Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis

Conroy, Lindsey R.; Clarke, Harrison A.; Allison, Derek B.; Sun, Qi; Hawkinson, Tara R.; Young, Lyndsay E.A.; Ferreira, Juanita E.; Hammonds, Autumn; Dunne, Jaclyn; McDonald, Robert J.; Absher, Kimberly J.; Dong, Bo; Bruntz, Ronald C.; Markussen, Kia H.; Juras, Jelena A.; Alilain, Warren J.; Liu, Jinze; Gentry, Matthew S.; Angel, Peggi; Waters, Christopher M.; Sun, Ramon C.

doi:10.1038/s41467-023-38437-1

Cited by 26 publications

(14 citation statements)

References 105 publications

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“…1H). Consistent with previous reports[16, 31, 32], gene set variation analysis (GSVA) demonstrated that the upregulation of N -Glycan biosynthesis, glycosaminoglycan biosynthesis, arginine and proline metabolism are associated with pulmonary fibrosis (Fig. 1D).…”

Section: Resultssupporting

confidence: 91%

“…3A). To further investigate the role of TREM2 in IPF patients, a single-cell RNA Seq dataset of lung samples from three healthy controls and three IPF patients (GSE128033) [31] in GEO public platform was analyzed. After quality control and filtering, we obtained 19,012 cells (3,626 cells from control lungs and 15,386 cells from IPF lungs) for further analysis.…”

Section: Resultsmentioning

confidence: 99%

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Blockade of TREM2 ameliorates pulmonary inflammation and fibrosis by modulating sphingolipid metabolism

Gu,

Kang,

Cao

et al. 2024

Preprint

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Pulmonary fibrosis is a chronic interstitial lung disease involving systemic inflammation and abnormal collagen deposition. Dysregulations in lipid metabolism, such as macrophage-dependent lipid catabolism, have been recognized as critical factors for the development of pulmonary fibrosis. However, little is known about the signaling pathways involved and the key regulators. Here we found that triggering receptor expressed on myeloid cells 2 (TREM2) plays a pivotal role in regulating the lipid handling capacities of pulmonary macrophages and triggering fibrosis. By integrating analysis of single-cell and bulk RNA sequencing data from patients and mice with pulmonary fibrosis, we revealed that pulmonary macrophages consist of heterogeneous populations with distinct pro-fibrotic properties, and found that both sphingolipid metabolism and the expression of chemotaxis-related genes are elevated in fibrotic lungs. TREM2, a sensor recognizing multiple lipid species, is specifically upregulated in a subset of monocyte- derived macrophages. Blockade of TREM2 by gene knock-out or soluble TREM2 administration can both attenuate bleomycin-induced pulmonary fibrosis. By utilizing scRNA Seq and lipidomics, we found thatTrem2deficiency downregulates the synthesis of various sphingomyelins, and inhibits the expression of chemokines such asCcl2. Together, our findings not only reveal the alterations in lipidomic profiles and the atlas of pulmonary macrophages during pulmonary fibrosis, but also suggest that targeting TREM2, the crucial regulator affecting both pulmonary sphingolipid metabolism and the chemokines secretion, can benefit pulmonary fibrosis patients in the future.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Blockade of TREM2 ameliorates pulmonary inflammation and fibrosis by modulating sphingolipid metabolism

Gu,

Kang,

Cao

et al. 2024

Preprint

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“…Conversely, 6-and 12-month-old mice showed increased hypoactivity, decreased motility time and mean velocity; however, the difference in 12-month-old YAC128 was higher (Figure 1). MALDI-MSI technology makes it possible to preserve the cellular, molecular and spatial integrity of tissues, along with region-specific alterations that may be lost during the homogenisation process (Baijnath et al, 2022;Conroy et al, 2023;Franck et al, 2009). Using the MALDI-MSI system, which enables to detect the expression changes of proteins without losing their spatial location, we determined that the intensity levels of 89, 83 and 82 proteins were significantly different in YAC128 versus their control mice at the pre-stage, mild stage and pathological stage, respectively.…”

