara; Riet, Céline; Yuasa, Y.; Cattenoz, Pierre B.; Nait‐Oumesmar, Brahim; Giangrande, Angela

doi:10.1016/j.celrep.2022.111506

Cited by 6 publications

(7 citation statements)

References 70 publications

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“…The molecular mechanisms of innate immunity between flies and mammals are highly evolutionarily conserved. For example, Drosophila Toll and IMD pathways are nuclear factor kappa B (NF-κB)-based signaling pathways that share similarities with the Toll-like receptor and tumor necrosis factor receptor 1 signaling pathways in mammals ( Pavlidaki et al, 2022 ; Kounatidis and Chtarbanova, 2018 ; Cao et al, 2013 ; Kounatidis et al, 2017 ). It has been previously shown that in glial cells, activation of the IMD pathway results in phosphorylation of the NF-κB transcription factor Relish, which is translocated to the nucleus to induce expression of the AMPs Attacin A, Cecropin A, and Diptericin ( Winkler et al, 2021 ; Kounatidis and Chtarbanova, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

“…This involves the recruitment of immune cells and the activation of immune-related genes. For instance, the signaling cascade of the glial cells missing transcription factor, which governs immune cell development and is triggered by aging and acute challenges, is conserved from flies to humans ( Pavlidaki et al, 2022 ). Additionally, the immune response includes antimicrobial peptides (AMPs) secreted by fat body cells, activated by Toll and immune deficiency (IMD) pathways.…”

Section: Introductionmentioning

confidence: 99%

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Unraveling the link between neuropathy target esterase NTE/SWS, lysosomal storage diseases, inflammation, abnormal fatty acid metabolism, and leaky brain barrier

Tsap,

Yatsenko,

Hegermann

et al. 2024

eLife

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Mutations in Drosophila Swiss Cheese (SWS) gene or its vertebrate orthologue Neuropathy Target Esterase (NTE) lead to progressive neuronal degeneration in flies and humans. Despite its enzymatic function as a phospholipase is well-established, the molecular mechanism responsible for maintaining nervous system integrity remains unclear. In this study, we found that NTE/SWS is present in surface glia that forms the blood-brain-barrier (BBB) and that NTE/SWS is important to maintain its structure and permeability. Importantly, BBB glia-specific expression of Drosophila NTE/SWS or human NTE in the sws mutant background fully rescues surface glial organization and partially restores BBB integrity, suggesting a conserved function of NTE/SWS. Interestingly, sws mutant glia showed abnormal organization of plasma membrane domains and tight junction rafts accompanied by the accumulation of lipid droplets, lysosomes, and multilamellar bodies. Since the observed cellular phenotypes closely resemble the characteristics described in a group of metabolic disorders known as lysosomal storage diseases (LSDs), our data established a novel connection between NTE/SWS and these conditions. We found that mutants with defective BBB exhibit elevated levels of fatty acids, which are precursors of eicosanoids and are involved in the inflammatory response. Also, as a consequence of a permeable BBB, several innate immunity factors are upregulated in an age-dependent manner, while BBB glia-specific expression of NTE/SWS normalizes inflammatory response. Treatment with anti-inflammatory agents prevents the abnormal architecture of the BBB, suggesting that inflammation contributes to the maintenance of a healthy brain barrier. Considering the link between a malfunctioning BBB and various neurodegenerative diseases, gaining a deeper understanding of the molecular mechanisms causing inflammation due to a defective BBB could help to promote the use of anti-inflammatory therapies for age-related neurodegeneration.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unraveling the link between neuropathy target esterase NTE/SWS, lysosomal storage diseases, inflammation, abnormal fatty acid metabolism, and leaky brain barrier

Tsap,

Yatsenko,

Hegermann

et al. 2024

eLife

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“…Importantly, the impact of Gcm on the inflammatory response of immune cells is conserved in mammals. In mouse, knock out for Gcm2 in microglia, the macrophage of the nervous system, leads to the production of microglia in a pro-inflammatory state (13).…”

Section: Discussionmentioning

confidence: 99%

“…The transcription factor Glial cell deficient/Glial cell missing (Glide/Gcm, Gcm throughout the manuscript) is specifically expressed in the hemocytes of the 1 st wave and has an anti-inflammatory role that is conserved in evolution (12, 13). Gcm inhibits the pathway by activating Jak/Stat inhibitors (12), raising the question of whether this transcription factor has a general role in the inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Gcm alleviates the inflammatory phenotype induced by Toll activation inDrosophilahemocytes

Bazzi,

Monticelli,

Delaporte

et al. 2023

Preprint

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Hemocytes, the myeloid-like immune cells of Drosophila, fulfil a variety of functions that are not completely understood, ranging from phagocytosis to transduction of inflammatory signals. We here show that downregulating the hemocyte-specific Glide/Gcm transcription factor enhances the inflammatory response to the constitutive activation of the Toll pathway. This correlates with lower levels of glutathione S transferase, suggesting an implication of Glide/Gcm in ROS signaling and calling for a widespread anti-inflammatory potential of Glide/Gcm. We show the expression of neurotransmitter receptors in hemocytes and that Toll activation affects their expressions, disclosing a novel aspect of the inflammatory response mediated by neurotransmitters. Finally, we provide evidence for acetylcholine receptor nAchRalpha6 regulating hemocyte proliferation. Altogether, this study provides new insights on the molecular pathways involved in the inflammatory response.

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“…The transcription factor Glial cell deficient/Glial cell missing (Glide/Gcm, Gcm throughout the article) is specifically expressed in the hemocytes of the first wave and has an anti-inflammatory role that is conserved in evolution ( 13 , 14 ). Gcm inhibits the pathway by activating Jak/Stat inhibitors ( 13 ), raising the question of whether this transcription factor has a general role in the inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Gcm counteracts Toll-induced inflammation and impacts hemocyte number through cholinergic signaling

Bazzi,

Monticelli,

Delaporte

et al. 2023

Front. Immunol.

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Hemocytes, the myeloid-like immune cells of Drosophila, fulfill a variety of functions that are not completely understood, ranging from phagocytosis to transduction of inflammatory signals. We here show that downregulating the hemocyte-specific Glial cell deficient/Glial cell missing (Glide/Gcm) transcription factor enhances the inflammatory response to the constitutive activation of the Toll pathway. This correlates with lower levels of glutathione S-transferase, suggesting an implication of Glide/Gcm in reactive oxygen species (ROS) signaling and calling for a widespread anti-inflammatory potential of Glide/Gcm. In addition, our data reveal the expression of acetylcholine receptors in hemocytes and that Toll activation affects their expressions, disclosing a novel aspect of the inflammatory response mediated by neurotransmitters. Finally, we provide evidence for acetylcholine receptor nicotinic acetylcholine receptor alpha 6 (nAchRalpha6) regulating hemocyte proliferation in a cell autonomous fashion and for non-cell autonomous cholinergic signaling regulating the number of hemocytes. Altogether, this study provides new insights on the molecular pathways involved in the inflammatory response.

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An anti-inflammatory transcriptional cascade conserved from flies to humans

Cited by 6 publications

References 70 publications

Unraveling the link between neuropathy target esterase NTE/SWS, lysosomal storage diseases, inflammation, abnormal fatty acid metabolism, and leaky brain barrier

Unraveling the link between neuropathy target esterase NTE/SWS, lysosomal storage diseases, inflammation, abnormal fatty acid metabolism, and leaky brain barrier

Gcm alleviates the inflammatory phenotype induced by Toll activation inDrosophilahemocytes

Gcm counteracts Toll-induced inflammation and impacts hemocyte number through cholinergic signaling

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