Section: Discussionmentioning

confidence: 99%

Detection of proteomic alterations at different stages in a Huntington's disease mouse model via matrix‐assisted laser desorption/ionization mass spectrometry (MALDI‐MS) imaging

Karayel-Basar

Uras

Kiris

et al. 2023

Eur J of Neuroscience

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Huntington's disease (HD) is a progressive and irreversible neurodegenerative disease leading to the inability to carry out daily activities and for which no cure exists. The underlying mechanisms of the disease have not been fully elucidated yet. Matrix‐assisted laser desorption/ionization mass spectrometry imaging (MALDI‐MSI) allows the spatial information of proteins to be obtained upon the tissue sections without homogenisation. In this study, we aimed to examine proteomic alterations in the brain tissue of an HD mouse model with MALDI‐MSI coupled to LC–MS/MS system. We used 3‐, 6‐ and 12‐month‐old YAC128 mice representing pre‐stage, mild stage and pathological stage of the HD and their non‐transgenic littermates, respectively. The intensity levels of 89 proteins were found to be significantly different in YAC128 in comparison to their control mice in the pre‐stage, 83 proteins in the mild stage, and 82 proteins in the pathological stage. Among them, Tau, EF2, HSP70, and NogoA proteins were validated with western blot analysis. In conclusion, the results of this study have provided remarkable new information about the spatial proteomic alterations in the HD mouse model, and we suggest that MALDI‐MSI is an excellent technique for identifying such regional proteomic changes and could offer new perspectives in examining complex diseases.

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“…MALDI-MSI combines the accuracy and sensitivity of mass spectrometry with added spatial information and glycogen architecture (Conroy et al, 2023;Young et al, 2022).…”

Section: B R Ain G Lycog En -De Tec Ti On and Loc Aliz Ationmentioning

confidence: 99%

The multifaceted roles of the brain glycogen

Markussen

Corti

Byrne

et al. 2023

Journal of Neurochemistry

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Glycogen is a biologically essential macromolecule that is directly involved in multiple human diseases. While its primary role in carbohydrate storage and energy metabolism in the liver and muscle is well characterized, recent research has highlighted critical metabolic and non‐metabolic roles for glycogen in the brain. In this review, the emerging roles of glycogen homeostasis in the healthy and diseased brain are discussed with a focus on advancing our understanding of the role of glycogen in the brain. Innovative technologies that have led to novel insights into glycogen functions are detailed. Key insights into how cellular localization impacts neuronal and glial function are discussed. Perturbed glycogen functions are observed in multiple disorders of the brain, including where it serves as a disease driver in the emerging category of neurological glycogen storage diseases (n‐GSDs). n‐GSDs include Lafora disease (LD), adult polyglucosan body disease (APBD), Cori disease, Glucose transporter type 1 deficiency syndrome (G1D), GSD0b, and late‐onset Pompe disease (PD). They are neurogenetic disorders characterized by aberrant glycogen which results in devastating neurological and systemic symptoms. In the most severe cases, rapid neurodegeneration coupled with dementia results in death soon after diagnosis. Finally, we discuss current treatment strategies that are currently being developed and have the potential to be of great benefit to patients with n‐GSD. Taken together, novel technologies and biological insights have resulted in a renaissance in brain glycogen that dramatically advanced our understanding of both biology and disease. Future studies are needed to expand our understanding and the multifaceted roles of glycogen and effectively apply these insights to human disease.image

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Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis

Cited by 26 publications

References 105 publications

Blockade of TREM2 ameliorates pulmonary inflammation and fibrosis by modulating sphingolipid metabolism

Blockade of TREM2 ameliorates pulmonary inflammation and fibrosis by modulating sphingolipid metabolism

Detection of proteomic alterations at different stages in a Huntington's disease mouse model via matrix‐assisted laser desorption/ionization mass spectrometry (MALDI‐MS) imaging

The multifaceted roles of the brain glycogen

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